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Sample records for potential pet ligand

  1. Bis(methylpyridine)-EDTA derivative as a potential ligand for PET imaging: synthesis, complexation, and biological evaluation.

    PubMed

    Singh, Pooja; Aggarwal, Swati; Tiwari, Anjani K; Kumar, Vikas; Pratap, Ramendra; Chuttani, Krishna; Mishra, Anil K

    2014-12-01

    A novel transitional metal ligand derivatized from EDTA-conjugated 2-amino-4-methyl pyridine, an acyclic vehicle (EDTA-Mepy2 ) was designed, synthesized, and characterized for PET imaging with ⁶⁸Ga. The drug likeliness and appropriate lipophilicity were first analyzed by molecular docking studies which shows interactive property of ligand with serum albumin protein (HSA: PDB 1E78), at Lys199, Arg257, and His242 residues, which make it more appropriate in transportation as a specific ligand for PET imaging. As a confirmation, binding constant of the ligand with human serum albumin was calculated at λex = 350 nm which was found to be 4.9 × 10³ m⁻¹. The pharmacokinetics of (68) Ga-EDTA-Mepy2 was analyzed by blood kinetics (t(1/2) slow: 3 h 56 min and t(1/2) fast: 32 min) and biodistribution (maximum % ID/g was found in kidney at 1 h). Further the capability of this ligand was analyzed as optical marker also, by recording λex = 380 nm, RFU = 8000; 710 nm, RFU = 1000 units at fixed λem = 280 nm. Additionally, in physiological conditions where its stability was calculated, suggests 15-20 times selectivity over the endogenously present metal ions (KG aL /KZ nL = 14.3, KG aL /KC uL = 18.1).

  2. PSMA Ligands for PET Imaging of Prostate Cancer.

    PubMed

    Schwarzenboeck, Sarah M; Rauscher, Isabel; Bluemel, Christina; Fendler, Wolfgang P; Rowe, Steven P; Pomper, Martin G; Asfhar-Oromieh, Ali; Herrmann, Ken; Eiber, Matthias

    2017-10-01

    Targeting the prostate-specific membrane antigen (PSMA) with (68)Ga-labeled and (18)F-labeled PET agents has become increasingly important in recent years. Imaging of biochemically recurrent prostate cancer has been established as a widely accepted clinical indication for PSMA ligand PET/CT in many parts of the world because of the results of multiple, primarily retrospective, studies that indicate superior detection efficacy compared with standard-of-care imaging. For high-risk primary prostate cancer, evidence is growing that this modality significantly aids in the detection of otherwise occult nodal and bone metastases. For both clinical indications in recurrent as well as in primary prostate cancer, preliminary data demonstrate a substantial impact on clinical management. Emerging data imply that intraprostatic tumor localization, therapy stratification, and treatment monitoring of advanced disease in specific clinical situations might become future indications. Current criteria for image reporting of PSMA ligand PET are evolving given the expanding body of literature on physiologic and pathologic uptake patterns and pitfalls. This article intends to give an educational overview on the current status of PSMA ligand PET imaging, including imaging procedure and interpretation, clinical indications, diagnostic potential, and impact on treatment planning. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  3. Radiosynthesis and preclinical evaluation of [11C]prucalopride as a potential agonist PET ligand for the 5-HT4 receptor

    PubMed Central

    2013-01-01

    Background Serotonin 5-HT4 receptor (5-HT4-R) agonists are potential therapeutic agents for enterokinetic and cognitive disorders and are marketed for treatment of constipation. The aim of this study was to develop an agonist positron emission tomography (PET) ligand in order to label the active G-protein coupled 5-HT4-R in peripheral and central tissues. For this purpose prucalopride, a high-affinity selective 5-HT4-R agonist, was selected. Methods [11C]Prucalopride was synthesized from [11C]methyl triflate and desmethyl prucalopride, and its LogDoct,pH7.4 was determined. Three distinct studies were performed with administration of IV [11C]prucalopride in male rats: (1) The biodistribution of radioactivity was measured ex vivo; (2) the kinetics of radioactivity levels in brain regions and peripheral organs was assessed in vivo under baseline conditions and following pre-treatment with tariquidar, a P-glycoprotein efflux pump inhibitor; and (3) in vivo stability of [11C]prucalopride was checked ex vivo in plasma and brain extracts using high-performance liquid chromatography. Results [11C]Prucalopride was synthesized in optimised conditions with a yield of 21% ± 4% (decay corrected) and a radiochemical purity (>99%), its LogDoct,pH7.4 was 0.87. Ex vivo biodistribution studies with [11C]prucalopride in rats showed very low levels of radioactivity in brain (maximal 0.13% ID·g−1) and ten times higher levels in certain peripheral tissues. The PET studies confirmed very low brain levels of radioactivity under baseline conditions; however, it was increased three times after pre-treatment with tariquidar. [11C]Prucalopride was found to be very rapidly metabolised in rats, with no parent compound detectable in plasma and brain extracts at 5 and 30 min following IV administration. Analysis of levels of radioactivity in peripheral tissues revealed a distinct PET signal in the caecum, which was reduced following tariquidar pre-treatment. The latter is in line with the

  4. Development of indazolylpyrimidine derivatives as high-affine EphB4 receptor ligands and potential PET radiotracers.

    PubMed

    Ebert, Kristin; Wiemer, Jens; Caballero, Julio; Köckerling, Martin; Steinbach, Jörg; Pietzsch, Jens; Mamat, Constantin

    2015-09-01

    Due to their essential role in the pathogenesis of cancer, members of the Eph (erythropoietin-producing hepatoma cell line-A2) receptor tyrosine kinase family represent promising candidates for molecular imaging. Thus, the development and preparation of novel radiotracers for the noninvasive imaging of the EphB4 receptor via positron emission tomography (PET) is described. First in silico investigations with the indazolylpyrimidine lead compound which is known to be highly affine to EphB4 were executed to identify favorable labeling positions for an introduction of fluorine-18 to retain the affinity. Based on this, reference compounds as well as precursors were developed and labeled with carbon-11 and fluorine-18, respectively. For this purpose, a protecting group strategy essentially had to be generated to prevent unwanted methylation and to enable the introduction of fluorine-18. Further, a convenient radiolabeling strategy using [(11)C]methyl iodide was established which afforded the isotopically labeled radiotracer in 30-35% RCY (d.c.) which is identical with the original inhibitor molecule. A spiro ammonium precursor was prepared for radiolabeling with fluorine-18. Unfortunately, the labeling did not lead to the desired (18)F-radiotracer under the chosen conditions.

  5. Synthesis, in vitro and in vivo evaluation of [11C]MMTP: A potential PET ligand for mGluR1 receptors

    PubMed Central

    Prabhakaran, Jaya; Majo, Vattoly J.; Milak, Matthew S.; Kassir, Suham A.; Palner, Mikael; Savenkova, Lyudmila; Pratap, Mali; Arango, Victoria; Mann, J. John; Parsey, Ramin V.; Dileep Kumar, J. S.

    2010-01-01

    Synthesis, in vitro and in vivo evaluation of [O-methyl-11C]dimethylamino-3(4-methoxyphenyl)-3H-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-one (1), a potential imaging agent for mGluR1 receptors using PET are described. Synthesis of the corresponding desmethyl precursor 2 was achieved by demethylation of the methoxyphenyl compound 1 in 90% yield. Methylation using [11C]MeOTf in presence of NaOH afforded [11C]1 in 30% yield (EOS) with >99 % chemical and radiochemical purities and with a specific activity of 3–5 Ci/μmol (n = 6). The total synthesis time was 30 minutes from EOB. The radiotracer selectively labeled mGluR1 receptors in slide-mounted sections of postmortem human brain containing cerebellum, hippocampus, prefrontal cortex and striatum as demonstrated by in vitro autoradiography using phosphor imaging. PET studies in anesthetized baboon show that [11C]1 penetrates the BBB and accumulates in cerebellum, a region reported to have higher expression of mGluR1. These findings suggest [11C]1 is a promising PET radiotracer candidate for mGluR1. PMID:20494576

  6. In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET.

    PubMed

    Vicidomini, Caterina; Panico, Mariarosaria; Greco, Adelaide; Gargiulo, Sara; Coda, Anna Rita Daniela; Zannetti, Antonella; Gramanzini, Matteo; Roviello, Giovanni N; Quarantelli, Mario; Alfano, Bruno; Tavitian, Bertrand; Dollé, Frederic; Salvatore, Marco; Brunetti, Arturo; Pappatà, Sabina

    2015-03-01

    The translocator protein 18 kDa (TSPO), a biochemical marker of neuroinflammation, is highly expressed in the brain activated microglia and it is also expressed by peripheral inflammatory cells and normal peripheral tissues. Thus, development of radioligands for the TSPO may contribute to further understanding the in vivo TSPO function in central and peripheral inflammatory processes and other pathologies. Here, we report the biodistribution, the specific binding and the radiometabolites of [(18)F]DPA-714, a promising fluorinated PET radiotracer, in normal mice using a microPET/CT scanner. The in vivo biodistribution and kinetics of [(18)F]DPA-714 were measured in mice brain and peripheral tissues. Specific binding to TSPO sites was assessed using pharmacological competitive studies by means of saturation experiments performed by i.v. injection of 1mg/kg of unlabeled DPA-714 or 3mg/kg of unlabeled PK11195. A region of interest analysis was performed to generate time-activity curves in the brain, heart, lung, kidney, spleen and liver. Metabolites assay was performed in the plasma and peripheral organs by radio-HPLC. [(18)F]DPA-714 reached high concentration in lung, heart, kidney and spleen, tissues well known to be rich in TSPO sites. [(18)F]DPA-714 kinetics were faster in the lung and slower in the kidney. Pre-injection of unlabeled DPA-714 or PK11195 inhibited about 80% of [(18)F]DPA-714 uptake in the lung and heart (p<0.0005). The percentage of inhibition in the kidney was lower and achieved at later times only with DPA-714 (p<0.05) but not with PK11195. Sixty minutes after radiotracer injection only unmetabolized radioligand was found in the brain, lung, heart and spleen. These results suggest that [(18)F]DPA-714 is a suitable PET ligand for imaging in mice brain and peripheral tissues since it binds with high specificity TSPO binding sites and it is almost unchanged at 60 minutes after radiotracer injection in the brain and TSPO-rich regions. Copyright © 2014

  7. Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging.

    PubMed

    Syvänen, Stina; Eriksson, Jonas; Genchel, Tove; Lindhe, Orjan; Antoni, Gunnar; Långström, Bengt

    2007-07-30

    The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171. [1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/mumol and 270 GBq/mumol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171. All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171. The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the ethyl-analogue (I).

  8. Synthesis of two potential NK1-receptor ligands using [1-11C]ethyl iodide and [1-11C]propyl iodide and initial PET-imaging

    PubMed Central

    Syvänen, Stina; Eriksson, Jonas; Genchel, Tove; Lindhe, Örjan; Antoni, Gunnar; Långström, Bengt

    2007-01-01

    Background The previously validated NK1-receptor ligand [O-methyl-11C]GR205171 binds with a high affinity to the NK1-receptor and displays a slow dissociation from the receptor. Hence, it cannot be used in vivo for detecting concentration changes in substance P, the endogenous ligand for the NK1-receptor. A radioligand used for monitoring these changes has to enable displacement by the endogenous ligand and thus bind reversibly to the receptor. Small changes in the structure of a receptor ligand can lead to changes in binding characteristics and also in the ability to penetrate the blood-brain barrier. The aim of this study was to use carbon-11 labelled ethyl and propyl iodide with high specific radioactivity in the synthesis of two new and potentially reversible NK1-receptor ligands with chemical structures based on [O-methyl-11C]GR205171. Methods [1-11C]Ethyl and [1-11C]propyl iodide with specific radioactivities of 90 GBq/μmol and 270 GBq/μmol, respectively, were used in the synthesis of [O-methyl-11C]GR205171 analogues by alkylation of O-desmethyl GR205171. The brain uptake of the obtained (2S,3S)-N-(1-(2- [1-11C]ethoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)-2-phenylpiperidin-3-amine (I) and (2S,3S)-2-phenyl-N-(1-(2- [1-11C]propoxy-5-(3-(trifluoromethyl)-4H-1,2,4-triazol-4-yl)phenyl)ethyl)piperidin-3-amine (II) was studied with PET in guinea pigs and rhesus monkeys and compared to the uptake of [O-methyl-11C]GR205171. Results All ligands had similar uptake distribution in the guinea pig brain. The PET-studies in rhesus monkeys showed that (II) had no specific binding in striatum. Ligand (I) had moderate specific binding compared to the [O-methyl-11C]GR205171. The ethyl analogue (I) displayed reversible binding characteristics contrary to the slow dissociation rate shown by [O-methyl-11C]GR205171. Conclusion The propyl-analogue (II) cannot be used for detecting changes in NK1-ligand levels, while further studies should be performed with the

  9. Synthesis and evaluation of potent and selective human V1a receptor antagonists as potential ligands for PET or SPECT imaging

    PubMed Central

    Fabio, Karine; Guillon, Christophe; Lacey, Carl J.; Lu, Shi-fang; Heindel, Ned D.; Ferris, Craig F.; Placzek, Michael; Jones, Graham; Brownstein, Michael J.; Simon, Neal G.

    2012-01-01

    SRX246 is a potent, highly selective human vasopressin V1a antagonist that crosses the blood–brain barrier in rats. CNS penetration makes SRX246 an ideal candidate for potential radiolabeling and use in visualization and characterization of the role of the V1a receptor in multiple stress-related disorders. Before radiolabeling studies, cold reference analogs of SRX246 were prepared. This study describes the synthesis and in vitro screening for human V1a receptor binding and permeability of fluoro, iodo, and methyl reference compounds for SRX246 and the preparation of a tin precursor. For each compound, the potential utility of corresponding radiolabeled analogs for PET and SPECT imaging is discussed. PMID:22249122

  10. (68)Ga-PSMA ligand PET/CT in patients with prostate cancer: How we review and report.

    PubMed

    Rauscher, Isabel; Maurer, Tobias; Fendler, Wolfgang P; Sommer, Wieland H; Schwaiger, Markus; Eiber, Matthias

    2016-06-08

    Recently, positron emission tomography (PET) imaging using PSMA-ligands has gained high attention as a promising new radiotracer in patients with prostate cancer (PC). Several studies promise accurate staging of primary prostate cancer and restaging after biochemical recurrence with (68)Ga-PSMA ligand Positron emission tomography/computed tomography (PET/CT). However, prospective trials and clinical guidelines for this new technique are still missing. Therefore, we summarized our experience with (68)Ga-PSMA ligand PET/CT examinations in patients with primary PC and biochemical recurrence. It focuses on the technical and logistical aspects of (68)Ga-PSMA ligand PET/CT examination as well as on the specific background for image reading discussing also potential pitfalls. Further, it includes relevant issues on free-text as well as structured reporting used in daily clinical routine.

  11. Ligands for SPECT and PET imaging of muscarinic-cholinergic receptors of the heart and brain

    SciTech Connect

    Knapp, F.F. Jr.; McPherson, D.W.; Luo, H.

    1995-06-01

    Interest in the potential use of cerebral SPECT and PET imaging for determination of the density and activity of muscarinic-cholinergic receptors (mAChR) has been stimulated by the changes in these receptors which occur in many neurological diseases. In addition, the important involvement of mAChR in modulating negative inotropic cardiac activity suggests that such receptor ligands may have important applications in evaluation of changes which may occur in cardiac disease. In this paper, the properties of several key muscarinic receptor ligands being developed or which have been used for clinical SPECT and PET are discussed. In addition, the ORNL development of the new iodinated IQNP ligand based on QNB and the results of in vivo biodistribution studies in rats, in vitro competitive binding studies and ex vivo autoradiographic experiments are described. The use of radioiodinated IQNP may offer several advantages in comparison to IQNB because of its easy and high yield preparation and high brain uptake and the potential usefulness of the {open_quotes}partial{close_quotes} subtype selective IONP isomers. We also describe the development of new IQNP-type analogues which offer the opportunity for radiolabeling with positron-emitting radioisotopes (carbon-11, fluorine-18 and bromine-76) for potential use with PET.

  12. Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study

    PubMed Central

    Buck, Jason R.; McKinley, Eliot T.; Fu, Allie; Abel, Ty W.; Thompson, Reid C.; Chambless, Lola; Watchmaker, Jennifer M.; Harty, James P.; Cooper, Michael K.; Manning, H. Charles

    2015-01-01

    Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes. PMID:26517124

  13. Subdomain 2 of the Autotransporter Pet Is the Ligand Site for Recognizing the Pet Receptor on the Epithelial Cell Surface

    PubMed Central

    Chavez-Dueñas, Lucia; Serapio-Palacios, Antonio; Nava-Acosta, Raul

    2016-01-01

    Most autotransporter passenger domains, regardless of their diversity in function, fold or are predicted to fold as right-handed β-helices carrying various loops that are presumed to confer functionality. Our goal here was to identify the subdomain (loop) or amino acid sequence of the Pet passenger domain involved in the receptor binding site on the host cell for Pet endocytosis. Here, we show that d1 and d2 subdomains, as well as the amino acid sequence linking the subdomain d2 and the adjacent β-helix (PDWET), are not required for Pet secretion through the autotransporter system and that none of our deletion mutants altered the predicted long right-handed β-helical structure. Interestingly, Pet lacking the d2 domain (PetΔd2) was unable to bind on the epithelial cell surface, in contrast to Pet lacking d1 (PetΔd1) subdomain or PDWET sequences. Moreover, the purified d1 subdomain, the biggest subdomain (29.8 kDa) containing the serine protease domain, was also unable to bind the cell surface. Thus, d2 sequence (54 residues without the PDWET sequence) was required for Pet binding to eukaryotic cells. In addition, this d2 sequence was also needed for Pet internalization but not for inducing cell damage. In contrast, PetΔd1, which was able to bind and internalize inside the cell, was unable to cause cell damage. Furthermore, unlike Pet, PetΔd2 was unable to bind cytokeratin 8, a Pet receptor. These data indicate that the surface d2 subdomain is essential for the ligand-receptor (Pet-Ck8) interaction for Pet uptake and to start the epithelial cell damage by this toxin. PMID:27113356

  14. Early Detection of Bilateral Testicular Metastases From Prostatic Adenocarcinoma Using 68Ga-PSMA Ligand PET/CT.

    PubMed

    Weiberg, Desiree; Radner, Herbert; Derlin, Thorsten; Thon, Walter F

    2017-03-31

    We present the case of a 76-year-old man with biochemical relapse after primary therapy for prostate cancer. Ga prostate-specific membrane antigen (PSMA) ligand PET/CT performed for localization of recurrent disease revealed bilateral metastases to the testes. Histopathologic evaluation after bilateral orchiectomy revealed testicular metastases. Metastases to the testes are rare and usually seen in advanced stages. Ga-PSMA ligand PET/CT is a highly sensitive and specific imaging method for the detection of primary and metastatic prostate cancer and has refined diagnostic approaches. This case highlights the potential of PSMA-targeted PET/CT for detection of prostate cancer metastases, even in very unusual localizations.

  15. Radiosynthesis and in vivo evaluation of a novel σ1 selective PET ligand

    PubMed Central

    Jin, Hongjun; Fan, Jinda; Zhang, Xiang; Li, Junfeng; Flores, Hubert P.; Perlmutter, Joel S.; Parsons, Stanley M.; Tu, Zhude

    2014-01-01

    The σ1 receptor is an important target for CNS disorders. We previously identified a σ1 ligand TZ3108 having highly potent (Ki-σ1 = 0.48 nM) and selective affinity for σ1 versus σ2 receptors. TZ3108 was 18F-labeled with F-18 for in vivo evaluation. Biodistribution and blocking studies of [18F]TZ3108 in male Sprague-Dawley rats demonstrated high brain uptake, which was σ1-specific with no in vivo defluorination. MicroPET studies in cynomolgus macaques showed high brain penetration of [18F]TZ3108; the regional brain distribution was consistent with that of the σ1 receptor. Pseudo-equilibrium in the brain was reached ~ 45 min post-injection. Metabolite analysis of [18F]TZ3108 in NHP blood and rodent blood and brain revealed that ~ 70% parent remained in the plasma of NHPs 60 min post-injection and the major radiometabolite did not cross the blood-brain barrier in rats. In summary, the potent, selective and metabolically stable σ1 specific radioligand [18F]TZ3108 represents a potentially useful PET radioligand for quantifying the σ1 receptor in the brain. PMID:25584182

  16. 68Ga-PSMA-Ligand PET/CT Uptake in Anthracosilicosis.

    PubMed

    McGuiness, Madeleine; Sounness, Brett

    2017-10-01

    This interesting image illustrates a case of biopsy-proven pulmonary anthracosilicosis, a mixed dust pneumoconiosis, associated with Ga-PSMA-ligand uptake. Prostate-specific membrane antigen (PSMA) is an emerging imaging biomarker, with clinical application in evaluation of prostate cancer using Ga-PSMA-ligand PET/CT. Contrary to its name, PSMA is expressed in a number of other normal tissues and pathological states. Prostate-specific membrane antigen expression has been linked to tumor angiogenesis in various other epithelial neoplasms, as well as neovasculature associated with tissue regeneration and repair. Awareness of nonneoplastic inflammatory conditions associated with Ga-PSMA-ligand uptake aids in patient assessment and management.

  17. Potential improvements in instrumentation for PET

    SciTech Connect

    Derenzo, S.E.

    1984-09-01

    This paper discusses the potential for improved detectors in Positron Emission Tomography (PET) and explores the ultimate limits that might be achieved in the areas of spatial resolution, sensitivity, and maximum imaging rates. It is shown that if an ultra-fast, high efficiency scintillator and a thin, low-noise, position-sensitive photodetector were available, a multi-layer time-of-flight tomograph would be possible with a 10 cm axial field of view, a 3-dimensional spatial resolution of 2 mm fwhm, and >700,000 prompt unscattered coincidences per sec for 1 ..mu..Ci per cm/sup 3/ in a 20 cm diam cylinder of water. 39 refs., 3 figs., 3 tabs.

  18. Docking study, synthesis, and in vitro evaluation of fluoro-MADAM derivatives as SERT ligands for PET imaging.

    PubMed

    Mavel, Sylvie; Vercouillie, Johnny; Garreau, Lucette; Raguza, Tiziana; Ravna, Aina Westrheim; Chalon, Sylvie; Guilloteau, Denis; Emond, Patrick

    2008-10-01

    In order to predict affinity of new diphenylsulfides for the serotonin transporter (SERT), a molecular modeling model was used to compare potential binding affinity of new compounds with known potent ligands. The aim of this study is to identify a suitable PET radioligand for imaging the SERT, new derivatives, and their precursors for a C-11 or F-18 radiolabeling, were synthesized. Two fluorinated derivatives displayed good in vitro affinity for the SERT (K(i)=14.3+/-1 and 10.1+/-2.7 nM) and good selectivity toward the other monoamine transporters as predicted by the docking study.

  19. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer.

    PubMed

    Afshar-Oromieh, Ali; Avtzi, Eleni; Giesel, Frederik L; Holland-Letz, Tim; Linhart, Heinz G; Eder, Matthias; Eisenhut, Michael; Boxler, Silvan; Hadaschik, Boris A; Kratochwil, Clemens; Weichert, Wilko; Kopka, Klaus; Debus, Jürgen; Haberkorn, Uwe

    2015-02-01

    Since the introduction of positron emission tomography (PET) imaging with (68)Ga-PSMA-HBED-CC (=(68)Ga-DKFZ-PSMA-11), this method has been regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). However, published data exist for small patient cohorts only. The aim of this evaluation was to analyse the diagnostic value of (68)Ga-PSMA-ligand PET/CT in a large cohort and the influence of several possibly interacting variables. We performed a retrospective analysis in 319 patients who underwent (68)Ga-PSMA-ligand PET/CT from 2011 to 2014. Potential influences of several factors such as prostate-specific antigen (PSA) level and doubling time (DT), Gleason score (GSC), androgen deprivation therapy (ADT), age and amount of injected tracer were evaluated. Histological verification was performed in 42 patients after the (68)Ga-PSMA-ligand PET/CT. Tracer uptake was measured in 901 representative tumour lesions. In 82.8% of the patients at least one lesion indicative of PCa was detected. Tumor-detection was positively associated with PSA level and ADT. GSC and PSA-DT were not associated with tumor-detection. The average maximum standardized uptake value (SUVmax) of tumour lesions was 13.3 ± 14.6 (0.7-122.5). Amongst lesions investigated by histology, 30 were false-negative in 4 different patients, and all other lesions (n = 416) were true-positive or true-negative. A lesion-based analysis of sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) revealed values of 76.6%, 100%, 91.4% and 100%. A patient-based analysis revealed a sensitivity of 88.1%. Of 116 patients available for follow-up, 50 received local therapy after (68)Ga-PSMA-ligand PET/CT. (68)Ga-PSMA-ligand PET/CT can detect recurrent PCa in a high number of patients. In addition, the radiotracer is highly specific for PCa. Tumour detection is positively associated with PSA and ADT. (68)Ga-PSMA-ligand PET/CT can help delay systemic

  20. [F-18]-(-,-)-FQNPe - an attractive ligand for evaluation of muscarinic-cholinergic neuron activity by PET

    SciTech Connect

    Luo, H.; McPherson, D.W.; Beets, A.L.; Knapp, F.F. Jr.

    1997-05-01

    The stereoisomers of 1-azabicyclo[2.2.2]oct-3-yl {alpha}-{alpha}-(1-fluoropentan-5-yl)-{alpha}-hydroxy-{alpha}-phenylacetate ({open_quotes}FQNPe{close_quotes}) have been resolved. (-,-)- receptors (K{sub i}, nM; ml, 0.3; m2, 0.1). [F-18]-(-,-)-FQNPe demonstrated high cerebral and myocardial uptake in rats in vivo. We now report significant blocking of [F-18]-(-.-)-FQNPe uptake in receptor-rich tissues in rats in vivo after (R)-QNB pretreatment and the absence of any TLC detectable FQNPe metabolites in tissue extracts. Rats were injected with (R)-QNB (3 mg/kg) 1 h prior to [F-18]-FQNPe injection (370-629 KBq). After 1 h, rats were sacrificed and tissues removed and counted. (R)-QNB significantly decreased FQNPe uptake in heart and all receptor-rich regions but not blood (Table; Mean % ID/g, n=5); C, control; Q, (R)-QNB; Hrt, heart; Cer, cerebellum; Pon, pons; Med, medulla; Cor, cortex; Stri, striatum; Hip, hippocampus; Th, thallamus; SuC, superior colliculi; InC, inferior colliculi. Tissues from untreated rats were Folch-extracted and 71-77% of activity was in organic extracts from brain and heart. TLC of organic extracts indicated a single radioactive component with R{sub f} of FQNPe. These combined results demonstrate that [F-18]-(-,-)-FQNPe does not appear to be metabolized in heart and brain, shows good receptor localization and is thus an attractive ligand for evaluation as a potential imaging agent by PET.

  1. A short-scan method for k(3) estimation with moderately reversible PET ligands: application of irreversible model to early-phase PET data.

    PubMed

    Sato, Koichi; Fukushi, Kiyoshi; Shinotoh, Hitoshi; Shimada, Hitoshi; Tanaka, Noriko; Hirano, Shigeki; Irie, Toshiaki

    2012-02-15

    Long dynamic scans (60-120 min) are often required for estimating the k(3) value, an index of receptor density, by positron emission tomography (PET). However, the precision of k(3) is usually low in kinetic analyses for reversible PET ligands compared with irreversible ligands. That is largely due to unstable estimation of the dissociation rate constant, k(4). We propose a novel '3P+' method for estimating k(3) of moderately reversible ligands, where a 3-parameter model without k(4) is applied to early-phase PET data to obtain a good model-fit of k(3) estimation. By using [(11)C] Pittsburgh compound B (PIB) (k(4) = 0.018/min) as an example of a moderately reversible ligand, the 3P+ method simulation with a 28 min PET scan yielded less than 3% k(3) relative bias with a +100% k(3) change. In [(11)C]PIB PET scans of 15 normal controls (NC) and nine patients with Alzheimer's disease (AD), the 3P+ method provided a precise k(3) estimate (mean SE of 13.6% in parietal cortex; covariance matrix method). The results revealed linear correlations (r = 0.964) of parietal k(3) values in 24 subjects between 28minute 3P+ method and conventional 90 minute 4-parameter method. A good separation of k(3) between NC and AD groups (P < 0.001; t-test) was replicated in 28 minute 3P+ method. The short-scan 3P+ method may be a practical alternative method for analyzing reversible ligands.

  2. Synthesis of four stereoisomers of 1-azabiocyclo[2.2.2]OCT-3-YL-{alpha}-fluoroalkyl-{alpha}-hydroxy-{alpha}-phenylacetate (FQNPe): Potential imaging ligands for the muscarinic-cholinergic receptor (m-AChR) by PET

    SciTech Connect

    Luo, H.; McPherson, D.W.; Knapp, F.F. Jr.

    1996-10-01

    Earlier studies with the racemic 1-azabiocyclo[2.2.2]oct-3-yl {alpha}-fluoroalkyl-{alpha}-hydroxy-{alpha}-phenylacetate (FQNPe) mixture had demonstrated high in vitro binding affinity for the muscarinic-cholinergic receptor (m-AChR). Pre-treatment of rats with this new agent significantly blocked receptor localization of subsequently injected [I-131]-Z-(-,-)-IQNP, which is an established high affinity m-AChR ligand. Syntheses and characterization of the four FQNPe stereoisomers: (-)(-) FQNPe, (-)(+) FQNPe, (+)(-) FQNPe, and (+)(+) FQNPe will be presented. The interesting NMR spectra of the diastereomeric salts formed in the resolution of racemic {alpha}-(1-chloropent-5-yl)-{alpha}-hydroxy {alpha}-phenylacetic acid will also be discussed.

  3. Pharmacological characterization of the cannabinoid CB₁ receptor PET ligand ortholog, [³H]MePPEP.

    PubMed

    Suter, Todd M; Chesterfield, Amy K; Bao, Chun; Schaus, John M; Krushinski, Joseph H; Statnick, Michael A; Felder, Christian C

    2010-12-15

    MePPEP ((3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one) is an inverse agonist shown to be an effective PET ligand for labeling cannabinoid CB₁ receptors in vivo. [¹¹C]MePPEP and structurally related analogs have been reported to specifically and reversibly label cannabinoid CB₁ receptors in rat and non-human primate brains, and [¹¹C]MePPEP has been used in human subjects as a PET tracer. We have generated [³H]MePPEP, an ortholog of [¹¹C]MePPEP, to characterize the molecular pharmacology of the cannabinoid CB₁ receptor across preclinical and clinical species. [³H]MePPEP demonstrates saturable, reversible, and single-site high affinity binding to cannabinoid CB₁ receptors. In cerebellar membranes purified from brains of rat, non-human primate and human, and cells ectopically expressing recombinant human cannabinoid CB₁ receptor, [³H]MePPEP binds cannabinoid CB₁ receptors with similar affinity with K(d) values of 0.09 nM, 0.19 nM, 0.14 nM and 0.16 nM, respectively. Both agonist and antagonist cannabinoid ligands compete [³H]MePPEP with predicted rank order potency. No specific binding is present in autoradiographic sections from cannabinoid CB₁ receptor knockout mouse brains, demonstrating that [³H]MePPEP selectively binds cannabinoid CB₁ receptors in native mouse tissue. Furthermore, [³H]MePPEP binding to anatomical sites in mouse and rat brain is comparable to the anatomical profiles of [¹¹C]MePPEP in non-human primate and human brain in vivo, as well as the binding profiles of other previously described cannabinoid CB₁ receptor agonist and antagonist radioligands. Therefore, [³H]MePPEP is a promising tool for translation of preclinical cannabinoid CB₁ receptor pharmacology to clinical PET ligand and cannabinoid CB₁ receptor inverse agonist therapeutic development.

  4. Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with gallium-68.

    PubMed

    Waldron, Bradley P; Parker, David; Burchardt, Carsten; Yufit, Dmitry S; Zimny, Melanie; Roesch, Frank

    2013-01-21

    Pre-organised tricarboxylate ligands based on 6-amino-perhydro-1,4-diazepine bind (68)Ga rapidly and selectively in acetate buffer at pH 4 to 7, forming kinetically stable complexes suitable for use in PET imaging.

  5. Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans.

    PubMed

    Endres, Christopher J; Pomper, Martin G; James, Michelle; Uzuner, Ovsev; Hammoud, Dima A; Watkins, Crystal C; Reynolds, Aaron; Hilton, John; Dannals, Robert F; Kassiou, Michael

    2009-08-01

    Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, (11)C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide ((11)C-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of (11)C-DPA-713 in human subjects using PET. Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity (11)C-DPA-713. For comparison, 2 additional healthy controls were studied with (11)C-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time-activity curves were fitted using 1- and 2-tissue-compartment models, with goodness-of-fit tests showing a preference for the 2-tissue model. In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for (11)C-R-PK11195. Accordingly, dose-normalized time-activity curves showed that (11)C-DPA-713 gives a larger brain signal. Studies in patient populations will help determine whether (11)C-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that (11)C-DPA-713 is a promising ligand for evaluating TSPO binding with PET.

  6. Initial Evaluation of 11C-DPA-713, a Novel TSPO PET Ligand, in Humans

    PubMed Central

    Endres, Christopher J.; Pomper, Martin G.; James, Michelle; Uzuner, Ovsev; Hammoud, Dima A.; Watkins, Crystal C.; Reynolds, Aaron; Hilton, John; Dannals, Robert F.; Kassiou, Michael

    2010-01-01

    Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, 11C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide (11C-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of 11C-DPA-713 in human subjects using PET. Methods Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity 11C-DPA-713. For comparison, 2 additional healthy controls were studied with 11C-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time–activity curves were fitted using 1- and 2-tissue-compartment models, with goodness-of-fit tests showing a preference for the 2-tissue model. Results In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for 11C-R-PK11195. Accordingly, dose-normalized time–activity curves showed that 11C-DPA-713 gives a larger brain signal. Conclusion Studies in patient populations will help determine whether 11C-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that 11C-DPA-713 is a promising ligand for evaluating TSPO binding with PET. PMID:19617321

  7. Potential applications for sigma receptor ligands in cancer diagnosis and therapy.

    PubMed

    van Waarde, Aren; Rybczynska, Anna A; Ramakrishnan, Nisha K; Ishiwata, Kiichi; Elsinga, Philip H; Dierckx, Rudi A J O

    2015-10-01

    Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.

  8. TSPO PET for glioma imaging using the novel ligand (18)F-GE-180: first results in patients with glioblastoma.

    PubMed

    Albert, Nathalie L; Unterrainer, M; Fleischmann, D F; Lindner, S; Vettermann, F; Brunegraf, A; Vomacka, L; Brendel, M; Wenter, V; Wetzel, C; Rupprecht, R; Tonn, J-C; Belka, C; Bartenstein, P; Niyazi, M

    2017-08-19

    The 18-kDa mitochondrial translocator protein (TSPO) was reported to be upregulated in gliomas. (18)F-GE-180 is a novel 3rd generation TSPO receptor ligand with improved target-to-background contrast compared to previous tracers. In this pilot study, we compared PET imaging with (18)F-GE-180 and MRI of patients with untreated and recurrent pretreated glioblastoma. Eleven patients with histologically confirmed IDH wildtype gliomas (10 glioblastomas, 1 anaplastic astrocytoma) underwent (18)F-GE-180 PET at initial diagnosis or recurrence. The PET parameters mean background uptake (SUVBG), maximal tumour-to-background ratio (TBRmax) and PET volume using different thresholds (SUVBG × 1.6, 1.8 and 2.0) were evaluated in the 60-80 min p.i. summation images. The different PET volumes were compared to the contrast-enhancing tumour volume on MRI. All gliomas were positive on (18)F-GE-180 PET and were depicted with extraordinarily high tumour-to-background contrast (median SUVBG 0.47 (0.37-0.93), TBRmax 6.61 (3.88-9.07)). (18)F-GE-180 uptake could be found even in areas without contrast enhancement on MRI, leading to significantly larger PET volumes than MRI-based volumes (median 90.5, 74.5, and 63.8 mL vs. 31.0 mL; p = 0.003, 0.004, 0.013). In percentage difference, the PET volumes were on average 179%, 135%, and 90% larger than the respective MRI volumes. The median spatial volumetric correlation (Sørensen-Dice coefficient) of PET volumes and MRI volumes prior to radiotherapy was 0.48, 0.54, and 0.58. (18)F-GE-180 PET provides a remarkably high tumour-to-background contrast in untreated and pretreated glioblastoma and shows tracer uptake even beyond contrast enhancement on MRI. To what extent (18)F-GE-180 uptake reflects the tumour extent of human gliomas and inflammatory cells remains to be evaluated in future prospective studies with guided stereotactic biopsies and correlation of histopathological results.

  9. (18)F-FPP: A PET Ligand for the 5-HT2C Receptor?

    PubMed

    Higgins, Guy A

    2017-05-17

    In the current issue of ACS Chemical Neuroscience, Kim et al. report on the early characterization of 4-(3-[(18)F] fluorophenethoxy)pyrimidine ((18)F-FPP) as a new positron emission tomography radiotracer for imaging brain 5-HT2C receptors ( Kim, J., et al. ( 2017 ) A potential PET radiotracer for the 5-HT2c receptor: Synthesis and in vivo evaluation of 4-(3-[(18)F]Fluorophenethoxy)pyrimidine. ACS Chem. Neurosci. 10.1021/acschemneuro.6b00445 ). At the present time, the tracer properties of (18)F-FPP have only been reported in rats. If (18)F-FPP is indeed shown to be suitable as a 5-HT2C receptor PET tracer in humans, it will very likely have an important impact both in the development of any new chemical entities (NCEs) targeted to 5-HT2C receptors, as well as a tool to advance understanding of 5-HT2C receptor function both in normal and abnormal brain states.

  10. Improved PET imaging of uPAR expression using new (64)Cu-labeled cross-bridged peptide ligands: comparative in vitro and in vivo studies.

    PubMed

    Persson, Morten; Hosseini, Masood; Madsen, Jacob; Jørgensen, Thomas J D; Jensen, Knud J; Kjaer, Andreas; Ploug, Michael

    2013-01-01

    The correlation between uPAR expression, cancer cell invasion and metastases is now well-established and has prompted the development of a number of uPAR PET imaging agents, which could potentially identify cancer patients with invasive and metastatic lesions. In the present study, we synthesized and characterized two new cross-bridged (64)Cu-labeled peptide conjugates for PET imaging of uPAR and performed a head-to-head comparison with the corresponding and more conventionally used DOTA conjugate. Based on in-source laser-induced reduction of chelated Cu(II) to Cu(I), we now demonstrate the following ranking with respect to the chemical inertness of their complexed Cu ions: DOTA-AE105 < CB-TE2A-AE105 < CB-TE2A-PA-AE105, which is correlated to their corresponding demetallation rate. No penalty in the uPAR receptor binding affinity of the targeting peptide was encountered by conjugation to either of the macrobicyclic chelators (IC50 ~ 5-10 nM) and high yields and radiochemical purities (>95%) were achieved in all cases by incubation at 95ºC. In vivo, they display identical tumor uptake after 1h, but differ significantly after 22 hrs, where the DOTA-AE105 uptake remains surprisingly high. Importantly, the more stable of the new uPAR PET tracers, (64)Cu-CB-TE2A-PA-AE105, exhibits a significantly reduced liver uptake compared to (64)Cu-DOTA-AE105 as well as (64)Cu-CB-TE2A-AE105, (p<0.0001), emphasizing that our new in vitro stability measurements by mass spectrometry predicts in vivo stability in mice. Specificity of the best performing ligand, (64)Cu-CB-TE2A-PA-AE105 was finally confirmed in vivo using a non-binding (64)Cu-labeled peptide as control ((64)Cu-CB-TE2A-PA-AE105(mut)). This control PET-tracer revealed significantly reduced tumor uptake (p<0.0001), but identical hepatic uptake compared to its active counterpart ((64)Cu-CB-TE2A-PA-AE105) after 1h. In conclusion, our new approach using in-source laser-induced reduction of Cu(II)-chelated PET-ligands provides

  11. Improved PET Imaging of uPAR Expression Using new 64Cu-labeled Cross-Bridged Peptide Ligands: Comparative in vitro and in vivo Studies

    PubMed Central

    Persson, Morten; Hosseini, Masood; Madsen, Jacob; Jørgensen, Thomas J. D.; Jensen, Knud J; Kjaer, Andreas; Ploug, Michael

    2013-01-01

    The correlation between uPAR expression, cancer cell invasion and metastases is now well-established and has prompted the development of a number of uPAR PET imaging agents, which could potentially identify cancer patients with invasive and metastatic lesions. In the present study, we synthesized and characterized two new cross-bridged 64Cu-labeled peptide conjugates for PET imaging of uPAR and performed a head-to-head comparison with the corresponding and more conventionally used DOTA conjugate. Based on in-source laser-induced reduction of chelated Cu(II) to Cu(I), we now demonstrate the following ranking with respect to the chemical inertness of their complexed Cu ions: DOTA-AE105 << CB-TE2A-AE105 < CB-TE2A-PA-AE105, which is correlated to their corresponding demetallation rate. No penalty in the uPAR receptor binding affinity of the targeting peptide was encountered by conjugation to either of the macrobicyclic chelators (IC50 ~ 5-10 nM) and high yields and radiochemical purities (>95%) were achieved in all cases by incubation at 95ºC. In vivo, they display identical tumor uptake after 1h, but differ significantly after 22 hrs, where the DOTA-AE105 uptake remains surprisingly high. Importantly, the more stable of the new uPAR PET tracers, 64Cu-CB-TE2A-PA-AE105, exhibits a significantly reduced liver uptake compared to 64Cu-DOTA-AE105 as well as 64Cu-CB-TE2A-AE105, (p<0.0001), emphasizing that our new in vitro stability measurements by mass spectrometry predicts in vivo stability in mice. Specificity of the best performing ligand, 64Cu-CB-TE2A-PA-AE105 was finally confirmed in vivo using a non-binding 64Cu-labeled peptide as control (64Cu-CB-TE2A-PA-AE105mut). This control PET-tracer revealed significantly reduced tumor uptake (p<0.0001), but identical hepatic uptake compared to its active counterpart (64Cu-CB-TE2A-PA-AE105) after 1h. In conclusion, our new approach using in-source laser-induced reduction of Cu(II)-chelated PET-ligands provides useful

  12. Synthesis, Structure-affinity Relationships and Radiolabeling of Selective High-affinity 5-HT4 Receptor Ligands as Prospective Imaging Probes for PET

    PubMed Central

    Xu, Rong; Hong, Jinsoo; Morse, Cheryl L.; Pike, Victor W.

    2010-01-01

    In a search for high-affinity receptor ligands that might serve for development as radioligands for the imaging of brain 5-HT4 receptors in vivo with positron emission tomography (PET), structural modifications were made to the high-affinity 5-HT4 antagonist, (1-butylpiperidin-4-yl)methyl 8-amino-7-iodo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate (1, SB 207710). These modifications were made mainly on the aryl side of the ester bond to permit possible rapid labeling of the carboxylic acid component with a positron-emitter, either carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2 = 109.7 min), and included, i) replacement of the iodine atom with a small substituent such as nitrile, methyl or fluoro, ii) methylation of the 8-amino group, iii) opening of the dioxan ring, and iv) alteration of the length of the N-alkyl goup. High-affinity ligands were discovered for recombinant human 5-HT4 receptors with amenability to labeling with a positron-emitter and potential for development as imaging probes. The ring-opened radioligand, (([methoxy-11C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [11C]13), showed an especially favorable array of properties for future evaluation as a PET radioligand for brain 5-HT4 receptors. PMID:20812727

  13. A PSMA Ligand Labeled with Cobalt-55 for PET Imaging of Prostate Cancer.

    PubMed

    Dam, Johan Hygum; Olsen, Birgitte Brinkmann; Baun, Christina; Høilund-Carlsen, Poul Flemming; Thisgaard, Helge

    2017-09-18

    confirmed the high tumor uptake and fast clearance of normal tissues over time and was found superior to imaging with [(68)Ga]PSMA-617. Radiolabeling of PSMA-617 was achieved in excellent yields and radiochemical purities. Favorable in vitro data comprising low K D values and high extent of internalization was determined for two PSMA-positive cell lines. In xenograft mice, high tumor accumulation and excellent tumor-to-normal tissues ratios were established by biodistribution experiments and PET/CT imaging and, hence, confirm the potential of [(55)Co]PSMA-617 for delayed clinical imaging of prostate cancer.

  14. [11C]CHIBA-1001 as a Novel PET Ligand for α7 Nicotinic Receptors in the Brain: A PET Study in Conscious Monkeys

    PubMed Central

    Hashimoto, Kenji; Nishiyama, Shingo; Ohba, Hiroyuki; Matsuo, Masaaki; Kobashi, Tatsuhiko; Takahagi, Makoto; Iyo, Masaomi; Kitashoji, Takeru; Tsukada, Hideo

    2008-01-01

    Background The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable positron emission tomography (PET) radioligands for imaging α7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of α7 nAChRs in the non-human primate brain. Methodology/Principal Findings A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at α7 nAChRs. Using conscious monkeys, we found that the distribution of radioactivity in the monkey brain after intravenous administration of [11C]CHIBA-1001 was consistent with the regional distribution of α7 nAChRs in the monkey brain. The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective α7 nAChR agonist SSR180711 (5.0 mg/kg). However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective α4β2 nAChR agonist A85380 (1.0 mg/kg). Interestingly, the binding of [11C]CHIBA-1001 in the frontal cortex of the monkey brain was significantly decreased by subchronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (0.3 mg/kg, twice a day for 13 days); which is a non-human primate model of schizophrenia. Conclusions/Significance The present findings suggest that [11C]CHIBA-1001 could be a novel useful PET ligand for in vivo study of the receptor occupancy and pathophysiology of α7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. PMID:18800169

  15. Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic {beta}-cell mass

    SciTech Connect

    Cline, Gary W.; Zhao, Xiaojian; Jakowski, Amy B.; Soeller, Walter C.; Treadway, Judith L.

    2011-09-02

    Highlights: {yields} We screened G-protein coupled receptors for imaging pancreatic. {yields} Database mining and immunohistochemistry identified GPCRs enriched in {beta}-cells. {yields} In vitro and in vivo assays were used to determine exocrine vs endocrine specificity. {yields} GPCR candidates for imaging of {beta}-cell mass are Prokineticin-1R, mGluR5, and GLP-1R. -- Abstract: A critical unmet need exists for methods to quantitatively measure endogenous pancreatic {beta}-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet {beta}-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y-2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R > GLP-1R > NPY-2R > mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R > VMAT2 {approx} GLP-1R > mGluR5. Favorable islet selectivity and biodistribution

  16. Feasibility and predictability of perioperative PET and estrogen receptor ligand in patients with invasive breast cancer.

    PubMed

    Gemignani, Mary L; Patil, Sujata; Seshan, Venkatraman E; Sampson, Michelle; Humm, John L; Lewis, Jason S; Brogi, Edi; Larson, Steven M; Morrow, Monica; Pandit-Taskar, Neeta

    2013-10-01

    The presence of estrogen receptor (ER) in breast cancer is a prognostic indicator for both disease-free and overall survival. 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) with PET is a noninvasive test for evaluation of ER expression and has been used for predicting response to endocrine therapy in patients with ER-positive metastatic breast cancer. The purpose of this study was to correlate (18)F-FES PET and ER expression in patients with primary, operable breast cancer. Forty-eight patients were prospectively enrolled in an institutional review board-approved protocol and signed an informed consent form. All patients had undergone (18)F-FES PET preoperatively. Clinical characteristics, tumor characteristics, and treatment outcomes were recorded. Immunohistochemical analysis for ER and progesterone receptor (PgR) percentage expression (46 surgical, 2 core biopsy specimens) was performed. (18)F-FES PET standardized uptake value (SUV) of the breast lesion was correlated with percentage immunohistochemistry ER and PgR expression. (18)F-FES PET SUV was quantified, with a value of 1.5 or more considered positive, and ER and PgR was quantified, with 1% or more considered positive. Formalin-fixed paraffin-embedded tissue was available for 44 patients (42 surgical, 2 core biopsy specimens). We used a microarray platform, and estrogen-related gene expression data (ESR1, ESR2, and PGR) were compared with (18)F-FES PET SUV (Spearman rank correlation). Tumor size, ductal histology, grade, HER2-neu overexpression, PgR expression, estradiol level, body mass index (BMI), and lean BMI were compared with (18)F-FES PET uptake using univariate and multivariate analysis. Forty-eight patients completed our protocol, and 2 patients did not undergo surgery because bone metastases were identified preoperatively on (18)F-FES PET. Eighty-three percent of our patients were stage I or II, with a median tumor size of 1.9 cm. Forty-one patients underwent a sentinel node biopsy. Twenty

  17. [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey.

    PubMed

    Hostetler, Eric D; Sanabria-Bohórquez, Sandra; Fan, Hong; Zeng, Zhizhen; Gammage, Linda; Miller, Patricia; O'Malley, Stacey; Connolly, Brett; Mulhearn, James; Harrison, Scott T; Wolkenberg, Scott E; Barrow, James C; Williams, David L; Hargreaves, Richard J; Sur, Cyrille; Cook, Jacquelynn J

    2011-11-01

    An (18)F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood-brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with (18)F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. [(18)F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC(50)=10.5±1.3 nM). [(18)F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Sulfonamido tripods: tuning redox potentials via ligand modifications

    PubMed Central

    Lau, Nathanael; Ziller, Joseph W.

    2014-01-01

    A series of FeII–OH2 complexes were synthesized with ligands based on the tetradentate sulfonamido tripod N,N',N"-[2,2',2"-nitrilotris(ethane-2,1-diyl)]-tris-({R-Ph}-sulfonamido). These complexes differ by the substituent on the aryl rings and were fully characterized, including their molecular structures via X-ray diffraction methods. All the complexes were five-coordinate with trigonal bipyramidal geometry. A linear correlation was observed between the electronic effects of each ligand, given by the Hammett constants of the para-substituents, and the potential of the FeII/FeIII redox couple, which were determined using cyclic voltammetry. It was found that the range of redox potentials for the complexes spanned approximately 160 mV. PMID:25419035

  19. Nonneoplastic Neuroma After Radical Prostatectomy Is Not a Mimicker of Lymph Node Metastases on 68Ga-PSMA Ligand PET/CT.

    PubMed

    Derlin, Thorsten; Schumacher, Udo; Bengel, Frank M

    2016-10-01

    Traumatic neuroma is frequently observed after surgery. PSMA expression has been demonstrated in neoplastic nerve sheath tumors, which may mimic metastases on PSMA imaging. In this case, histopathologic evaluation of a pelvic lesion with assumed intense tracer uptake on Ga-PSMA ligand PET/CT in a patient with biochemical recurrence of prostate cancer revealed an amputation neuroma. However, immunohistochemical evaluation showed absent PSMA expression, and follow-up PET confirmed persistence of the metastasis. Unlike neoplastic nerve sheath tumors, traumatic neuroma does not show PSMA expression and is not a mimicker of metastases on Ga-PSMA PET/CT.

  20. First 18F-labeled ligand for PET imaging of uPAR: In vivo studies in human prostate cancer xenografts☆

    PubMed Central

    Persson, Morten; Liu, Hongguang; Madsen, Jacob; Cheng, Zhen; Kjaer, Andreas

    2014-01-01

    Urokinase-type plasminogen activator receptor (uPAR) is overexpressed in human prostate cancer and uPAR has been found to be associated with metastatic disease and poor prognosis. AE105 is a small linear peptide with high binding affinity to uPAR. We synthesized an N-terminal NOTA-conjugated version (NOTA-AE105) for development of the first 18F-labeled uPAR positron-emission-tomography PET ligand using the Al18F radiolabeling method. In this study, the potential of 18F-AlF-NOTA-AE105 to specifically target uPAR-positive prostate tumors was investigated. Methods NOTA-conjugated AE105 was synthesized and radiolabeled with 18F-AlF according to a recently published optimized protocol. The labeled product was purified by reverse phase high performance liquid chromatography RP-HPLC. The tumor targeting properties were evaluated in mice with subcutaneously inoculated PC-3 xenografts using small animal PET and ex vivo biodistribution studies. uPAR-binding specificity was studied by coinjection of an excess of a uPAR antagonist peptide AE105 analogue (AE152). Results NOTA-AE105 was labeled with 18F-AlF in high radiochemical purity (> 92%) and yield (92.7%) and resulted in a specific activity of greater than 20 GBq/μmol. A high and specific tumor uptake was found. At 1 h post injection, the uptake of 18F-AlF-NOTA-AE105 in PC-3 tumors was 4.22 ± 0.13%ID/g. uPAR-binding specificity was demonstrated by a reduced uptake of 18F-AlF-NOTA-AE105 after coinjection of a blocking dose of uPAR antagonist at all three time points investigated. Good tumor-to-background ratio was observed with small animal PET and confirmed in the biodistribution analysis. Ex vivo uPAR expression analysis on extracted tumors confirmed human uPAR expression that correlated close with tumor uptake of 18F-AlF-NOTA-AE105. Conclusion The first 18F-labeled uPAR PET ligand, 18F-AlF-NOTA-AE105, has successfully been prepared and effectively visualized noninvasively uPAR positive prostate cancer. The favorable in

  1. [64Cu]XYIMSR-06: A dual-motif CAIX ligand for PET imaging of clear cell renal cell carcinoma

    PubMed Central

    Minn, Il; Koo, Soo Min; Lee, Hye Soo; Brummet, Mary; Rowe, Steven P.; Gorin, Michael A.; Sysa-Shah, Polina; Lewis, William D.; Ahn, Hye-Hyun; Wang, Yuchuan; Banerjee, Sangeeta Ray; Mease, Ronnie C.; Nimmagadda, Sridhar; Allaf, Mohamad E.; Pomper, Martin G.; Yang, Xing

    2016-01-01

    Carbonic anhydrase IX (CAIX) is a cell surface enzyme that is over-expressed in approximately 95% of cases of clear cell renal cell carcinoma (ccRCC), the most common renal cancer. We synthesized and performed in vitro and in vivo evaluation of a dual-motif ligand, [64Cu]XYIMSR-06, for imaging CAIX expression on ccRCC tumors using positron emission tomography (PET). [64Cu]XYIMSR-06 was generated in yields of 51.0 ± 4.5% (n=5) and specific activities of 4.1 – 8.9 GBq/μmol (110-240 Ci/mmol). Tumor was visualized on PET images by 1 h post-injection with high tumor-to-background levels (>100 tumor-to-blood and -muscle) achieved within 24 h. Biodistribution studies demonstrated a maximum tumor uptake of 19.3% injected dose per gram of radioactivity at 4 h. Tumor-to-blood, -muscle and -kidney ratios were 129.6 ± 18.8, 84.3 ± 21.0 and 2.1 ± 0.3, respectively, at 8 h post-injection. At 24 h a tumor-to-kidney ratio of 7.1 ± 2.5 was achieved. These results indicate pharmacokinetics superior to those of previously reported imaging agents binding to CAIX. [64Cu]XYIMSR-06 is a new low-molecular-weight PET ligand targeting CAIX, which can image localized and metastatic ccRCC. PMID:27437764

  2. The antifibrogenic potential of PPARgamma ligands in pulmonary fibrosis.

    PubMed

    Sime, Patricia J

    2008-02-01

    Pulmonary fibrosis is characterized by the accumulation of fibroblasts, myofibroblasts, collagen, and other extracellular matrix proteins in the interstitium of the lung, with subsequent scarring and destruction of the alveolar capillary interface. In some cases, pulmonary fibrosis is preceded by lung inflammation and can be treated with anti-inflammatory therapies. However, idiopathic pulmonary fibrosis is characterized by a relative paucity of underlying inflammation and currently has no effective treatment. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor (PPAR) gamma plays an important role in controlling cell differentiation and that PPARgamma ligands can modify inflammatory and fibrotic responses. Peroxisome proliferator-activated receptor gamma ligands, including the thiazolidinedione class of antidiabetic drugs and novel triterpenoid compounds derived from oleanic acid, inhibit TGF-beta-stimulated profibrotic differentiation of lung fibroblasts in vitro and reduce lung scarring in animal models of fibrosis. The mechanism of action of the PPARgamma ligands is under investigation but seems to involve both PPARgamma-dependent and PPARgamma-independent pathways. These in vitro and in vivo data highlight the potentially exciting role of PPARgamma ligands as novel therapies for fibrosis of the lung and other organ systems prone to scarring. Many of the synthetic PPARgamma ligands are orally active, and several are currently available and Food Drug Administration approved for use in therapy of type 2 diabetes. Further research is urgently required to more clearly elucidate the mechanism of action of these drugs and to develop more potent antifibrotic agents for patients with scarring diseases for whom there are currently few effective therapies.

  3. Investigation of an F-18 oxytocin receptor selective ligand via PET imaging.

    PubMed

    Smith, Aaron L; Freeman, Sara M; Voll, Ronald J; Young, Larry J; Goodman, Mark M

    2013-10-01

    The compound 1-(1-(2-(2-(2-fluoroethoxy)-4-(piperidin-4-yloxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) was synthesized and positively evaluated in vitro for high potency and selectivity with human oxytocin receptors. The positron emitting analogue, [F-18]1, was synthesized and investigated in vivo via PET imaging using rat and cynomolgus monkey models. PET imaging studies in female Sprague-Dawley rats suggested [F-18]1 reached the brain and accumulated in various regions of the brain, but washed out too rapidly for adequate quantification and localization. In vivo PET imaging studies in a male cynomolgus monkey suggested [F-18]1 had limited brain penetration while specific uptake of radioactivity significantly accumulated within the vasculature of the cerebral ventricles in areas representative of the choroid plexus. Copyright © 2013. Published by Elsevier Ltd.

  4. Synthesis and evaluation of vesamicol analog (-)-O-[11C]methylvesamicol as a PET ligand for vesicular acetylcholine transporter.

    PubMed

    Kawamura, Kazunori; Shiba, Kazuhiro; Tsukada, Hideo; Nishiyama, Shingo; Mori, Hirofumi; Ishiwata, Kiichi

    2006-07-01

    (-)-O-Methylvesamicol ((-)-OMV) exhibited in vitro a high affinity for vesicular acetylcholine transporter (VAChT) (Ki, 6.7 nM) and a relatively low affinity for sigmal receptor (Ki, 33.7 nM). We prepared (-)-[11C]OMV by a palladium-promoted cross-coupling reaction using [11C]methyl iodide, in a radiochemical yield of 38 +/- 6.9% (n=3), a radiochemical purity of 98 +/- 2.3% (n = 5), and a specific activity of 11 +/- 7.0 TBq/mmol at 30 minutes after EOB (n=5). Then, we evaluated in vivo whether (-)-[11C]OMV has properties as a PET radioligand for mapping VAChT. In rats, the brain uptake of (-)-[11C]OMV was 1.1%ID/g at 5 minutes postinjection, and was retained of a high level for 60 minutes. The brain uptake was significantly inhibited by the co-injection (500 nmol/kg) of cold (-)-OMV (58-66%), (-)-vesamicol (57-65%), and two sigma receptor ligands with modulate affinities for VAChTs: SA4503 (56-71%) and haloperidol (39-64%) in all of the brain regions, including the cerebellum with a low density of VAChTs, but not of sigmal-selective ligand (+)-pentazocine. However, the pretreatment with a large excess amount of (+/-)-pentazocine (50 micromol/kg) reduced the uptake in a different manner in the brain regions: 25% reduction in the striatum with a high density of VAChTs, and a 50-55% reduction in the other regions with a lower density of VAChTs. Ex vivo autoradiography using (-)-[11C]OMV showed a similar regional brain distribution of [3H](-)-vesamicol. In the PET study of the monkey brain, the regional brain distribution pattern of (-)-[11C]OMV was different from that of [11C]SA4503. The uptake of (-)-[11C]OMV was relatively higher in the striatum, was reversible, and an apparent equilibrium state was found at 20-40 minutes. In conclusion, (-)-[11C]OMV exhibited appropriate brain kinetics during the time frame of 11C-labeled tracers and bound mainly to VAChTs; however, the binding to sigmal receptors was not disregarded. Therefore, (-)-[11C]OMV-PET together with help

  5. Metabotropic glutamate receptor ligands as potential therapeutics for addiction

    PubMed Central

    Olive, M. F.

    2009-01-01

    There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials. PMID:19630739

  6. Pharmacology and therapeutic potential of sigma(1) receptor ligands.

    PubMed

    Cobos, E J; Entrena, J M; Nieto, F R; Cendán, C M; Del Pozo, E

    2008-12-01

    Sigma (sigma) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of sigma receptors, termed sigma(1) and sigma(2). Of these two subtypes, the sigma(1) receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for sigma(1) receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates sigma(1) receptors. Certain neurosteroids are known to interact with sigma(1) receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca(2+) signaling. Sigma(1) receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, sigma(1) receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of sigma(1) receptors, focussing on sigma(1) ligand neuropharmacology and the role of sigma(1) receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of sigma(1) ligands.

  7. Metabotropic glutamate receptor ligands as potential therapeutics for addiction.

    PubMed

    Olive, M Foster

    2009-01-01

    There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials.

  8. Optimization of Acquisition time of 68Ga-PSMA-Ligand PET/MRI in Patients with Local and Metastatic Prostate Cancer

    PubMed Central

    Lütje, Susanne; Blex, Sebastian; Gomez, Benedikt; Schaarschmidt, Benedikt M.; Umutlu, Lale; Forsting, Michael; Jentzen, Walter; Bockisch, Andreas; Poeppel, Thorsten D.; Wetter, Axel

    2016-01-01

    Objective The aim of this optimization study was to minimize the acquisition time of 68Ga-HBED-CC-PSMA positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with local and metastatic prostate cancer (PCa) to obtain a sufficient image quality and quantification accuracy without any appreciable loss. Methods Twenty patients with PCa were administered intravenously with the 68Ga-HBED-CC-PSMA ligand (mean activity 99 MBq/patient, range 76–148 MBq) and subsequently underwent PET/MRI at, on average, 168 min (range 77–320 min) after injection. PET and MR imaging data were acquired simultaneously. PET acquisition was performed in list mode and PET images were reconstructed at different time intervals (1, 2, 4, 6, 8, and 10 min). Data were analyzed regarding radiotracer uptake in tumors and muscle tissue and PET image quality. Tumor uptake was quantified in terms of the maximum and mean standardized uptake value (SUVmax, SUVmean) within a spherical volume of interest (VOI). Reference VOIs were drawn in the gluteus maximus muscle on the right side. PET image quality was evaluated by experienced nuclear physicians/radiologists using a five-point ordinal scale from 5–1 (excellent—insufficient). Results Lesion detectability linearly increased with increasing acquisition times, reaching its maximum at PET acquisition times of 4 min. At this image acquisition time, tumor lesions in 19/20 (95%) patients were detected. PET image quality showed a positive correlation with increasing acquisition time, reaching a plateau at 4–6 min image acquisition. Both SUVmax and SUVmean correlated inversely with acquisition time and reached a plateau at acquisition times after 4 min. Conclusion In the applied image acquisition settings, the optimal acquisition time of 68Ga-PSMA-ligand PET/MRI in patients with local and metastatic PCa was identified to be 4 min per bed position. At this acquisition time, PET image quality and lesion detectability reach a maximum

  9. Di-macrocyclic terephthalamide ligands as chelators for the PET radionuclide zirconium-89

    SciTech Connect

    Pandya, Darpan N.; Pailloux, Sylvie; Tatum, David; Magda, Darren; Wadas, Thaddeus J.

    2014-12-18

    The development of bifunctional chelators (BFCs) which can stably chelate zirconium-89 ((89)Zr) while being conjugated to targeting molecules is an area of active research. Herein we report the first octadentate terephthalamide ligands, which are easily radiolabeled with (89)Zr and are highly stable in vitro. Lastly, they represent a novel class of chelators, which are worthy of further development as BFCs for (89)Zr.

  10. Di-macrocyclic terephthalamide ligands as chelators for the PET radionuclide zirconium-89

    DOE PAGES

    Pandya, Darpan N.; Pailloux, Sylvie; Tatum, David; ...

    2014-12-18

    The development of bifunctional chelators (BFCs) which can stably chelate zirconium-89 ((89)Zr) while being conjugated to targeting molecules is an area of active research. Herein we report the first octadentate terephthalamide ligands, which are easily radiolabeled with (89)Zr and are highly stable in vitro. Lastly, they represent a novel class of chelators, which are worthy of further development as BFCs for (89)Zr.

  11. Radiosynthesis and quality control of [(11)C]TASP457 as a clinically useful PET ligand for imaging of histamine H3 receptors in human brain.

    PubMed

    Hanyu, Masayuki; Kawamura, Kazunori; Takei, Makoto; Furutsuka, Kenji; Shiomi, Satoshi; Fujishiro, Tomoya; Ogawa, Masanao; Nengaki, Nobuki; Hashimoto, Hiroki; Fukumura, Toshimitsu; Zhang, Ming-Rong

    2016-11-01

    Recently, 6-[(1-cyclobutylpiperidin-4-yl)oxy]-1-(6-[(11)C]methoxypyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one ([(11)C]TASP457, [(11)C]2) has been developed as a novel PET ligand for histamine H3 receptors in brain. [(11)C]2 is potentially suitable for imaging H3 receptors in rat and monkey brains, which has motivated us to perform first-in-human study of [(11)C]2 for qualifying H3 receptors in human brain. In this paper, we report an efficient radiosynthesis of [(11)C]2 to obtain sufficient radioactivity and high quality for clinical application. In manual synthesis, we optimized the reaction conditions of desmethyl precursor 1, which contains a 2-hydroxypyridine moiety, with [(11)C]MeI or [(11)C]MeOTf. After optimization, we performed automated synthesis and quality control of [(11)C]2. Bubbling [(11)C]MeOTf into a heated mixture of precursor 1 and cesium carbonate in DMF at 100°C for 90s produced [(11)C]2 with decay-corrected radiochemical yields of (based on [(11)C]CO2) 7.9±1.8% (n=78). The specific activity of [(11)C]2 was 156±52GBq/μmol (n=78) at the end of synthesis. The total synthesis time was approximately 35min from the end of bombardment. All the quality control results of [(11)C]2 were in compliance with our in-house quality control/assurance specifications. We radiosynthesized [(11)C]TASP457 ([(11)C]2) with sufficient amounts of radioactivity and high quality for clinical usefulness. This radioligand is being used for PET assessment of H3 receptors in human brain in our facility. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Vertebral Hemangioma Mimicking Bone Metastasis in 68Ga-PSMA Ligand PET/CT.

    PubMed

    Artigas, Carlos; Otte, François-Xavier; Lemort, Marc; van Velthoven, Roland; Flamen, Patrick

    2017-05-01

    Ga-PSMA PET/CT was performed in a 68-year-old man to evaluate recurrent prostate cancer due to elevated serum prostate-specific antigen level. Images showed a focal uptake in the prostatic gland, suggesting local relapse, and an intense uptake in the 12th thoracic vertebra, with no morphological abnormalities in CT slices. In order to confirm extraprostatic disease and before radiotherapy planning, a full-spine MRI was performed, resulting with the morphological pattern of a vertebral hemangioma. Hystological analysis confirmed the local relapse in the prostate. No radiotherapy treatment was given to the vertebra, and after 1 year of follow-up without systemic treatment, prostate-specific antigen is still undetectable.

  13. Melanoma Cell Galectin-1 Ligands Functionally Correlate with Malignant Potential.

    PubMed

    Yazawa, Erika M; Geddes-Sweeney, Jenna E; Cedeno-Laurent, Filiberto; Walley, Kempland C; Barthel, Steven R; Opperman, Matthew J; Liang, Jennifer; Lin, Jennifer Y; Schatton, Tobias; Laga, Alvaro C; Mihm, Martin C; Qureshi, Abrar A; Widlund, Hans R; Murphy, George F; Dimitroff, Charles J

    2015-07-01

    Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening antitumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity, and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely dysplastic nevi, as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAM(KD)) or ST6GalNAc2-overexpressing (ST6(O/E)) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAM(KD) or ST6(O/E) melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1/melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.

  14. PSMA Expression in Tumor Neovasculature Endothelial Cells of Follicular Thyroid Adenoma as Identified by Molecular Imaging Using 68Ga-PSMA Ligand PET/CT.

    PubMed

    Derlin, Thorsten; Kreipe, Hans-Heinrich; Schumacher, Udo; Soudah, Bisharah

    2017-03-01

    The prostate-specific membrane antigen (PSMA) is expressed by both prostate cancer and other neoplasms. We report the case of a 65-year-old man with castration-resistant metastatic prostate cancer who underwent Ga-PSMA ligand PET/CT for restaging of disease. Ga-PSMA ligand accumulation was noted in a thyroid lesion, suspicious for thyroid malignancy on complementary ultrasound. Subsequent resection and histopathological analysis showed follicular thyroid adenoma with PSMA expression in tumor neovasculature endothelial cells, but not in thyroid epithelial cells. It is important to be aware that both malignant and benign thyroid neoplasms may show PSMA expression to avoid misinterpretation.

  15. Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1.

    PubMed

    Gunn, Roger N; Murthy, Venkatesha; Catafau, Ana M; Searle, Graham; Bullich, Santiago; Slifstein, Mark; Ouellet, Daniele; Zamuner, Stefano; Herance, Raul; Salinas, Cristian; Pardo-Lozano, Ricardo; Rabiner, Eugenii A; Farre, Magi; Laruelle, Marc

    2011-12-01

    The current interest in developing Glycine transporter Type 1 (GlyT-1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT-1 PET molecular imaging tool to aid drug development and dose selection. We report on [(11) C]GSK931145 as a novel GlyT-1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma-occupancy relationship of the GlyT-1 inhibitor GSK1018921. Human PET studies were performed to determine the test-retest reproducibility of [(11) C]GSK931145 and the plasma-occupancy relationship of GSK1018921. [(11) C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (f(P) : 0.8 vs. 8%) and delivery (K(1) : 0.025 vs. 0.126 ml cm(-3) min(-1) ) were significantly lower in humans. Test-retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(V(T) ): 29-38%), but was improved using a pseudo reference tissue model (VAR(BP(ND) ): 16-23%). GSK1018921 EC(50) estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively.

  16. THE POTENTIAL FOR HUMAN EXPOSURES TO PET-BORNE DIAZINON RESIDUES FOLLOWING RESIDENTIAL LAWN APPLICATIONS

    EPA Science Inventory

    This observational study examined the potential for indoor/outdoor pet dogs to be an important pathway for transporting diazinon residues into homes and onto occupants following residential lawn applications. The primary objective was to investigate the potential exposures of chi...

  17. THE POTENTIAL FOR HUMAN EXPOSURES TO PET-BORNE DIAZINON RESIDUES FOLLOWING RESIDENTIAL LAWN APPLICATIONS

    EPA Science Inventory

    This observational study examined the potential for indoor/outdoor pet dogs to be an important pathway for transporting diazinon residues into homes and onto occupants following residential lawn applications. The primary objective was to investigate the potential exposures of chi...

  18. Evaluating the potential for recycling all PET bottles into new food packaging.

    PubMed

    Begley, T H; McNeal, T P; Biles, J E; Paquette, K E

    2002-01-01

    To evaluate the feasibility of recycling all PET bottles into food packaging, realistic estimates of the maximum concentration of contaminants that might be expected in the polymer are needed. To estimate the maximum concentration of a contaminant that might be in PET from the storage of non-food substances, sorption experiments into two types of PET were performed. These test materials were 0.8mm thick amorphous PET (a relative sink for contaminants) and commercial PET bottle wall. Using a commercial shampoo containing 1% lindane (C6H6Cl6), the test materials were stored in contact with the shampoo at 20 and 40 degrees C for 231 days. This commercial shampoo also represents an extreme case because it contains 7% acetone, a solvent which swells PET, further enhancing sorption of chemicals. Additional sorption experiments into PET were performed by preparing solutions of 10% toluene in Miglyol (a fractionated coconut oil), 10% benzophenone in Miglyol, 5% 2-butoxyethoxy ethanol (2-BE) in 50/50 water/ethanol, and 10% methyl stearate in heptane. Sorption data from the shampoo into PET illustrate Fickian behaviour. Specifically, the amount of sorption at room temperature is approximately40 times less than that at 40 degrees C. The amount of lindane sorbed into PET from the shampoo after 231 days was 0.1 and 3.7 mgdm(-2) at 20 and 40 degrees C respectively. These values correspond to 28 and 765 mg kg(-1) on a mass/mass basis. All sorptions are within the ranges measured and published by other authors using surrogate contamination testing schemes. Additionally, actual bottles from recycle bins were analysed for the amout of contamination. Results are discussed in terms of potential consumer exposure to non-food contaminants in food containers made of recycled PET and in relation to the surrogate testing methods recommended by the Food and Drug Administration (FDA) for determining the compatibility of a PET recycling process to produce containers suitable for food

  19. Initial investigation of three selective and potent small molecule oxytocin receptor PET ligands in New World monkeys.

    PubMed

    Smith, Aaron L; Freeman, Sara M; Barnhart, Todd E; Abbott, David H; Ahlers, Elizabeth O; Kukis, David L; Bales, Karen L; Goodman, Mark M; Young, Larry J

    2016-07-15

    The neuropeptide oxytocin is part of a neuroendocrine system that has physiological effects ranging from ensuring uterine myometrial contractions at parturition and post-partum mammary gland milk ejection to the modulation of neural control of social relationships. This initial study was performed to investigate the potential use of positron emission tomography (PET) for localizing oxytocin receptors in two New World primates. Three biomarkers for PET (1-3) that are known to have high affinity and selectivity for the human oxytocin receptor were investigated in the common marmoset (Callithrix jacchus) via PET imaging. Brain penetration, and uptake in the salivary gland area were both observed with biomarkers 2 and 3. No brain penetration was observed with 1, but uptake was observed more specifically in several peripheral endocrine glands compared to 2 or 3. Biomarker 2, which displayed the best brain penetration of the three biomarkers in the marmoset, was then investigated in the monogamous coppery titi monkey (Callicebus cupreus) in a brain scan and a limited full body scan. No significant brain penetration of 2 was observed in the titi monkey, but significant uptake was observed in various locations throughout the periphery. Metabolism of 2 was suspected to have been significant based upon HPLC analysis of blood draws, but parent compound was still present near the end of the scan. Follow-up investigations will focus on next generation biomarkers bearing improved binding characteristics and brain penetrability as well as investigating tissue in regions where biomarker uptake was observed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. The degradation potential of PET bottles in the marine environment: An ATR-FTIR based approach

    PubMed Central

    Ioakeimidis, C.; Fotopoulou, K. N.; Karapanagioti, H. K.; Geraga, M.; Zeri, C.; Papathanassiou, E.; Galgani, F.; Papatheodorou, G.

    2016-01-01

    The dominance and persistence of plastic debris in the marine environment are well documented. No information exists in respect to their lifespan in the marine environment. Nevertheless, the degradation potential of plastic litter items remains a critical issue for marine litter research. In the present study, polyethylene terephthalate bottles (PETs) collected from the submarine environment were characterized using ATR-FTIR in respect to their degradation potential attributed to environmental conditions. A temporal indication was used as indicative to the years of presence of the PETs in the environment as debris. PETs seem to remain robust for approximately fifteen years. Afterwards, a significant decrease of the native functional groups was recorded; some even disappear; or new-not typical for PETs-are created. At a later stage, using the PET time series collected from the Saronikos Gulf (Aegean Sea–E. Mediterranean), it was possible to date bottles that were collected from the bottom of the Ionian Sea (W. Greece). It is the first time that such a study has been conducted with samples that were actually degraded in the marine environment. PMID:27000994

  1. The degradation potential of PET bottles in the marine environment: An ATR-FTIR based approach.

    PubMed

    Ioakeimidis, C; Fotopoulou, K N; Karapanagioti, H K; Geraga, M; Zeri, C; Papathanassiou, E; Galgani, F; Papatheodorou, G

    2016-03-22

    The dominance and persistence of plastic debris in the marine environment are well documented. No information exists in respect to their lifespan in the marine environment. Nevertheless, the degradation potential of plastic litter items remains a critical issue for marine litter research. In the present study, polyethylene terephthalate bottles (PETs) collected from the submarine environment were characterized using ATR-FTIR in respect to their degradation potential attributed to environmental conditions. A temporal indication was used as indicative to the years of presence of the PETs in the environment as debris. PETs seem to remain robust for approximately fifteen years. Afterwards, a significant decrease of the native functional groups was recorded; some even disappear; or new-not typical for PETs-are created. At a later stage, using the PET time series collected from the Saronikos Gulf (Aegean Sea-E. Mediterranean), it was possible to date bottles that were collected from the bottom of the Ionian Sea (W. Greece). It is the first time that such a study has been conducted with samples that were actually degraded in the marine environment.

  2. The degradation potential of PET bottles in the marine environment: An ATR-FTIR based approach

    NASA Astrophysics Data System (ADS)

    Ioakeimidis, C.; Fotopoulou, K. N.; Karapanagioti, H. K.; Geraga, M.; Zeri, C.; Papathanassiou, E.; Galgani, F.; Papatheodorou, G.

    2016-03-01

    The dominance and persistence of plastic debris in the marine environment are well documented. No information exists in respect to their lifespan in the marine environment. Nevertheless, the degradation potential of plastic litter items remains a critical issue for marine litter research. In the present study, polyethylene terephthalate bottles (PETs) collected from the submarine environment were characterized using ATR-FTIR in respect to their degradation potential attributed to environmental conditions. A temporal indication was used as indicative to the years of presence of the PETs in the environment as debris. PETs seem to remain robust for approximately fifteen years. Afterwards, a significant decrease of the native functional groups was recorded; some even disappear; or new-not typical for PETs-are created. At a later stage, using the PET time series collected from the Saronikos Gulf (Aegean Sea–E. Mediterranean), it was possible to date bottles that were collected from the bottom of the Ionian Sea (W. Greece). It is the first time that such a study has been conducted with samples that were actually degraded in the marine environment.

  3. PET Neuroimaging: Insights on Dystonia and Tourette Syndrome and Potential Applications

    PubMed Central

    Alongi, Pierpaolo; Iaccarino, Leonardo; Perani, Daniela

    2014-01-01

    Primary dystonia (pD) is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Gilles de la Tourette syndrome (GTS) is a childhood-onset neuropsychiatric developmental disorder characterized by motor and phonic tics, which could progress to behavioral changes. GTS and obsessive–compulsive disorders are often seen in comorbidity, also suggesting that a possible overlap in the pathophysiological bases of these two conditions. PET techniques are of considerable value in detecting functional and molecular abnormalities in vivo, according to the adopted radioligands. For example, PET is the unique technique that allows in vivo investigation of neurotransmitter systems, providing evidence of changes in GTS or pD. For example, presynaptic and post-synaptic dopaminergic studies with PET have shown alterations compatible with dysfunction or loss of D2-receptors bearing neurons, increased synaptic dopamine levels, or both. Measures of cerebral glucose metabolism with 18F-fluorodeoxyglucose PET (18F-FDG PET) are very sensitive in showing brain functional alterations as well. 18F-FDG PET data have shown metabolic changes within the cortico-striato-pallido-thalamo-cortical and cerebello-thalamo-cortical networks, revealing possible involvement of brain circuits not limited to basal ganglia in pD and GTS. The aim of this work is to overview PET consistent neuroimaging literature on pD and GTS that has provided functional and molecular knowledge of the underlying neural dysfunction. Furthermore, we suggest potential applications of these techniques in monitoring treatments. PMID:25295029

  4. PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease.

    PubMed

    Koivunen, J; Verkkoniemi, A; Aalto, S; Paetau, A; Ahonen, J-P; Viitanen, M; Någren, K; Rokka, J; Haaparanta, M; Kalimo, H; Rinne, J O

    2008-07-01

    Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1Delta E9). VarAD is neuropathologically characterized by the presence of unusually large, Abeta42 positive, non-cored 'cotton wool' plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [(11)C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [(11)C]PIB binding to the amount and type of Abeta deposits in another group of deceased VarAD patients' brains. We studied four patients with VarAD and eight healthy controls with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60-90 min. Group differences in [(11)C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [(11)C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Abeta in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [(11)C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [(11)C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [(11)C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [(11)C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to

  5. Imaging human brown adipose tissue under room temperature conditions with 11C-MRB, a selective norepinephrine transporter PET ligand

    PubMed Central

    Hwang, Janice J.; Yeckel, Catherine W.; Gallezot, Jean-Dominique; Aguiar, Renata Belfort-De; Ersahin, Devrim; Gao, Hong; Kapinos, Michael; Nabulsi, Nabeel; Huang, Yiyun; Cheng, David; Carson, Richard E.; Sherwin, Robert; Ding, Yu-Shin

    2015-01-01

    Introduction Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with 11C-MRB ((S,S)-11C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. Methods Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7 kg/m2; 5 F: age 25.4±2.1, BMI 22.1±1.0 kg/m2) underwent 11C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to 18F-FDG PET-CT imaging. Uptake of 11C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. Results As expected, 18F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT 11C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of 11C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with 18F-FDG (p=0.63). Furthermore, there were gender differences in 11C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in 11C-MRB as a function of both body composition and body temperature. Conclusions Unlike 18F-FDG, the uptake of 11C-MRB in BAT offers a unique opportunity to

  6. Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand.

    PubMed

    Hwang, Janice J; Yeckel, Catherine W; Gallezot, Jean-Dominique; Aguiar, Renata Belfort-De; Ersahin, Devrim; Gao, Hong; Kapinos, Michael; Nabulsi, Nabeel; Huang, Yiyun; Cheng, David; Carson, Richard E; Sherwin, Robert; Ding, Yu-Shin

    2015-06-01

    Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7kg/m(2); 5 F: age 25.4±2.1, BMI 22.1±1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of

  7. Usefulness of a dopamine transporter PET ligand [18F]β-CFT in assessing disability in Parkinson's disease

    PubMed Central

    Rinne, J.; Ruottinen, H.; Bergman, J.; Haaparanta, M.; Sonninen, P.; Solin, O.

    1999-01-01

    OBJECTIVES—The usefulness of a novel dopamine transporter PET ligand, [18F]β-CFT in assessing disability in Parkinson's disease was studied.
METHODS—Twenty seven patients with Parkinson's disease in different disability stages (of which nine were patients with early disease) and nine healthy controls were studied. The regions of interest were drawn on a magnetic resonance image resliced according to the PET image.
RESULTS—There was a significant reduction in [18F]β-CFT uptake in the posterior putamen (to 18% of the control mean, p<0.00001), anterior putamen (28%, p<0.00001), and caudate nucleus (51%, p<0.00001) in the total population of patients with Parkinson's disease. The reduction in [18F]β-CFT uptake was more pronounced with more severe disability of the patients, the correlations between the total motor score of the unified Parkinson's disease rating scale (UPDRS) and [18F]β-CFT uptake being significant in the posterior putamen (r=−0.62 p=0.0005), anterior putamen (r=-0.64, p=0.0003), and the caudate nucleus (r=−0.62, p=0.0006). There was a significant negative correlation with putaminal [18F]β-CFT uptake and the hypokinesia and rigidity scores, but not with the tremor score of the UPDRS motor part. In nine patients with early disease and without any antiparkinsonian medication the reduction in the [18F]β-CFT uptake (average of ipsilateral and contralateral side) was reduced in the total putamen to 34% of the mean control value (p<0.00001). The corresponding figures in the other brain areas were: posterior putamen 21% (p<0.00001), anterior putamen 43% (p<0.00001), and caudate nucleus 76% (p<0.01). The reductions in [18F]β-CFT uptake were more severe in the contralateral than in the ipsilateral side. Individually, [18F]β-CFT uptake in the putamen in all patients was below 3 SD from the control mean. 
CONCLUSIONS—[18F]β-CFT is a sensitive marker of nigrostriatal dopaminergic dysfunction in Parkinson's disease and can be used in the

  8. Potential of PET-MRI for imaging of non-oncologic musculoskeletal disease

    PubMed Central

    Fan, Audrey P.; Gold, Garry E.

    2016-01-01

    Early detection of musculoskeletal disease leads to improved therapies and patient outcomes, and would benefit greatly from imaging at the cellular and molecular level. As it becomes clear that assessment of multiple tissues and functional processes are often necessary to study the complex pathogenesis of musculoskeletal disorders, the role of multi-modality molecular imaging becomes increasingly important. New positron emission tomography-magnetic resonance imaging (PET-MRI) systems offer to combine high-resolution MRI with simultaneous molecular information from PET to study the multifaceted processes involved in numerous musculoskeletal disorders. In this article, we aim to outline the potential clinical utility of hybrid PET-MRI to these non-oncologic musculoskeletal diseases. We summarize current applications of PET molecular imaging in osteoarthritis (OA), rheumatoid arthritis (RA), metabolic bone diseases and neuropathic peripheral pain. Advanced MRI approaches that reveal biochemical and functional information offer complementary assessment in soft tissues. Additionally, we discuss technical considerations for hybrid PET-MR imaging including MR attenuation correction, workflow, radiation dose, and quantification. PMID:28090451

  9. Central nicotinic receptors: structure, function, ligands, and therapeutic potential.

    PubMed

    Romanelli, M Novella; Gratteri, Paola; Guandalini, Luca; Martini, Elisabetta; Bonaccini, Claudia; Gualtieri, Fulvio

    2007-06-01

    The growing interest in nicotinic receptors, because of their wide expression in neuronal and non-neuronal tissues and their involvement in several important CNS pathologies, has stimulated the synthesis of a high number of ligands able to modulate their function. These membrane proteins appear to be highly heterogeneous, and still only incomplete information is available on their structure, subunit composition, and stoichiometry. This is due to the lack of selective ligands to study the role of nAChR under physiological or pathological conditions; so far, only compounds showing selectivity between alpha4beta2 and alpha7 receptors have been obtained. The nicotinic receptor ligands have been designed starting from lead compounds from natural sources such as nicotine, cytisine, or epibatidine, and, more recently, through the high-throughput screening of chemical libraries. This review focuses on the structure of the new agonists, antagonists, and allosteric ligands of nicotinic receptors, it highlights the current knowledge on the binding site models as a molecular modeling approach to design new compounds, and it discusses the nAChR modulators which have entered clinical trials.

  10. Potential Applications of Using 68Ga-Evans Blue PET/CT in the Evaluation of Lymphatic Disorder: Preliminary Observations.

    PubMed

    Zhang, Wei; Wu, Peilin; Li, Fang; Tong, Guansheng; Chen, Xiaoyuan; Zhu, Zhaohui

    2016-04-01

    Potentials of 68Ga-NEB as a PET tracer in the evaluation of a variety of lymphatic drainage disorders were analyzed. 68Ga-NEB was injected subcutaneously, and the PET/CT images were acquired in 13 patients with different suspected lymphatic drainage abnormality. The 68Ga-NEB PET/CT findings were compared with Tc-SC lymphoscintigraphy. 68Ga-NEB activity could be clearly observed in the lymphatic route on the PET/CT images from all the patients. In 5 (38.5%) of 13 patients tested, 68Ga-NEB PET/CT provided more information than the Tc-SC lymphoscintigraphy. 68Ga-NEB PET/CT can be used as an alternative of Tc-SC lymphoscintigraphy in the evaluation of lymphatic disorders, which enables fast results and might be more accurate than the conventional Tc-SC lymphoscintigraphy.

  11. Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands.

    PubMed

    Salama, Ismail; Hocke, Carsten; Utz, Wolfgang; Prante, Olaf; Boeckler, Frank; Hübner, Harald; Kuwert, Torsten; Gmeiner, Peter

    2007-02-08

    Elucidation of the physiological role of the D3 receptor and its distribution in the brain using positron emission tomography (PET) is hampered by the lack of bioavailable subtype selective tracer ligands. To develop appropriate D3 radioligands, we designed an integrative procedure involving the elucidation of structural features determining D3 selectivity over both congeners D2 and D4 by comparative molecular analysis. Thus, we have successfully generated CoMFA and CoMSIA models based on the affinitiy differences of a series of 79 ligands representing a broad range of selectivities. These models yielded highly significant cross-validations (q2cv(D3/D2) = 0.86; q2cv(D3/D4) = 0.92) and excellent predictions of a 16-ligand test set (r2pred = 0.79-0.93). Exploiting this information, synthesis and receptor binding studies directed us to the fluorinated lead compounds 78 and 79, featuring subnanomolar D3 affinities and considerable selectivities over D2 and D4 and, subsequently, to the subtype selective PET tracers [18F]78 and [18F]79.

  12. (68)Ga-PSMA Ligand PET/CT-based Radiotherapy for Lymph Node Relapse of Prostate Cancer After Primary Therapy Delays Initiation of Systemic Therapy.

    PubMed

    Henkenberens, Christoph; VON Klot, Christoph A; Ross, Tobias L; Bengel, Frank M; Wester, Hans-Jürgen; Katja, Hüper; Christiansen, Hans; Derlin, Thorsten

    2017-03-01

    To evaluate (68)Ga-PSMA ligand positron-emission tomography-computed tomography (PET/CT)-based radiotherapy for lymph node metastases of prostate cancer after primary therapy. Twenty-three patients received radiotherapy for PSMA ligand-positive lymph node metastases. The median follow-up time was 12.4 (range=6.0-28.5) months. The median pre-treatment prostate-specific antigen (PSA) decreased from 2.75 (range=0.52-8.92) ng/ml to a nadir of 1.37 (range=0.11-8.00) ng/ml (p=0.001) following radiotherapy. Except for one patient (4.4%), PSA level decreased in 22 patients (95.6%). The biochemical failure-free survival and time to initiation of systemic therapy at the median follow-up were 95.6% and 100%, respectively. Three patients (12.9%) presented with recurrent disease outside the initial radiation field. No grade III acute toxicities or late grade II toxicities were observed. (68)Ga-PSMA ligand PET/CT-based radiotherapy is a promising local treatment option for isolated lymph node metastases of prostate cancer. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. PPARγ and Its Ligands: Potential Antitumor Agents in the Digestive System.

    PubMed

    Shu, Linjing; Huang, Renhuan; Wu, Songtao; Chen, Zhaozhao; Sun, Ke; Jiang, Yan; Cai, Xiaoxiao

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a versatile member of the ligand-activated nuclear hormone receptor superfamily of transcription factors, with expression in several different cell lines, especially in the digestive system. After being activated by its ligand, PPARγ can suppress the growth of oral, esophageal, gastric, colorectal, liver, biliary, and pancreatic tumor cells, suggesting that PPARγ ligand is a potential anticancer agent in PPARγ-expressing tumors. This review highlights key advances in understanding the effects of PPARγ ligands in the treatment of tumors in the digestive system.

  14. Ligand-supported homology modelling of protein binding-sites using knowledge-based potentials.

    PubMed

    Evers, Andreas; Gohlke, Holger; Klebe, Gerhard

    2003-11-21

    A new approach, MOBILE, is presented that models protein binding-sites including bound ligand molecules as restraints. Initially generated, homology models of the target protein are refined iteratively by including information about bioactive ligands as spatial restraints and optimising the mutual interactions between the ligands and the binding-sites. Thus optimised models can be used for structure-based drug design and virtual screening. In a first step, ligands are docked into an averaged ensemble of crude homology models of the target protein. In the next step, improved homology models are generated, considering explicitly the previously placed ligands by defining restraints between protein and ligand atoms. These restraints are expressed in terms of knowledge-based distance-dependent pair potentials, which were compiled from crystallographically determined protein-ligand complexes. Subsequently, the most favourable models are selected by ranking the interactions between the ligands and the generated pockets using these potentials. Final models are obtained by selecting the best-ranked side-chain conformers from various models, followed by an energy optimisation of the entire complex using a common force-field. Application of the knowledge-based pair potentials proved efficient to restrain the homology modelling process and to score and optimise the modelled protein-ligand complexes. For a test set of 46 protein-ligand complexes, taken from the Protein Data Bank (PDB), the success rate of producing near-native binding-site geometries (rmsd<2.0A) with MODELLER is 70% when the ligand restrains the homology modelling process in its native orientation. Scoring these complexes with the knowledge-based potentials, in 66% of the cases a pose with rmsd <2.0A is found on rank 1. Finally, MOBILE has been applied to two case studies modelling factor Xa based on trypsin and aldose reductase based on aldehyde reductase.

  15. Urokinase Plasminogen Activator Receptor-PET with (68)Ga-NOTA-AE105: First Clinical Experience with a Novel PET Ligand.

    PubMed

    Skovgaard, Dorthe; Persson, Morten; Kjaer, Andreas

    2017-07-01

    Urokinase plasminogen activator receptor (uPAR) is a key component in proteolysis and extracellular matrix degradation during cancer invasion and metastasis. uPAR overexpression is an important biomarker for aggressiveness in several solid tumors and provides independent clinical information. A recent major breakthrough was obtained with human translation of uPAR PET using (68)Ga-NOTA-AE105. Clinical results are encouraging and several large-scale clinical trials are now ongoing. This review focuses on uPAR PET with (68)Ga-NOTA-AE105 as a new broadly applicable diagnostic and prognostic imaging biomarker in cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. The synthesis and in vivo evaluation of [18F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH).

    PubMed

    Skaddan, Marc B; Zhang, Lei; Johnson, Douglas S; Zhu, Aijun; Zasadny, Kenneth R; Coelho, Richard V; Kuszpit, Kyle; Currier, Gwen; Fan, Kuo-Hsien; Beck, Elizabeth M; Chen, Laigao; Drozda, Susan E; Balan, Gayatri; Niphakis, Micah; Cravatt, Benjamin F; Ahn, Kay; Bocan, Thomas; Villalobos, Anabella

    2012-10-01

    Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo. We report here the synthesis and in vivo evaluation of [(18)F]PF-9811, a novel PET ligand for non-invasive imaging of FAAH in the brain. The potency and selectivity of unlabeled PF-9811 were determined by activity-based protein profiling (ABPP) both in vitro and in vivo. [(18)F]PF-9811 was synthesized in a 3-step, one-pot reaction sequence, followed by HPLC purification. Biological evaluation was performed by biodistribution and dynamic PET imaging studies in male rats. The specificity of [(18)F]PF-9811 uptake was evaluated by pre-administration of PF-04457845, a potent and selective FAAH inhibitor, 1h prior to radiotracer injection. Biodistribution studies show good uptake (SUV~0.8 at 90 min) of [(18)F]PF-9811 in rat brain, with significant reduction of the radiotracer in all brain regions (37%-73% at 90 min) in blocking experiments. Dynamic PET imaging experiments in rat confirmed the heterogeneous uptake of [(18)F]PF-9811 in brain regions with high FAAH enzymatic activity, as well as statistically significant reductions in signal following pre-administration of the blocking compound PF-04457845. [(18)F]PF-9811 is a promising PET imaging agent for FAAH. Biodistribution and PET imaging experiments show that the tracer has good uptake in brain, regional heterogeneity, and specific binding as determined by blocking experiments with the highly potent and selective FAAH inhibitor, PF-04457845. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Detection Efficacy of Hybrid (68)Ga-PSMA Ligand PET/CT in Prostate Cancer Patients with Biochemical Recurrence After Primary Radiation Therapy Defined by Phoenix Criteria.

    PubMed

    Einspieler, Ingo; Rauscher, Isabel; Düwel, Charlotte; Krönke, Markus; Rischpler, Christoph; Habl, Gregor; Dewes, Sabrina; Ott, Armin; Wester, Hans-Jürgen; Schwaiger, Markus; Maurer, Tobias; Eiber, Matthias

    2017-07-01

    The aim of this retrospective study was to evaluate the detection rate of Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)] ((68)Ga-PSMA ligand; PSMA is prostate-specific membrane antigen) PET/CT in patients with biochemical recurrent prostate cancer defined by Phoenix criteria after external-beam radiotherapy or brachytherapy as primary treatment. Methods: One hundred eighteen patients with a median prostate-specific antigen (PSA) of 6.4 ng/mL (range, 2.2-158.4 ng/mL; interquartile range, 4.2-10.2 ng/mL) were finally eligible for this retrospective analysis. Seventy-seven and 41 patients had been treated by external-beam radiotherapy or brachytherapy, respectively. Of the 118 patients, 45 were receiving androgen-deprivation therapy (ADT) within at least 6 mo before the PET/CT. The detection rates were stratified by PSA. The influence of primary Gleason score and ADT was assessed. Relationships between SUV and clinical as well as pathologic features in patients with positive findings were analyzed using univariate and multivariable linear regression models. Results: One hundred seven of 118 patients (90.7%) showed pathologic findings indicative for tumor recurrence in (68)Ga-PSMA ligand PET/CT. The detection rates were 81.8% (36/44), 95.3% (41/43), and 96.8% (30/31) for PSA of 2 to <5, 5 to <10, and ≥10 ng/mL, respectively (P = 0.0377). (68)Ga-PSMA ligand PET/CT indicated local recurrence in 68 of 107 patients (63.5%), distant lesions in 64 of 107 patients (59.8%), and local recurrence as well as distant lesions in 25 of 107 patients (23.4%). The detection rate was significantly higher in patients with ADT (97.7%) versus without ADT (86.3%, P = 0.0381), but independent from primary Gleason score ≥ 8 (92.0%) versus ≤ 7 (90.2%, P = 0.6346). SUVmax and SUVmean were significantly associated with PSA and ADT (P = 0.018 and 0.004 for SUVmax, respectively; P = 0.025 and 0.007 for SUVmean, respectively). Conclusion:(68)Ga-PSMA ligand PET/CT demonstrates high detection rates

  18. Electron capture by the thiyl radical and disulfide bond: ligand effects on the reduction potential.

    PubMed

    Roos, Goedele; De Proft, Frank; Geerlings, Paul

    2013-04-15

    The effect of non-polar and polar ligands and of monovalent cations on the one-electron reduction potential of the thiyl radical and the disulfide bond was evaluated. The reduction potentials E° for the CH3S(.)-nL/CH3S(-)-nL and CH3SSCH3-L/CH3SSCH3(.-)-L redox couples were calculated at the B3LYP, M06-2X and MP2 levels of theory, with n=1, 2 and L=CH4, C2H4, H2O, CH3OH, NH3, CH3COOH, CH3CONH2, NH4(+), Na(+), K(+) and Li(+). Non-polar ligands decrease the E° value of the thiyl radical and disulfide bond, while neutral polar ligands favour electron uptake. Charged polar ligands and cations favour electron capture by the thiyl radical while disfavouring electron uptake by the disulfide bond. Thus, the same type of ligand can have a different effect on E° depending on the redox couple. Therefore, properties of an isolated ligand cannot uniquely determine E°. The ligand effects on E° are discussed in terms of the vertical electron affinity and reorganization energy, as well as molecular orbital theory. For a given redox couple, the ligand type influences the nature of the anion formed upon electron capture and the corresponding reorganization process towards the reduced geometry.

  19. New multifunctional ligands for potential use in the design therapeutic or diagnostic radiopharmaceutical imaging agents

    DOEpatents

    Katti, Kattesh V.; Volkert, Wynn A.; Ketring, Alan R.; Singh, Prahlad R.

    1997-01-01

    A class of diagnostic and therapeutic compounds derived from phosphinimines that include ligands containing either a single phosphinimine functionality or both a phosphinimine group and a phosphine or arsine group, or an aminato group, or a second phosphinimine moiety. These phosphinimine ligands are complexed to early transition metal radionuclides (e.g. .sup.99m Tc or .sup.186 Re/.sup.188 Re) or late transition metals (e.g., .sup.105 Rh or .sup.109 Pd). The complexes with these metals .sup.186 Re/.sup.188 Re, .sup.99m Tc and .sup.109 Pd exhibit a high in vitro and high in vivo stability. The complexes are formed in high yields and can be neutral or charged. These ligands can also be used to form stable compounds with paramagnetic transition metals (e.g. Fe and Mn) for potential use as MRI contrast agents. Applications for the use of ligands and making the ligands are also disclosed.

  20. Potential ligand-binding residues in rat olfactory receptors identified by correlated mutation analysis

    NASA Technical Reports Server (NTRS)

    Singer, M. S.; Oliveira, L.; Vriend, G.; Shepherd, G. M.

    1995-01-01

    A family of G-protein-coupled receptors is believed to mediate the recognition of odor molecules. In order to identify potential ligand-binding residues, we have applied correlated mutation analysis to receptor sequences from the rat. This method identifies pairs of sequence positions where residues remain conserved or mutate in tandem, thereby suggesting structural or functional importance. The analysis supported molecular modeling studies in suggesting several residues in positions that were consistent with ligand-binding function. Two of these positions, dominated by histidine residues, may play important roles in ligand binding and could confer broad specificity to mammalian odor receptors. The presence of positive (overdominant) selection at some of the identified positions provides additional evidence for roles in ligand binding. Higher-order groups of correlated residues were also observed. Each group may interact with an individual ligand determinant, and combinations of these groups may provide a multi-dimensional mechanism for receptor diversity.

  1. Potential ligand-binding residues in rat olfactory receptors identified by correlated mutation analysis

    NASA Technical Reports Server (NTRS)

    Singer, M. S.; Oliveira, L.; Vriend, G.; Shepherd, G. M.

    1995-01-01

    A family of G-protein-coupled receptors is believed to mediate the recognition of odor molecules. In order to identify potential ligand-binding residues, we have applied correlated mutation analysis to receptor sequences from the rat. This method identifies pairs of sequence positions where residues remain conserved or mutate in tandem, thereby suggesting structural or functional importance. The analysis supported molecular modeling studies in suggesting several residues in positions that were consistent with ligand-binding function. Two of these positions, dominated by histidine residues, may play important roles in ligand binding and could confer broad specificity to mammalian odor receptors. The presence of positive (overdominant) selection at some of the identified positions provides additional evidence for roles in ligand binding. Higher-order groups of correlated residues were also observed. Each group may interact with an individual ligand determinant, and combinations of these groups may provide a multi-dimensional mechanism for receptor diversity.

  2. Therapeutic potential of neuropeptide Y (NPY) receptor ligands

    PubMed Central

    Brothers, Shaun P; Wahlestedt, Claes

    2010-01-01

    Neuropeptide Y (NPY) is widely distributed in the human body and contributes to a vast number of physiological processes. Since its discovery, NPY has been implicated in metabolic regulation and, although interest in its role in central mechanisms related to food intake and obesity has somewhat diminished, the topic remains a strong focus of research concerning NPY signalling. In addition, a number of other uses for modulators of NPY receptors have been implied in a range of diseases, although the development of NPY receptor ligands has been slow, with no clinically approved receptor therapeutics currently available. Nevertheless, several interesting small molecule compounds, notably Y2 receptor antagonists, have been published recently, fueling optimism in the field. Herein we review the role of NPY in the pathophysiology of a number of diseases and highlight instances where NPY receptor signalling systems are attractive therapeutic targets. PMID:20972986

  3. Specific, reversible binding of [18F]benperidol to baboon D2 receptors: PET evaluation of an improved 18F-labeled ligand.

    PubMed

    Moerlein, S M; Perlmutter, J S; Welch, M J

    1995-08-01

    [18F]Benperidol ([18F]BP), a positron-emitting analogue of the dopaminergic D2 antagonist benperidol, was evaluated as a radiopharmaceutical for use with positron emission tomography (PET). PET imaging of baboons after i.v. injection of [18F]BP indicated that the radiofluorinated ligand rapidly localized in vivo within dopaminergic receptor-rich cerebral tissues, and that selective disposition was retained for over 2 h. Pretreatment of an animal with unlabeled receptor-specific antagonists prior to injection of [18F]BP confirmed that the radioligand bound specifically to central D2 receptors in vivo, and not to S2 or D1 receptors. [18F]BP bound to D2 receptors in a reversible manner; unlabeled eticlopride displaced D2 receptor-bound [18F]BP in vivo. The radioligand was metabolized in the periphery to polar metabolites which are not expected to cross the blood-brain barrier. [18F]BP has advantages over other tracers as a radiopharmaceutical for PET study of central D2 receptor activity, and can be applied for noninvasive evaluation of the interaction of unlabeled drugs with central D2 receptor sites.

  4. Evoked Potentials and Neuropsychological Tests Validate Positron Emission Topography (PET) Brain Metabolism in Cognitively Impaired Patients

    PubMed Central

    Braverman, Eric R.; Blum, Kenneth; Damle, Uma J.; Kerner, Mallory; Dushaj, Kristina; Oscar-Berman, Marlene

    2013-01-01

    Fluorodeoxyglucose (FDG) Positron Emission Topography (PET) brain hypometabolism (HM) correlates with diminished cognitive capacity and risk of developing dementia. However, because clinical utility of PET is limited by cost, we sought to determine whether a less costly electrophysiological measure, the P300 evoked potential, in combination with neuropsychological test performance, would validate PET HM in neuropsychiatric patients. We found that patients with amnestic and non-amnestic cognitive impairment and HM (n = 43) evidenced significantly reduced P300 amplitudes, delayed latencies, and neuropsychological deficits, compared to patients with normal brain metabolism (NM; n = 187). Data from patients with missing cognitive test scores (n = 57) were removed from the final sample, and logistic regression modeling was performed on the modified sample (n = 173, p = .000004). The logistic regression modeling, based on P300 and neuropsychological measures, was used to validate membership in the HM vs. NM groups. It showed classification validation in 13/25 HM subjects (52.0%) and in 125/148 NM subjects (84.5%), correlating with total classification accuracy of 79.8%. In this paper, abnormal P300 evoked potentials coupled with cognitive test impairment validates brain metabolism and mild/moderate cognitive impairment (MCI). To this end, we cautiously propose incorporating electrophysiological and neuropsychological assessments as cost-effective brain metabolism and MCI indicators in primary care. Final interpretation of these results must await required additional studies confirming these interesting results. PMID:23526928

  5. Potential Role of Pet Cats As a Sentinel Species for Human Exposure to Flame Retardants

    PubMed Central

    Henríquez-Hernández, Luis A.; Carretón, Elena; Camacho, María; Montoya-Alonso, José Alberto; Boada, Luis D.; Bernal Martín, Verónica; Falcón Cordón, Yaiza; Falcón Cordón, Soraya; Zumbado, Manuel; Luzardo, Octavio P.

    2017-01-01

    Flame retardants are a wide group of chemicals used by the industry to avoid combustion of materials. These substances are commonly found in plastics, electronic equipment, fabrics, and in many other everyday articles. Subsequently, ubiquitous environmental contamination by these common chemical is frequently reported. In the present study, we have evaluated the level of exposure to polychlorinated biphenyls (PCBs), brominated diphenyl ethers (BDEs), and organophosphorous flame retardants (OPFRs) in pet cats through the analysis of their serum. We also analyzed the level exposure to such chemicals in a series of 20 cat owners, trying to disclose the role of pet cats as sentinel species of human exposure to FRs. Our results showed that PCBs, banned 40 years ago, showed the lowest levels of exposure, followed by BDEs—banned recently. Congeners PCB-138 and PCB-180 were detected in ≥50% of the series, while BDE-47 was detected in near 90% of the pet cats. On the other hand, the highest levels were that of OPFRs, whose pattern of detection was similar to that observed in humans, thus suggesting a potential role of cats as a sentinel species for human exposure to these currently used FRs. Six out of 11 OPFRs determined [2-ethylhexyldiphenyl phosphate, tributylphosphate, triisobutylphosphate, triphenylphosphate, tris (2-chloroethyl) phosphate, and tris (2-chloroisopropyl) phosphate] were detected in 100% of the samples. It will be interesting to perform future studied aimed to elucidating the potential toxicological effects of these highly detected chemicals both, in cats and humans. PMID:28620612

  6. Combined (18)F-Fluciclovine PET/MRI shows potential for detection and characterization of high-risk prostate cancer.

    PubMed

    Elschot, Mattijs; Selnæs, Kirsten M; Sandsmark, Elise; Krüger-Stokke, Brage; Størkersen, Øystein; Giskeødegård, Guro F; Tessem, May-Britt; Moestue, Siver A; Bertilsson, Helena; Bathen, Tone F

    2017-10-06

    The objective of this study is to investigate if quantitative imaging features derived from combined (18)F-Fluciclovine Positron Emission Tomograpy (PET) / multiparametric Magnetic Resonance Imaging (MRI) show potential for detection and characterization of primary prostate cancer. Methods: Twenty-eight (28) patients diagnosed with high-risk prostate cancer underwent simultaneous (18)F-Fluciclovine PET/MRI before radical prostatectomy. Volumes-of-interest (VOIs) of prostate tumors, benign prostatic hyperplasia (BPH) nodules, prostatitis, and healthy tissue were delineated on T2-weighted images using histology as a reference. Tumor VOIs were marked as high-grade (≥ Gleason Grade group 3) or not. MRI and PET features were extracted on the voxel and VOI-level. Partial least-squared discriminant analysis (PLS-DA) with double leave-one-patient-out cross validation was performed to classify tumor from benign tissue (BPH, prostatitis, healthy tissue) and high-grade tumor from other tissue (low-grade tumor, benign tissue). The performances of PET, MRI, and combined PET/MRI features were compared using the area under the receiver operating characteristic curve (AUC). Results: Voxel and VOI features were extracted from 40 tumor (26 high-grade), 36 BPH, 6 prostatitis, and 37 healthy tissue VOIs. PET/MRI performed better than MRI and PET for classification of tumor vs benign tissue (voxel: AUC 87%, 81%, and 83%; VOI: AUC 96%, 93%, and 93%, respectively) and high-grade tumor vs other tissue (voxel: AUC 85%, 79%, and 81%; VOI: AUC 93%, 93%, and 91%, respectively). T2-weighted MRI, diffusion-weighted MRI and PET features were most important for classification. Conclusion: Combined (18)F-Fluciclovine PET/multiparametric MRI shows potential for improving detection and characterization of high-risk prostate cancer, in comparison to MRI and PET alone. Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  7. Designing and Developing PET-Based Precision Model in Thyroid Carcinoma: The Potential Avenues for a Personalized Clinical Care.

    PubMed

    Basu, Sandip; Parghane, Rahul Vithalrao

    2017-01-01

    This communication enumerates the current uses and potential areas where PET could be clinically utilized for developing "precision medicine" type model in thyroid carcinoma. (1) In routine clinics, PET imaging (with fluorodeoxyglucose [FDG]) is utilized to investigate patients of differentiated thyroid carcinoma (DTC) with high thyroglobulin and negative iodine scintigraphy (TENIS) and in medullary carcinoma thyroid (MCT) when the tumor markers (eg, calcitonin and carcino embryonic antigen [CEA]) are raised postoperatively (PET with FDG, (68)Ga-DOTA-NOC/TATE, FDOPA). Both are examples of management personalization, where PET-computed tomography (CT) has been found substantially useful in detecting sites of metastatic disease and making decision with regard to feasibility and planning of surgery on an individual patient basis. (2) The next important area of management personalization is in patients of TENIS with metastatic disease not amenable to surgery through examining FDG-PET findings in tandem with radio iodine scan and (68)Ga-DOTA-TATE/NOC PET/CT. Heterogeneous behavior of the metastatic lesions is frequently observed clinically: analyzing the findings of three studies aids in sub-segmenting patients into subgroups and thereby deciding upon the best approach (observation with LT4 suppression vs PRRT vs tyrosine kinase inhibitors) that could be individualized in a given case. (3) In metastatic/inoperable MCT, (68)Ga-DOTA-TATE/NOC PET-CT helps in deciding upon feasibility of targeted PRRT in an individual patient and helps in follow-up and response evaluation. (4) Disease prognostification with FDG-PET is evolving both in DTC and MCT, where FDG avidity would indicate an aggressive biology, though the implication of this from treatment viewpoint is unclear at this point. Conversely, a negative FDG-PET in DTC and TENIS would suggest a favorable prognosis in an individual. (5) Iodine-124 PET/CT has the added potential of obtaining lesional dosimetry compared to

  8. Prospects for vaccination against the ticks of pets and the potential impact on pathogen transmission.

    PubMed

    de la Fuente, José; Villar, Margarita; Contreras, Marinela; Moreno-Cid, Juan A; Merino, Octavio; Pérez de la Lastra, José M; de la Fuente, Gabriela; Galindo, Ruth C

    2015-02-28

    Diseases transmitted by arthropod vectors such as ticks greatly impact human and animal health. In particular, many diseases of dogs and cats are potentially transmissible to people by arthropod vectors and therefore their control is important for the eradication of vector-borne diseases (VBD). Vaccination is an environmentally friendly alternative for vector control that allows control of several VBD by targeting their common vector. Recent results have shown that it is possible to use vector protective antigens for the control of arthropod vector infestations and pathogen infection. However, as reviewed in this paper, very little progress has been made for the control of ectoparasite infestations and VBD in pets using vaccination with vector protective antigens. The growing interaction between pets and people underlines the importance of developing new interventions for the monitoring and control of VBD. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Development of bimetallic (Zn@Au) nanoparticles as potential PET-imageable radiosensitizers.

    PubMed

    Cho, Jongmin; Wang, Min; Gonzalez-Lepera, Carlos; Mawlawi, Osama; Cho, Sang Hyun

    2016-08-01

    . The Monte Carlo results showed that radioactive Zn@Au NPs and solid GNPs provided similar characteristics in terms of their secondary electron spectra when irradiated. The Zn@Au NPs developed in this investigation have the potential to be used as PET-imageable radiosensitizers for radiotherapy applications as well as PET tracers for molecular imaging applications.

  10. Development of bimetallic (Zn@Au) nanoparticles as potential PET-imageable radiosensitizers

    PubMed Central

    Cho, Jongmin; Wang, Min; Gonzalez-Lepera, Carlos; Mawlawi, Osama; Cho, Sang Hyun

    2016-01-01

    mostly decaying 66Ga. The Monte Carlo results showed that radioactive Zn@Au NPs and solid GNPs provided similar characteristics in terms of their secondary electron spectra when irradiated. Conclusions: The Zn@Au NPs developed in this investigation have the potential to be used as PET-imageable radiosensitizers for radiotherapy applications as well as PET tracers for molecular imaging applications. PMID:27487895

  11. A group of thermodynamic potentials applicable to ligand binding by a polyfunctional macromolecule.

    PubMed Central

    Wyman, J

    1975-01-01

    The binding of ligands by a macromolecule can be well described by a group of potentials derivable from the energy and of which the original binding potential is one. The group is Abelian and is isomorphic with a group of symmetries. Each member corresponds to a particular set of experimental conditions--system open to some, closed to others, of the ligand-and the group as a whole is an immediate source of all possible linkage relations applicable to the macromolecule. Seen in terms of information theory it can be interpreted as a program for the response of the macromolecule to its ligands according to the conditions with which it is faced. The group provides a ready formulation of the effect of a ligand on the equilibrium constant for a reaction involving a set of macromolecules, and it leads to a clear-cut distinction between true and pseudolinkage. PMID:1055419

  12. Assessing potential peptide targeting ligands by quantification of cellular adhesion of model nanoparticles under flow conditions.

    PubMed

    Broda, Ellen; Mickler, Frauke Martina; Lächelt, Ulrich; Morys, Stephan; Wagner, Ernst; Bräuchle, Christoph

    2015-09-10

    Sophisticated drug delivery systems are coated with targeting ligands to improve the specific adhesion to surface receptors on diseased cells. In our study, we developed a method with which we assessed the potential of peptide ligands to specifically bind to receptor overexpressing target cells. Therefore, a microfluidic setup was used where the cellular adhesion of nanoparticles with ligand and of control nanoparticles was observed in parallel under the same experimental conditions. The effect of the ligand on cellular binding was quantified by counting the number of adhered nanoparticles with ligand and differently labeled control nanoparticles on single cells after incubation under flow conditions. To provide easy-to-synthesize, stable and reproducible nanoparticles which mimic the surface characteristics of drug delivery systems and meet the requirements for quantitative analysis, latex beads based on amine-modified polystyrene were used as model nanoparticles. Two short peptides were tested to serve as targeting ligand on the beads by increasing the specific binding to HuH7 cells. The c-Met binding peptide cMBP2 was used for hepatocyte growth factor receptor (c-Met) targeting and the peptide B6 for transferrin receptor (TfR) targeting. The impact of the targeting peptide on binding was investigated by comparing the beads with ligand to different internal control beads: 1) without ligand and tailored surface charge (electrostatic control) and 2) with scrambled peptide and similar surface charge, but a different amino acid sequence (specificity control). Our results demonstrate that the method is very useful to select suitable targeting ligands for specific nanoparticle binding to receptor overexpressing tumor cells. We show that the cMBP2 ligand specifically enhances nanoparticle adhesion to target cells, whereas the B6 peptide mediates binding to tumor cells mainly by nonspecific interactions. All together, we suggest that cMBP2 is a suitable choice for

  13. Cryptosporidium spp. in pet birds: genetic diversity and potential public health significance.

    PubMed

    Qi, Meng; Wang, Rongjun; Ning, Changshen; Li, Xiaoyu; Zhang, Longxian; Jian, Fuchun; Sun, Yanru; Xiao, Lihua

    2011-08-01

    To characterize the prevalence and assess the zoonotic transmission burden of Cryptosporidium species/genotypes in pet birds in Henan, China, 434 fecal samples were acquired from 14 families of birds in pet shops. The overall prevalence of Cryptopsoridium was 8.1% (35/434) by the Sheather's sugar flotation technique. The Cryptosporidium-positive samples were analyzed by DNA sequence analysis of the small subunit (SSU) rRNA gene. Three Cryptosporidium species and two genotypes were identified, including C. baileyi (18/35 or 51.4%) in five red-billed leiothrixes (Leiothrix lutea), four white Java sparrows (Padda oryzivora), four common mynas (Acridotheres tristis), two zebra finches (Taeniopygia guttata), a crested Lark (Galerida cristata), a Gouldian finch (Chloebia gouldiae), and a black-billed magpie (Pica pica); Cryptosporidium meleagridis (3/35 or 8.6%) in a Bohemian waxwing (Bombycilla garrulus), a Rufous turtle dove (Streptopelia orientalis), and a fan-tailed pigeon (Columba livia); Cryptosporidium galli (5/35 or 14.3%) in four Bohemian waxwings (Bombycilla garrulus) and a silver-eared Mesia (Leiothrix argentauris); Cryptosporidium avian genotype III (3/35 or 8.6%) in two cockatiels (Nymphicus hollandicus) and a red-billed blue magpie (Urocissa erythrorhyncha); and Cryptosporidium avian genotype V (6/35 or 17.1%) in six cockatiels (Nymphicus hollandicus). Among the pet birds, 12 species represented new hosts for Cryptosporidum infections. The presence of C. meleagridis raises questions on potential zoonotic transmission of cryptosporidiosis from pet birds to humans. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds specifically to microglia in a rat model of traumatic brain injury: implications for PET imaging

    PubMed Central

    Venneti, Sriram; Wagner, Amy K.; Wang, Guoji; Slagel, Susan L.; Chen, Xiangbai; Lopresti, Brian J.; Mathis, Chester A.; Wiley., Clayton A.

    2007-01-01

    Traumatic brain injury (TBI) is a significant cause of mortality, morbidity, and disability. Microglial activation is commonly observed in response to neuronal injury which, when prolonged, is thought to be detrimental to neuronal survival. Activated microglia can be labeled using PK11195, a ligand that bind the peripheral benzodiazepine receptor (PBR), receptors which are highly expressed in activated microglia and sparse in the resting brain. We compared the binding properties of two PBR ligands PK11195 and DAA1106 in rats using the controlled cortical impact (CCI) model of experimental TBI. While both ligands showed relative increases with specific binding in the cortex ipsilateral to injury compared to the contralateral side, [3H]DAA1106 showed higher binding affinity compared with [3H](R)-PK11195. Combined immunohistochemistry and autoradiography in brain tissues near the injury site showed that [3H]DAA1106 binding co-registered with activated microglia more than astrocytes. Further, increased [3H]DAA1106 specific binding positively correlated with degree of microglial activation, and to a lesser degree with reactive astrocytosis. Finally, in vivo administration of each ligand in rats with TBI showed greater retention of [11C]DAA1106 compared to [11C](R)-PK11195 at the site of the contusion as assessed by ex vivo autoradiography. These results in a rat model of TBI indicate that [11C]DAA1106 binds with higher affinity to microglia when compared with PK11195, suggesting that [11C]DAA1106 may represent a better ligand than [11C](R)-PK11195 for in vivo PET imaging of activated microglia in TBI. PMID:17658516

  15. Exploring the potential of protein-based pharmacophore models in ligand pose prediction and ranking

    PubMed Central

    Hu, Bingjie; Lill, Markus A.

    2013-01-01

    Protein-based pharmacophore models derived from the protein binding site atoms without the inclusion of any ligand information have become more popular in virtual screening studies. However, the accuracy of protein-based pharmacophore models for reproducing the critical protein-ligand interactions has never been explicitly assessed. In this study, we used known protein-ligand contacts from a large set of experimentally determined protein-ligand complexes to assess the quality of the protein-based pharmacophores in reproducing these critical contacts. We demonstrate how these contacts can be used to optimize the pharmacophore generation procedure to produce pharmacophore models that optimally cover the known protein-ligand interactions. Finally, we explored the potential of the optimized protein-based pharmacophore models for pose prediction and pose rankings. Our results demonstrate that there are significant variations in the success of protein-based pharmacophore models to reproduce native contacts and consequently native ligand poses dependent on the details of the pharmacophore-generation process. We show that the generation of optimized protein-based pharmacophore models is a promising approach for ligand pose prediction and pose rankings. PMID:23621564

  16. The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions.

    PubMed

    Afshar-Oromieh, Ali; Hetzheim, Henrik; Kratochwil, Clemens; Benesova, Martina; Eder, Matthias; Neels, Oliver C; Eisenhut, Michael; Kübler, Wolfgang; Holland-Letz, Tim; Giesel, Frederik L; Mier, Walter; Kopka, Klaus; Haberkorn, Uwe

    2015-11-01

    PET imaging with the prostate-specific membrane antigen (PSMA)-targeted radioligand (68)Ga-PSMA-11 is regarded as a significant step forward in the diagnosis of prostate cancer (PCa). More recently, a PSMA ligand was developed that can be labeled with (68)Ga, (111)In, (177)Lu, and (90)Y. This ligand, named PSMA-617, therefore enables both diagnosis and therapy of PCa. The aims of this evaluation were to clinically investigate the distribution of (68)Ga-PSMA-617 in normal tissues and in PCa lesions as well as to evaluate the radiation exposure by the radioligand in PET imaging. Nineteen patients, most of them with recurrent PCa, were referred for (68)Ga-PSMA-617 PET/CT. The quantitative assessment of tracer uptake of several organs and of 53 representative tumor lesions was performed in 15 patients at 1 and 3 h after injection. In 4 additional patients, the same procedure was conducted at 5 min, 1 h, 2 h, 3 h, 4 h, and 5 h after injection. On the basis of the data for these 4 patients (mean injected dose, 231 MBq), the radiation exposure of a (68)Ga-PSMA-617 PET/CT was identified. Intense tracer uptake was observed in the kidneys and salivary glands. In 14 of 19 patients (73.7%), at least 1 lesion suspected of being a tumor was detected at 3 h after injection. Of 53 representative tumor lesions selected at 3 h after injection, 47 lesions were visible at 1 h after injection. The mean tumor-to-background ratio for maximum standardized uptake value was 20.4 ± 17.3 (range, 2.3-84.0) at 1 h after injection and 38.2 ± 38.6 (range, 3.6-154.3) at 3 h after injection. The average radiation exposure (effective dose) was approximately 0.021 mSv/MBq. Within healthy organs, the kidneys and salivary glands showed the highest (68)Ga-PSMA-617 uptake. The radiation exposure was relatively low. (68)Ga-PSMA-617 shows PCa lesions with high contrast. Images obtained between 2 and 3 h after injection seem to be the best option with regard to radiotracer uptake and tumor contrast. Later

  17. Soluble Fas Ligand as a Potential Marker of Severity of Dengue Infection

    PubMed Central

    Zain, Nurfadly; Putra, Suhartono Taat; Zein, Umar; Hariman, Herman

    2017-01-01

    Background The apoptosis of microvascular endothelial cells causes plasma leakage in dengue haemorrhagic fever patients. The soluble Fas ligand is a protein with molecular weight of 40 kDa that acts as a mediator of apoptosis. This study aimed to prove whether soluble Fas ligand can be used as a potential marker to predict the severity of dengue infection by comparing the soluble Fas ligand levels in dengue fever (DF) and dengue haemorrhagic fever (DHF) patients early in the course of illness. Method This was a prospective study. It included 42 dengue patients (22 DF patients and 20 DHF patients) and 20 healthy people as a control group. The soluble Fas ligand was measured by the enzyme-linked immunosorbent assay (ELISA). Result Soluble Fas ligand was increased significantly (P < 0.001) in DHF patients (median = 130.19, IQR = 36.26) compared to DF patients (median = 104.73, IQR = 53.94) and the control group (median = 87.16, IQR = 24.91). Conclusion Soluble Fas ligand can be used as a potential marker to predict the severity of dengue infection in the early course of the illness. However, a larger sample size and further objective studies are needed to confirm these findings. PMID:28894401

  18. Soluble Fas Ligand as a Potential Marker of Severity of Dengue Infection.

    PubMed

    Zain, Nurfadly; Putra, Suhartono Taat; Zein, Umar; Hariman, Herman

    2017-03-01

    The apoptosis of microvascular endothelial cells causes plasma leakage in dengue haemorrhagic fever patients. The soluble Fas ligand is a protein with molecular weight of 40 kDa that acts as a mediator of apoptosis. This study aimed to prove whether soluble Fas ligand can be used as a potential marker to predict the severity of dengue infection by comparing the soluble Fas ligand levels in dengue fever (DF) and dengue haemorrhagic fever (DHF) patients early in the course of illness. This was a prospective study. It included 42 dengue patients (22 DF patients and 20 DHF patients) and 20 healthy people as a control group. The soluble Fas ligand was measured by the enzyme-linked immunosorbent assay (ELISA). Soluble Fas ligand was increased significantly (P < 0.001) in DHF patients (median = 130.19, IQR = 36.26) compared to DF patients (median = 104.73, IQR = 53.94) and the control group (median = 87.16, IQR = 24.91). Soluble Fas ligand can be used as a potential marker to predict the severity of dengue infection in the early course of the illness. However, a larger sample size and further objective studies are needed to confirm these findings.

  19. Diagnostic Accuracy of Ga-68-HBED-CC-PSMA-Ligand-PET/CT before Salvage Lymph Node Dissection for Recurrent Prostate Cancer.

    PubMed

    Jilg, Cordula A; Drendel, Vanessa; Rischke, H Christian; Beck, Teresa; Vach, Werner; Schaal, Kathrin; Wetterauer, Ulrich; Schultze-Seemann, Wolfgang; Meyer, Philipp T

    2017-01-01

    Background: By targeting the prostate-specific membrane antigen (PSMA) on prostate cancer (PCa) cells PSMA-PET/CT shows great potential in locating the site of biochemical recurrence even at low PSA (Prostate-specific antigen)-levels. Accurate imaging of PCa recurrent lymph node metastases (LNM) is crucial for metastases directed therapies such as salvage-lymph node dissection (salvage-LND). Objective: To evaluate the diagnostic accuracy of PSMA-PET/CT for detection of affected lymph-node regions at salvage-LND for nodal recurrence of PCa. Design, setting and participants: 30 patients with the suspicion of exclusively nodal PCa-relapse after primary therapy underwent a template pelvic and/or retroperitoneal salvage-LND after whole body 68-Ga-PSMA-PET/CT. The diagnostic accuracy of PET/CT was evaluated in comparison to the histopathology of 965 resected lymph nodes (LN) dissected from 68 main regions (pelvic left/right, retroperitoneal) and 289 subregions (common iliac, external iliac, obturator, internal iliac, presacral, aortic-bifurcation, aortal, caval). LNM and tumor deposits in LNM were measured bidimensionally in the histopathology. PSMA-expression was analyzed by immunohistochemistry in LNM. Results: LNM were present in 11.4% of the resected LN (110/965) resulting in 45 positive main regions and 85 positive subregions. PET/CT was true positive in 41 main regions and 69 subregions. Three PET-negative main regions and 16 PET-negative subregions finally contained LNM, the majority of these false negative subregions (13/16) were in neighboring regions of true-positive subregions. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were: main region-based 93.2%, 100%, 100%, 88.9% and 95.6%, subregion-based 81.2%, 99.5%, 98.6%, 92.7 and 94.1%. Median short diameters of tumor deposits in LNM resected from false-negative subregions (1.3 mm) were significantly smaller than in LNM removed from true-positive subregions (5.5 mm, p

  20. Single-step High-yield Radiosynthesis and Evaluation of a Sensitive 18F-Labeled Ligand for Imaging Brain Peripheral Benzodiazepine Receptors with PET

    PubMed Central

    Briard, Emmanuelle; Zoghbi, Sami S.; Siméon, Fabrice G.; Imaizumi, Masao; Gourley, Jonathan P.; Shetty, H. Umesha; Lu, Shuiyu; Fujita, Masahiro; Innis, Robert B.; Pike, Victor W.

    2009-01-01

    Elevated levels of peripheral benzodiazepine receptors (PBR) are associated with activated microglia in their response to inflammation. Hence, PBR imaging in vivo is valuable for investigating brain inflammatory conditions. Sensitive, easily prepared and readily available radioligands for imaging with positron emission tomography (PET) are desirable for this purpose. We describe a new 18F-labeled PBR radioligand, namely [18F]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline ([18F]9). [18F]9 was produced easily through a single and highly efficient step, the reaction of [18F]fluoride ion with the corresponding bromo precursor, 8. Ligand 9 exhibited high affinity for PBR in vitro. PET showed that [18F]9 was avidly taken into monkey brain and gave a high ratio of PBR-specific to nonspecific binding. [18F]9 was devoid of defluorination in rat and monkey and gave predominantly polar radiometabolite(s). In rat, a low level radiometabolite of intermediate lipophilicity was identified as [18F]2-fluoro-N-(2-phenoxyphenyl)acetamide ([18F]11). [18F]9 is a promising radioligand for future imaging of PBR in living human brain. PMID:19119848

  1. Potential Toxicity of Up-Converting Nanoparticles Encapsulated with a Bilayer Formed by Ligand Attraction

    PubMed Central

    2015-01-01

    The cellular toxicity of nanoparticles that were capped with a bilayered ligand was studied using an up-converting (UC) phosphor material as a representative nanoparticle (NP). The results indicate that although UC NPs are known to be nontoxic, the toxicity of the NPs depends strongly on ligand coordination conditions, in addition to the other commonly known parameters such as size, structure, surface charge etc. Oleate-capped hydrophobic NaYF4:Yb,Er NPs were surface modified to yield three extreme conditions: bare particles that were stripped of the oleate ligands; particles with covalently bound poly(ethylene glycol) (PEG) ligands; and particles with an bilayer of PEG-oleate ligands using the oleate surface group that was remained after synthesis. It was found that the bare particles and the covalent PEG NPs induced little toxicity. However, particles that were rendered biocompatible by forming a bilayer with an amphiphilic ligand (i.e., PEG-oleate) resulted in significant cell toxicity. These findings strongly suggest that the PEG-oleate group dissociated from the bilayered oleate-capped NPs, resulting in significant toxicity by exposing the hydrophobic oleate-capped NPs to the cell. Based on results with bare particles, the NaLnF4:Yb,Er (Ln = Y, Gd) up-converting phosphors are essentially less-toxic. Capping and functionalizing these particles with ligand intercalation may, however, not be a suitable method for rendering the NPs suitable for bioapplication as the ligand can potentially dissociate upon cellular interaction, leading to significant toxicity. PMID:24971524

  2. Phthalocyanines: a new class of G-quadruplex-ligands with many potential applications.

    PubMed

    Yaku, Hidenobu; Fujimoto, Takeshi; Murashima, Takashi; Miyoshi, Daisuke; Sugimoto, Naoki

    2012-06-25

    A G-quadruplex is a four-stranded DNA structure featuring stacked guanine tetrads, G-quartets. Formation of a G-quadruplex in telomere DNA can inhibit telomerase activity; therefore, development of G-quadruplex-ligands, which induce and/or stabilize G-quadruplexes, has become an area of great interest. Phthalocyanine derivatives have substantial potential as high-affinity G-quadruplex-ligands because these planar chromophores are similar in size and shape to the G-quartets. Here, we focus on the latest findings on phthalocyanine derivatives as G-quadruplex-ligands, and discuss the mechanisms by which phthalocyanines bind to G-quadruplexes with high affinity and selectivity. We also discuss potential biomedical and organic electronic applications of phthalocyanines that are dependent on their photophysical properties.

  3. Discovery of N-(Pyridin-4-yl)-1,5-naphthyridin-2-amines as Potential Tau Pathology PET Tracers for Alzheimer's Disease.

    PubMed

    Rombouts, Frederik J R; Andrés, José-Ignacio; Ariza, Manuela; Alonso, José Manuel; Austin, Nigel; Bottelbergs, Astrid; Chen, Lu; Chupakhin, Vladimir; Cleiren, Erna; Fierens, Katleen; Fontana, Alberto; Langlois, Xavier; Leenaerts, Joseph E; Mariën, Jonas; Martínez Lamenca, Carolina; Salter, Rhys; Schmidt, Mark E; Te Riele, Paula; Wintmolders, Cindy; Trabanco, Andrés A; Zhang, Wei; Macdonald, Gregor; Moechars, Dieder

    2017-02-23

    A mini-HTS on 4000 compounds selected using 2D fragment-based similarity and 3D pharmacophoric and shape similarity to known selective tau aggregate binders identified N-(6-methylpyridin-2-yl)quinolin-2-amine 10 as a novel potent binder to human AD aggregated tau with modest selectivity versus aggregated β-amyloid (Aβ). Initial medicinal chemistry efforts identified key elements for potency and selectivity, as well as suitable positions for radiofluorination, leading to a first generation of fluoroalkyl-substituted quinoline tau binding ligands with suboptimal physicochemical properties. Further optimization toward a more optimal pharmacokinetic profile led to the discovery of 1,5-naphthyridine 75, a potent and selective tau aggregate binder with potential as a tau PET tracer.

  4. Analysis of plasma metabolites during human PET-studies with three receptor ligands, [11C]YM-09151-2, [11C]doxepin and [11C]pyrilamine.

    PubMed

    Ishiwata, K; Yanai, K; Iwata, R; Takahashi, T; Hatazawa, J; Itoh, M; Watabe, K; Watanabe, T; Ido, T

    1996-02-01

    Carbon-11 labeled metabolites in human plasma were analyzed by high-performance liquid chromatography during positron emission tomography (PET) studies using the dopamine D2 ligand [11C]YM-09151-2 as well as the histamine H1 ligands [11C]doxepin and [11C]pyrilamine. For all the three tracers, blood clearance of the radioactivity was extremely rapid after an i.v. injection. The plasma protein-binding of [11C]YM-09151-2 and [11C]doxepin had protective effects upon the metabolic alteration of the ligands, whereas [11C]pyrilamine was free from the protein-binding and immediately degraded. The degradation of [11C]doxepin was more rapid in epileptic patients on medication than in normal subjects. These results indicate that analysis of metabolites in the plasma is necessary to determine the accurate arterial input function for quantitative PET measurement.

  5. Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development.

    PubMed

    Brouwer, Chad; Jenko, Kimberly J; Zoghbi, Sami S; Morse, Cheryl L; Innis, Robert B; Pike, Victor W

    2016-11-29

    Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinflammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand. Replacement of a phenyl group on the amido nitrogen with an isopropyl group was similarly effective. Among others, compound 20 (N-methyl-N-phenyl-2-[2-(pyridin-2-yl)-1,8-naphthyridin-4-yloxy]propanamide) appears especially appealing for PET radioligand development, based on high selectivity and high affinity (Ki = 0.5 nM) for rat TSPO, moderate lipophilicity (logD = 2.48), and demonstrated amenability to labeling with carbon-11. Published by Elsevier Masson SAS.

  6. Tunable and noncytotoxic PET/SPECT-MRI multimodality imaging probes using colloidally stable ligand-free superparamagnetic iron oxide nanoparticles.

    PubMed

    Pham, Th Nguyen; Lengkeek, Nigel A; Greguric, Ivan; Kim, Byung J; Pellegrini, Paul A; Bickley, Stephanie A; Tanudji, Marcel R; Jones, Stephen K; Hawkett, Brian S; Pham, Binh Tt

    2017-01-01

    Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the superparamagnetic maghemite iron oxide (γ-Fe2O3) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH2 end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature. (57)Co(2+) ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive (67)Ga(3+) and Cu(2+)-labeled SPIONs were also produced successfully using the optimized conditions from the (57)Co(2+)-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe.

  7. Tunable and noncytotoxic PET/SPECT-MRI multimodality imaging probes using colloidally stable ligand-free superparamagnetic iron oxide nanoparticles

    PubMed Central

    Pham, TH Nguyen; Lengkeek, Nigel A; Greguric, Ivan; Kim, Byung J; Pellegrini, Paul A; Bickley, Stephanie A; Tanudji, Marcel R; Jones, Stephen K; Hawkett, Brian S; Pham, Binh TT

    2017-01-01

    Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the superparamagnetic maghemite iron oxide (γ-Fe2O3) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH2 end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature. 57Co2+ ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive 67Ga3+ and Cu2+-labeled SPIONs were also produced successfully using the optimized conditions from the 57Co2+-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe. PMID:28184160

  8. PILOT STUDY OF THE POTENTIAL FOR HUMAN EXPOSURES TO PET-BORNE DIAZINON RESIDUES FOLLOWING LAWN APPLICATIONS IN NORTH CAROLINA

    EPA Science Inventory

    This study examined the potential for indoor/outdoor pet dogs to be an important pathway for transporting diazinon residues into homes and onto occupants following residential lawn applications. The primary objective was to investigate the potential exposures of children and thei...

  9. PILOT STUDY OF THE POTENTIAL FOR HUMAN EXPOSURES TO PET-BORNE DIAZINON RESIDUES FOLLOWING LAWN APPLICATIONS IN NORTH CAROLINA

    EPA Science Inventory

    This study examined the potential for indoor/outdoor pet dogs to be an important pathway for transporting diazinon residues into homes and onto occupants following residential lawn applications. The primary objective was to investigate the potential exposures of children and thei...

  10. Identification of mangiferin as a potential Glucokinase activator by structure-based virtual ligand screening

    PubMed Central

    Min, Qiuxia; Cai, Xinpei; Sun, Weiguang; gao, Fei; Li, Zhimei; Zhang, Qian; Wan, Luo-Sheng; Li, Hua; Chen, Jiachun

    2017-01-01

    The natural product mangiferin (compound 7) has been identified as a potential glucokinase activator by structure-based virtual ligand screening. It was proved by enzyme activation experiment and cell-based assays in vitro, with potency in micromolar range. Meanwhile, this compound showed good antihyperglycemic activity in db/db mice without obvious side effects such as excessive hypoglycaemia. PMID:28317897

  11. New multifunctional ligands for potential use in the design therapeutic or diagnostic radiopharmaceutical imaging agents

    DOEpatents

    Katti, K.V.; Volkert, W.A.; Ketring, A.R.; Singh, P.R.

    1997-02-11

    A class of diagnostic and therapeutic compounds are derived from phosphinimines that include ligands containing either a single phosphinimine functionality or both a phosphinimine group and a phosphine or arsine group, or an aminato group, or a second phosphinimine moiety. These phosphinimine ligands are complexed to early transition metal radionuclides (e.g., {sup 99m}Tc or {sup 186}Re/{sup 188}Re) or late transition metals (e.g., {sup 105}Rh or {sup 109}Pd). The complexes with these metals {sup 186}Re/{sup 188}Re, {sup 99m}Tc and {sup 109}Pd exhibit a high in vitro and high in vivo stability. The complexes are formed in high yields and can be neutral or charged. These ligands can also be used to form stable compounds with paramagnetic transition metals (e.g., Fe and Mn) for potential use as MRI contrast agents. Applications for the use of ligands and making the ligands are also disclosed.

  12. Pharmacophore searching: A potential solution for correcting unknown ligands (UNK) labelling errors in Protein Data Bank (PDB'S).

    PubMed

    Ibrahim, Musadiq; Lapthorn, Adrian Jonathan; Ibrahim, Mohammad

    2017-08-01

    The Protein Data Bank (PDB) is the single most important repository of structural data for proteins and other biologically relevant molecules. Therefore, it is critically important to keep the PDB data, error-free as much as possible. In this study, we have critically examined PDB structures of 292 protein molecules which have been deposited in the repository along with potentially incorrect ligands labelled as Unknown ligands (UNK). Pharmacophores were generated for all the protein structures by using Discovery Studio Visualizer (DSV) and Accelrys, Catalyst(®). The generated pharmacophores were subjected to the database search containing the reported ligand. Ligands obtained through Pharmacophore searching were then checked for fitting the observed electron density map by using Coot(®). The predicted ligands obtained via Pharmacophore searching fitted well with the observed electron density map, in comparison to the ligands reported in the PDB's. Based on our study we have learned that till may 2016, among 292 submitted structures in the PDB, at least 20 structures have ligands with a clear electron density but have been incorrectly labelled as unknown ligands (UNK). We have demonstrated that Pharmacophore searching and Coot(®) can provide potential help to find suitable known ligands for these protein structures, the former for ligand search and the latter for electron density analysis. The use of these two techniques can facilitate the quick and reliable labelling of ligands where the electron density map serves as a reference. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Emerging clinical applications of PET based molecular imaging in oncology: the promising future potential for evolving personalized cancer care

    PubMed Central

    Dhingra, Vandana K; Mahajan, Abhishek; Basu, Sandip

    2015-01-01

    This review focuses on the potential of advanced applications of functional molecular imaging in assessing tumor biology and cellular characteristics with emphasis on positron emission tomography (PET) applications with both 18-fluorodeoxyglucose (FDG) and non-FDG tracers. The inherent heterogeneity of cancer cells with their varied cellular biology and metabolic and receptor phenotypic expression in each individual patient and also intra-and inter-lesionally in the same individual mandates for transitioning from a generalized “same-size-fits-all” approach to personalized medicine in oncology. The past two decades have witnessed improvement of oncological imaging through CT, MR imaging, PET, subsequent movement through hybrid or fusion imaging with PET/CT and single-photon emission computerized tomography (SPECT-CT), and now toward the evolving PET/MR imaging. These recent developments have proven invaluable in enhancing oncology care and have the potential to help image the tumor biology at the cellular level, followed by providing a tailored treatment. Molecular imaging, integrated diagnostics or Radiomics, biology-driven interventional radiology and theranostics, all hold immense potential to serve as a guide to give “start and stop” treatment for a patient on an individual basis. This will likely have substantial impact on both treatment costs and outcomes. In this review, we bring forth the current trends in molecular imaging with established techniques (PET/CT), with particular emphasis on newer molecules (such as amino acid metabolism and hypoxia imaging, somatostatin receptor based imaging, and hormone receptor imaging) and further potential for FDG. An introductory discussion on the novel hybrid imaging techniques such as PET/MR is also made to understand the futuristic trends. PMID:26752813

  14. [(11)C]-Acetoacetate PET imaging: a potential early marker for cardiac heart failure.

    PubMed

    Croteau, Etienne; Tremblay, Sébastien; Gascon, Suzanne; Dumulon-Perreault, Véronique; Labbé, Sébastien M; Rousseau, Jacques A; Cunnane, Stephen C; Carpentier, André C; Bénard, François; Lecomte, Roger

    2014-01-01

    The ketone body acetoacetate could be used as an alternate nutrient for the heart, and it also has the potential to improve cardiac function in an ischemic-reperfusion model or reduce the mitochondrial production of oxidative stress involved in cardiotoxicity. In this study, [(11)C]-acetoacetate was investigated as an early marker of intracellular damage in heart failure. A rat cardiotoxicity heart failure model was induced by doxorubicin, Dox(+). [(14)C]-Acetoacetate, a non-positron (β-) emitting radiotracer, was used to characterize the arterial blood input function and myocardial mitochondrial uptake. Afterward, [(11)C]-acetoacetate (β+) myocardial PET images were obtained for kinetic analysis and heart function assessment in control Dox(-) (n=15) and treated Dox(+) (n=6) rats. The uptake rate (K1) and myocardial clearance rate (k2or kmono) were extracted. [(14)C]-Acetoacetate in the blood was increased in Dox(+), from 2 min post-injection until the last withdrawal point when the heart was harvested, as well as the uptake in the heart and myocardial mitochondria (unpaired t-test, p <0.05). PET kinetic analysis of [(11)C]-acetoacetate showed that rate constants K1, k2 and kmono were decreased in Dox(+) (p <0.05) combined with a reduction of 24% of the left ventricular ejection fraction (p <0.001). Radioactive acetoacetate ex vivo analysis [(14)C], and in vivo kinetic [(11)C] studies provided evidence that [(11)C]-acetoacetate can assess heart failure Dox(+). Contrary to myocardial flow reserve (rest-stress protocol), [(11)C]-acetoacetate can be used to assess reduced kinetic rate constants without requirement of hyperemic stress response. The proposed [(11)C]-acetoacetate cardiac radiotracer in the investigation of heart disease is novel and paves the way to a potential role for [(11)C]-acetoacetate in cardiac pathophysiology. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Performance of F-18 FDG PET/CT for Predicting Malignant Potential of Gastrointestinal Stromal Tumors: A Systematic Review and Meta-analysis.

    PubMed

    Kim, Seong-Jang; Lee, Sang-Woo

    2017-10-10

    We aimed to explore the role of the diagnostic accuracy of F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET) or positron emission tomography/computed tomography (PET/CT) for prediction of malignant potential of gastrointestinal stromal tumor (GIST) through a systematic review and meta-analysis. The MEDLINE, EMBASE, and Cochrane Library database, from the earliest available date of indexing through May 31, 2017, were searched for studies evaluating the diagnostic performance of F-18 FDG PET or PET/CT for prediction of malignant potential of GIST. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves. Across 7 studies (188 patients), the pooled sensitivity for F-18 FDG PET or PET/CT was 0.88 (95% CI; 0.80-0.94) without heterogeneity (χ(2) =6.15, p=0.72) and a pooled specificity of 0.88 (95% CI; 0.75-0.94) with heterogeneity (χ(2) =23.2, p= 0.01). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 7.2 (95% CI; 3.3-15.3) and negative likelihood ratio (LR-) of 0.13 (95% CI; 0.07-0.24). The pooled DOR was 54 (95% CI; 16-181). F-18 FDG PET or PET/CT demonstrated good sensitivity and specificity for the prediction of malignant potential of GIST. At present, the literature regarding the use of F-18 FDG PET or PET/CT for the prediction of malignant potential of GIST remains still limited; thus, further large multicenter studies would be necessary to substantiate the diagnostic accuracy of F-18 FDG PET or PET/CT prediction of malignant potential of GIST. This article is protected by copyright. All rights reserved.

  16. The untapped potential of Gallium 68-PET: the next wave of ⁶⁸Ga-agents.

    PubMed

    Smith, Daniel L; Breeman, Wouter A P; Sims-Mourtada, Jennifer

    2013-06-01

    (68)Gallium-PET ((68)Ga-PET) agents have significant clinical promise. The radionuclide can be produced from a (68)Ge/(68)Ga generator on site and is a convenient alternative to cyclotron-based PET isotopes. The short half-life of (68)Ga permits imaging applications with sufficient radioactivity while maintaining patient dose to an acceptable level. Furthermore, due to superior resolution, (68)Ga-PET agents have the ability to replace current SPECT agents in many applications. This article outlines the upcoming agents and challenges faced during the translational development of (68)Ga agents. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. The Potential of 11C-acetate PET for Monitoring the Fatty Acid Synthesis Pathway in Tumors

    PubMed Central

    DeFord-Watts, Laura M.; Mintz, Akiva; Kridel, Steven J.

    2013-01-01

    Positron emission tomography (PET) is a molecular imaging modality that provides the opportunity to rapidly and non-invasively visualize tumors derived from multiple organs. In order to do so, PET utilizes radiotracers, such as 18F-FDG and 11C-acetate, whose uptake coincides with altered metabolic pathways within tumors. Increased expression and activity of enzymes in the fatty acid synthesis pathway is a frequent hallmark of cancer cells. As a result, this pathway has become a prime target for therapeutic intervention. Although multiple drugs have been developed that both directly and indirectly interfere with fatty acid synthesis, an optimal means to assess their efficacy is lacking. Given that 11C-acetate is directly linked to the fatty acid synthesis pathway, this probe provides a unique opportunity to monitor lipogenic tumors by PET. Herein, we review the relevance of the fatty acid synthesis pathway in cancer. Furthermore, we address the potential utility of 11C-acetate PET in imaging tumors, especially those that are not FDG-avid. Last, we discuss several therapeutic interventions that could benefit from 11C-acetate PET to monitor therapeutic response in patients with certain types of cancers. PMID:23597406

  18. A FEASIBILITY STUDY EXAMINING THE POTENTIAL FOR HUMAN HEALTH EXPOSURE TO PET-BORNE DIAZINON RESIDUES FOLLOWING RESIDENTIAL TURF APPLICATIONS

    EPA Science Inventory

    The domestic dog may be a vehicle for translocation of pesticide residues following residential applications to turf. In addition, human occupants may be exposed to residues deposited inside homes by pets or by intimate contacts with them. This study examines the potential of a...

  19. A FEASIBILITY STUDY EXAMINING THE POTENTIAL FOR HUMAN EXPOSURE TO PET-BORNE DIAZINON RESIDUES FOLLOWING RESIDENTIAL TURF APPLICATIONS

    EPA Science Inventory

    The domestic dog may be a vehicle for translocation of pesticide residues following residential applications to turf. In addition, human occupants may be exposed to residues deposited inside homes by pets or by intimate contacts with them. This study examines the potential of ...

  20. A FEASIBILITY STUDY EXAMINING THE POTENTIAL FOR HUMAN HEALTH EXPOSURE TO PET-BORNE DIAZINON RESIDUES FOLLOWING RESIDENTIAL TURF APPLICATIONS

    EPA Science Inventory

    The domestic dog may be a vehicle for translocation of pesticide residues following residential applications to turf. In addition, human occupants may be exposed to residues deposited inside homes by pets or by intimate contacts with them. This study examines the potential of a...

  1. A FEASIBILITY STUDY EXAMINING THE POTENTIAL FOR HUMAN EXPOSURE TO PET-BORNE DIAZINON RESIDUES FOLLOWING RESIDENTIAL TURF APPLICATIONS

    EPA Science Inventory

    The domestic dog may be a vehicle for translocation of pesticide residues following residential applications to turf. In addition, human occupants may be exposed to residues deposited inside homes by pets or by intimate contacts with them. This study examines the potential of ...

  2. Cancer targeting potential of some ligand-anchored poly(propylene imine) dendrimers: a comparison.

    PubMed

    Kesharwani, Prashant; Tekade, Rakesh K; Gajbhiye, Virendra; Jain, Keerti; Jain, Narendra K

    2011-06-01

    The present investigation was aimed at developing and comparing the cancer-targeting potential of ligand-anchored dendrimers. Folate-, dextran-, and galactose-anchored poly(propylene imine) dendrimers were synthesized and characterized. Dendritic formulations were evaluated for ex vivo cytotoxicity on HeLa and SiHa cell lines. Flow cytometry studies were performed on the HeLa cell line. An ex vivo MTT assay on HeLa cells indicated IC(50) values of 0.05, 0.2, 0.8, and 0.08 μM for folate, dextran, and galactose formulations, and for free paclitaxel (PTX), respectively. An analogous observation was carried out in SiHa cells, where IC(50) values of 0.6, 0.8, 10, and 6 μM were observed by folate, dextran, and galactose formulations, and free PTX, respectively. The outcome of the MTT assay and flow cytometry suggested the order of targeting potential of various ligands under investigation as folate > dextran > galactose. The outcome is deemed to be of scientific value and is believed to assist drug delivery scientists during selection of targeting ligands. The cancer targeting potential of folate, dextran and galactose functionalized polypropyleneimine (PPI) dendrimers was studied by this group of investigators, reporting the order of targeting potential as folate > dextran > galactose. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Metrical oxidation states of 2-amidophenoxide and catecholate ligands: structural signatures of metal-ligand π bonding in potentially noninnocent ligands.

    PubMed

    Brown, Seth N

    2012-02-06

    Catecholates and 2-amidophenoxides are prototypical "noninnocent" ligands which can form metal complexes where the ligands are best described as being in the monoanionic (imino)semiquinone or neutral (imino)quinone oxidation state instead of their closed-shell dianionic form. Through a comprehensive analysis of structural data available for compounds with these ligands in unambiguous oxidation states (109 amidophenolates, 259 catecholates), the well-known structural changes in the ligands with oxidation state can be quantified. Using these correlations, an empirical "metrical oxidation state" (MOS) which gives a continuous measure of the apparent oxidation state of the ligand can be determined based on least-squares fitting of its C-C, C-O, and C-N bond lengths to this single parameter (a simple procedure for doing so is provided via a spreadsheet in the Supporting Information). High-valent d(0) metal complexes, particularly those of vanadium(V) and molybdenum(VI), have ligands with unexpectedly positive, and generally nonintegral, MOS values. The structural effects in these complexes are attributed not to electron transfer, but rather to amidophenoxide- or catecholate-to-metal π bonding, an interpretation supported by the systematic variation of the MOS values as a function of the degree of competition with the other π-donating groups in the structures.

  4. Tumor escape mechanisms: Potential role of soluble HLA antigens and NK cells activating ligands

    PubMed Central

    Campoli, Michael; Ferrone, Soldano

    2009-01-01

    The crucial role played by HLA antigens and natural killer (NK) cell activating ligands in the interactions of malignant cells with components of the host's immune system has stimulated interest in the characterization of their expression by malignant cells. Convincing evidence generated by the immunohistochemical staining of surgically removed malignant lesions with monoclonal antibodies (mAb) recognizing HLA antigens and NK cell activating ligands indicates that the surface expression of these molecules is frequently altered on malignant cells. These changes appear to have clinical significance, since in some types of malignant disease they are associated with the histopathological characteristics of the lesions as well as with disease free interval and survival. These associations have been suggested to reflect the effect of HLA antigen and NK cell activating ligand abnormalities on the interactions of tumor cells with antigen-specific cytotoxic T lymphocytes (CTL) and with NK cells. Nevertheless, there are examples in which disease progresses in the face of appropriate HLA antigen and/or NK cell activating ligand as well as tumor antigen expression by malignant cells and of functional antigen-specific CTL in the investigated patient. In such scenarios, it is likely that the tumor microenvironment is unfavorable for CTL and NK cell activity and contributes to tumor immune escape. Many distinct escape mechanisms have been shown to protect malignant cells from immune recognition and destruction in the tumor microenvironment. In this paper, following the description of the structural and functional characteristics of soluble HLA antigens and NK cell activating ligands, we will review changes in their serum level in malignant disease and discuss their potential role in the escape mechanisms utilized by tumor cells to avoid recognition and destruction. PMID:18700879

  5. Leptospirosis and Pets

    MedlinePlus

    ... Bacterial Special Pathogens Branch (BSPB) BSPB Laboratory Submissions Pets Recommend on Facebook Tweet Share Compartir Leptospirosis is ... that can affect human and animals, including your pets. All animals can potentially become infected with Leptospirosis. ...

  6. Induced Long-Range Attractive Potentials of Human Serum Albumin by Ligand Binding

    SciTech Connect

    Sato, Takaaki; Komatsu, Teruyuki; Nakagawa, Akito; Tsuchida, Eishun

    2007-05-18

    Small-angle x-ray scattering and dielectric spectroscopy investigation on the solutions of recombinant human serum albumin and its heme hybrid revealed that heme incorporation induces a specific long-range attractive potential between protein molecules. This is evidenced by the enhanced forward intensity upon heme binding, despite no hindrance to rotatory Brownian motion, unbiased colloid osmotic pressure, and discontiguous nearest-neighbor distance, confirming monodispersity of the proteins. The heme-induced potential may play a trigger role in recognition of the ligand-filled human serum albumins in the circulatory system.

  7. Pannexin-1 as a potentiator of ligand-gated receptor signaling.

    PubMed

    Isakson, Brant E; Thompson, Roger J

    2014-01-01

    Pannexins are a class of plasma membrane spanning proteins that presumably form a hexameric, non-selective ion channel. Although similar in secondary structure to the connexins, pannexins notably do not form endogenous gap junctions and act as bona fide ion channels. The pannexins have been primarily studied as ATP-release channels, but the overall diversity of their functions is still being elucidated. There is an intriguing theme with pannexins that has begun to develop. In this review we analyze several recent reports that converge on the idea that pannexin channels (namely Panx1) can potentiate ligand-gated receptor signaling. Although the literature remains sparse, this emerging concept appears consistent between both ionotropic and metabotropic receptors of several ligand families.

  8. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease

    PubMed Central

    Sehlin, Dag; Fang, Xiaotian T.; Cato, Linda; Antoni, Gunnar; Lannfelt, Lars; Syvänen, Stina

    2016-01-01

    Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood–brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease. The amyloid β (Aβ) antibody mAb158 is radiolabelled and conjugated to a transferrin receptor antibody to enable receptor-mediated transcytosis across the BBB. PET imaging of two different mouse models with Aβ pathology clearly visualize Aβ in the brain. The PET signal increases with age and correlates closely with brain Aβ levels. Thus, we demonstrate that antibody-based PET ligands can be successfully used for brain imaging. PMID:26892305

  9. Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders.

    PubMed

    Hayashi, Teruo; Su, Tsung-Ping

    2004-01-01

    The sigma receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that sigma receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of sigma receptor exist, the sigma-1 receptor and the sigma-2 receptor. sigma-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with sigma-1 receptors. sigma-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders. Selective sigma-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to sigma-1 receptors. As a result of these findings, sigma-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of sigma-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. sigma-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients. A number of preclinical studies have shown that selective agonists of sigma-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that sigma-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the sigma-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of sigma-1 receptor ligands is

  10. (18)F-fluoromisonidazole (FMISO) PET may have the potential to detect cardiac sarcoidosis.

    PubMed

    Manabe, Osamu; Hirata, Kenji; Shozo, Okamoto; Shiga, Tohru; Uchiyama, Yuko; Kobayashi, Kentaro; Watanabe, Shiro; Toyonaga, Takuya; Kikuchi, Hisaya; Oyama-Manabe, Noriko; Tamaki, Nagara

    2017-02-01

    (18)F-fluoromisonidazole (FMISO) is a positron emission tomography (PET) tracer that accumulates in hypoxic tissues. We here present a case of suspected cardiac sarcoidosis which was detected with increased FMISO uptake.

  11. Potential medical applications of the plasma focus in the radioisotope production for PET imaging

    NASA Astrophysics Data System (ADS)

    Roshan, M. V.; Razaghi, S.; Asghari, F.; Rawat, R. S.; Springham, S. V.; Lee, P.; Lee, S.; Tan, T. L.

    2014-06-01

    Devices other than the accelerators are desired to be investigated for generating high energy particles to induce nuclear reaction and positron emission tomography (PET) producing radioisotopes. The experimental data of plasma focus devices (PF) are studied and the activity scaling law for External Solid Target (EST) activation is established. Based on the scaling law and the techniques to enhance the radioisotopes production, the feasibility of generating the required activity for PET imaging is studied.

  12. Multilocus genotyping of potentially zoonotic Giardia duodenalis in pet chinchillas (Chinchilla lanigera) in China.

    PubMed

    Qi, Meng; Yu, Fuchang; Li, Shouyi; Wang, Haiyan; Luo, Nannan; Huang, Jianying; Zhang, Longxian

    2015-03-15

    Giardia duodenalis is a common protozoan that colonizes and reproduces in the small intestine, causing giardiasis. This parasite infects a wide range of vertebrate hosts, including humans, domestic animals and wildlife. It has been suggested that chinchillas (Chinchilla lanigera) kept as domestic pets are potential reservoirs for the zoonotic transmission of G. duodenalis. In this study, 140 chinchilla samples from four cities in China were examined to determine the prevalence of G. duodenalis. Thirty-eight (27.1%) chinchillas were found to be positive for G. duodenalis. The prevalence of infection was analyzed in relation to collection site, age and sex. Molecular characterization was also carried out on the 38 chinchilla samples to determine common genotypes. G. duodenalis assemblages A and B were identified in the chinchilla samples by analysis of the small subunit ribosomal RNA (ssur RNA) gene. Genotyping at the subtype level using multiple genes (glutamate dehydrogenase (gdh), triose phosphate isomerase (tpi) and β-giardin (bg) genes) determined that the majority of assemblage A isolate sequences were identical to subtype AI. Assemblage B isolates showed variability among the nucleotide sequences belonging to subtype BIV. This is the first report of G. duodenalis in chinchillas from China. As subtype AI and BIV are associated with human infection, G. duodenalis in chinchillas should be regarded as zoonotic.

  13. Design of vanadium mixed-ligand complexes as potential anti-protozoa agents.

    PubMed

    Benítez, Julio; Guggeri, Lucía; Tomaz, Isabel; Arrambide, Gabriel; Navarro, Maribel; Pessoa, João Costa; Garat, Beatriz; Gambino, Dinorah

    2009-04-01

    In the search for new therapeutic tools against Chagas' disease (American Trypanosomiasis) four novel mixed-ligand vanadyl complexes, [V(IV)O(L(2)-2H)(L(1))], including a bidentate polypyridyl DNA intercalator (L(1)) and a tridentate salycylaldehyde semicarbazone derivative (L(2)) as ligands were synthesized, characterized by a combination of techniques, and in vitro evaluated. EPR suggest a distorted octahedral geometry with the tridentate semicarbazone occupying three equatorial positions and the polypyridyl ligand coordinated in an equatorial/axial mode. Both complexes including dipyrido[3,2-a: 2',3'-c]phenazine (dppz) as polypyridyl coligand showed IC(50) values in the muM range against Dm28c strain (epimastigotes) of Trypanosoma cruzi, causative agent of the disease, being as active as the anti-trypanosomal reference drug Nifurtimox. To get an insight into the trypanocidal mechanism of action of these compounds, DNA was evaluated as a potential parasite target and EPR, and (51)V NMR experiments were also carried out upon aging aerated solutions of the complexes. Data obtained by electrophoretic analysis suggest that the mechanism of action of these complexes could include DNA interactions.

  14. Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies.

    PubMed

    Ono, Maiko; Sahara, Naruhiko; Kumata, Katsushi; Ji, Bin; Ni, Ruiqing; Koga, Shunsuke; Dickson, Dennis W; Trojanowski, John Q; Lee, Virginia M-Y; Yoshida, Mari; Hozumi, Isao; Yoshiyama, Yasumasa; van Swieten, John C; Nordberg, Agneta; Suhara, Tetsuya; Zhang, Ming-Rong; Higuchi, Makoto

    2017-03-01

    Diverse neurodegenerative disorders are characterized by deposition of tau fibrils composed of conformers (i.e. strains) unique to each illness. The development of tau imaging agents has enabled visualization of tau lesions in tauopathy patients, but the modes of their binding to different tau strains remain elusive. Here we compared binding of tau positron emission tomography ligands, PBB3 and AV-1451, by fluorescence, autoradiography and homogenate binding assays with homologous and heterologous blockades using tauopathy brain samples. Fluorescence microscopy demonstrated intense labelling of non-ghost and ghost tangles with PBB3 and AV-1451, while dystrophic neurites were more clearly detected by PBB3 in brains of Alzheimer's disease and diffuse neurofibrillary tangles with calcification, characterized by accumulation of all six tau isoforms. Correspondingly, partially distinct distributions of autoradiographic labelling of Alzheimer's disease slices with 11C-PBB3 and 18F-AV-1451 were noted. Neuronal and glial tau lesions comprised of 4-repeat isoforms in brains of progressive supranuclear palsy, corticobasal degeneration and familial tauopathy due to N279K tau mutation and 3-repeat isoforms in brains of Pick's disease and familial tauopathy due to G272V tau mutation were sensitively detected by PBB3 fluorescence in contrast to very weak AV-1451 signals. This was in line with moderate 11C-PBB3 versus faint 18F-AV-1451 autoradiographic labelling of these tissues. Radioligand binding to brain homogenates revealed multiple binding components with differential affinities for 11C-PBB3 and 18F-AV-1451, and higher availability of binding sites on progressive supranuclear palsy tau deposits for 11C-PBB3 than 18F-AV-1451. Our data indicate distinct selectivity of PBB3 compared to AV-1451 for diverse tau fibril strains. This highlights the more robust ability of PBB3 to capture wide-range tau pathologies.

  15. Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel

    PubMed Central

    Sauguet, Ludovic; Howard, Rebecca J.; Malherbe, Laurie; Lee, Ui S.; Corringer, Pierre-Jean; Harris, R. Adron; Delarue, Marc

    2014-01-01

    Ethanol alters nerve signalling by interacting with proteins in the central nervous system, particularly pentameric ligand-gated ion channels. A recent series of mutagenesis experiments on Gloeobacter violaceus ligand-gated ion channel, a prokaryotic member of this family, identified a single-site variant that is potentiated by pharmacologically relevant concentrations of ethanol. Here we determine crystal structures of the ethanol-sensitized variant in the absence and presence of ethanol and related modulators, which bind in a transmembrane cavity between channel subunits and may stabilize the open form of the channel. Structural and mutagenesis studies defined overlapping mechanisms of potentiation by alcohols and anaesthetics via the inter-subunit cavity. Furthermore, homology modelling show this cavity to be conserved in human ethanol-sensitive glycine and GABA(A) receptors, and to involve residues previously shown to influence alcohol and anaesthetic action on these proteins. These results suggest a common structural basis for ethanol potentiation of an important class of targets for neurological actions of ethanol. PMID:23591864

  16. TREM-1 and its potential ligands in non-infectious diseases: from biology to clinical perspectives.

    PubMed

    Tammaro, Alessandra; Derive, Marc; Gibot, Sebastien; Leemans, Jaklien C; Florquin, Sandrine; Dessing, Mark C

    2017-09-01

    Triggering receptor expressed on myeloid cells-1 (TREM-1) is expressed on the majority of innate immune cells and to a lesser extent on parenchymal cells. Upon activation, TREM-1 can directly amplify an inflammatory response. Although it was initially demonstrated that TREM-1 was predominantly associated with infectious diseases, recent evidences shed new light into its role in sterile inflammatory diseases. Indeed, TREM-1 receptor and its signaling pathways contribute to the pathology of several non-infectious acute and chronic inflammatory diseases, including atherosclerosis, ischemia reperfusion-induced tissue injury, colitis, fibrosis and cancer. This review, aims to give an extensive overview of TREM-1 in non-infectious diseases, with the focus on the therapeutic potential of TREM-1 intervention strategies herein. In addition, we provide the reader with a functional enrichment analysis of TREM-1 signaling pathway and potential TREM-1 ligands in these diseases, obtained via in silico approach. We discuss pre-clinical studies which show that TREM-1 inhibition, via synthetic soluble TREM-1 protein mimickers, is effective in treating (preventing) specific inflammatory disorders, without significant effects on antibacterial response. Further research aimed at identifying specific TREM-1 ligands, in different inflammatory disorders, is required to further unravel the role of this receptor, and explore new avenues to modulate its function. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Visualization of early infarction in rat brain after ischemia using a translocator protein (18 kDa) PET ligand [11C]DAC with ultra-high specific activity.

    PubMed

    Yui, Joji; Hatori, Akiko; Kawamura, Kazunori; Yanamoto, Kazuhiko; Yamasaki, Tomoteru; Ogawa, Masanao; Yoshida, Yuichiro; Kumata, Katsushi; Fujinaga, Masayuki; Nengaki, Nobuki; Fukumura, Toshimitsu; Suzuki, Kazutoshi; Zhang, Ming-Rong

    2011-01-01

    The aim of this study was to visualize early infarction in the rat brain after ischemia using a translocator protein (TSPO) (18 kDa) PET ligand [(11)C]DAC with ultra-high specific activity (SA) of 3670-4450 GBq/μmol. An infarction model of rat brain was prepared by ischemic surgery and evaluated 2 days after ischemia using small-animal PET and in vitro autoradiography. Early infarction with a small increase of TSPO expression in the brain was visualized using PET with high SA [(11)C]DAC (average 4060 GBq/μmol), but was not distinguished clearly with usually reported SA [(11)C]DAC (37 GBq/μmol). Infarction in the rat brain 4 days after ischemia was visualized using high and usually reported SAs [(11)C]DAC. Displacement experiments with unlabeled TSPO-selective AC-5216 or PK11195 diminished the difference in radioactivity between ipsilateral and contralateral sides, confirming that the increased uptake on the infracted brain was specific to TSPO. In vitro autoradiography with high SA [(11)C]DAC showed that the TSPO expression increased on early infarction in the rat brain. High SA [(11)C]DAC is a useful and sensitive biomarker for the visualization of early infarction and the characterization of TSPO expression which was slightly elevated in the infarcted brain using PET.

  18. An observational study of the potential for human exposures to pet-borne diazinon residues following lawn applications

    SciTech Connect

    Morgan, Marsha K. Stout, Daniel M.; Jones, Paul A.; Barr, Dana B.

    2008-07-15

    This study examined the potential for pet dogs to be an important pathway for transporting diazinon residues into homes and onto its occupants following residential lawn applications. The primary objectives were to investigate the potential exposures of occupants and their pet dogs to diazinon after an application to turf at their residences and to determine if personal contacts between occupants and their pet dogs resulted in measurable exposures. It was conducted from April to August 2001 before the Agency phased out all residential uses of diazinon in December 2004. Six families and their pet dogs were recruited into the study. Monitoring was conducted at pre-, 1, 2, 4, and 8 days post-application of a commercial, granular formulation of diazinon to the lawn by the homeowner. Environmental samples collected included soil, indoor air, carpet dust, and transferable residues from lawns and floors. Samples collected from the pet dogs consisted of paw wipes, fur clippings, and transferable residues from the fur by a technician or child wearing a cotton glove(s). First morning void (FMV) urine samples were collected from each child and his/her parent on each sampling day. Diazinon was analyzed in all samples, except urine, by GC-MS. The metabolite 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy) was analyzed in the urine samples by HPLC-MS/MS. Mean airborne residues of diazinon on day 1 post-application were at least six times higher in both the living rooms (235{+-}267 ng/m{sup 3}) and children's bedrooms (179{+-}246 ng/m{sup 3}) than at pre-application. Mean loadings of diazinon in carpet dust samples were at least 20 times greater on days 2, 4, and 8 post-application than mean loadings (0.03{+-}0.04 ng/cm{sup 2}) at pre-application. The pet dogs had over 900 times higher mean loadings of diazinon residues on their paws on day 1 post-application (88.1{+-}100.1 ng/cm{sup 2}) compared to mean loadings (<0.09 ng/cm{sup 2}) at pre-application. The mean diazinon loadings

  19. An observational study of the potential for human exposures to pet-borne diazinon residues following lawn applications.

    PubMed

    Morgan, Marsha K; Stout, Daniel M; Jones, Paul A; Barr, Dana B

    2008-07-01

    This study examined the potential for pet dogs to be an important pathway for transporting diazinon residues into homes and onto its occupants following residential lawn applications. The primary objectives were to investigate the potential exposures of occupants and their pet dogs to diazinon after an application to turf at their residences and to determine if personal contacts between occupants and their pet dogs resulted in measurable exposures. It was conducted from April to August 2001 before the Agency phased out all residential uses of diazinon in December 2004. Six families and their pet dogs were recruited into the study. Monitoring was conducted at pre-, 1, 2, 4, and 8 days post-application of a commercial, granular formulation of diazinon to the lawn by the homeowner. Environmental samples collected included soil, indoor air, carpet dust, and transferable residues from lawns and floors. Samples collected from the pet dogs consisted of paw wipes, fur clippings, and transferable residues from the fur by a technician or child wearing a cotton glove(s). First morning void (FMV) urine samples were collected from each child and his/her parent on each sampling day. Diazinon was analyzed in all samples, except urine, by GC-MS. The metabolite 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPy) was analyzed in the urine samples by HPLC-MS/MS. Mean airborne residues of diazinon on day 1 post-application were at least six times higher in both the living rooms (235+/-267 ng/m(3)) and children's bedrooms (179+/-246 ng/m(3)) than at pre-application. Mean loadings of diazinon in carpet dust samples were at least 20 times greater on days 2, 4, and 8 post-application than mean loadings (0.03+/-0.04 ng/cm(2)) at pre-application. The pet dogs had over 900 times higher mean loadings of diazinon residues on their paws on day 1 post-application (88.1+/-100.1 ng/cm(2)) compared to mean loadings (<0.09 ng/cm(2)) at pre-application. The mean diazinon loadings on the fur clippings

  20. In Vitro and In Vivo Evaluation of a 18F-Labeled High Affinity NOTA Conjugated Bombesin Antagonist as a PET Ligand for GRPR-Targeted Tumor Imaging

    PubMed Central

    Velikyan, Irina; Lindeberg, Gunnar; Sörensen, Jens; Larhed, Mats; Antoni, Gunnar; Sandström, Mattias; Tolmachev, Vladimir; Orlova, Anna

    2013-01-01

    Expression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethylene glycol (PEG2) spacer (NOTA-P2-RM26) labeled with 68Ga and 111In. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a 18F-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with 18F using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50) of the [natF]AlF-NOTA-P2-RM26 was compared to that of the natGa-loaded peptide using 125I-Tyr4-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with 18F within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/µmol). The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [natF]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4±0.8 nM). The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [18F]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p.i. was 5.5±0.7 %ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87±42, 159±47, 38±16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p.i. The initial biological

  1. In vitro and in vivo evaluation of a (18)F-labeled high affinity NOTA conjugated bombesin antagonist as a PET ligand for GRPR-targeted tumor imaging.

    PubMed

    Varasteh, Zohreh; Aberg, Ola; Velikyan, Irina; Lindeberg, Gunnar; Sörensen, Jens; Larhed, Mats; Antoni, Gunnar; Sandström, Mattias; Tolmachev, Vladimir; Orlova, Anna

    2013-01-01

    Expression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) via a diethylene glycol (PEG2) spacer (NOTA-P2-RM26) labeled with (68)Ga and (111)In. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a (18)F-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with (18)F using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50) of the [(nat)F]AlF-NOTA-P2-RM26 was compared to that of the (nat)Ga-loaded peptide using (125)I-Tyr(4)-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with (18)F within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/µmol). The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [(nat)F]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4±0.8 nM). The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [(18)F]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p.i. was 5.5±0.7 %ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87±42, 159±47, 38±16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p

  2. [C-11]{beta}CNT: A new monoamine uptake ligand for studying serotonin and dopamine transporter sites in the living brain with PET

    SciTech Connect

    Mulholland, G.K.; Zheng, Q.H.; Zhou, F.C.

    1996-05-01

    There is considerable interest in measuring serotonin (5HT) and dopamine (DA) function in the human brain. Altered levels of 5HT and DA are recognized in drug abuse, neurotoxicities, psychiatric disorders, and neurodegenerative conditions including Alzheimer`s and Parkinson`s disease. Several phenyltropane analogs of cocaine bind tightly to both DA and 5HT uptake proteins. We have made a new agent from this class called {beta}CNT, 2{beta}-carboxymethyl-3{beta}-(2-naphthyl)-tropane, the isosteric O-for-CH{sub 2} analog of a compound reported to have among the highest measured affinities for DA and 5HT transporters and studied its in vivo brain distributions in animals for the first time. Optically pure {beta}CNT was made from cocaine, and labeled at the O-methyl position by esterification of {beta}CNT-acid with [C-11]CH{sub 3}OTfl under conditions similar to Wilson`s. HPLC-purified (99+%) final products (15-50% eob yield from CO{sub 2}, 40 min synth) had specific activities 0.1-1.2 Ci/{mu}mol at the time of injection. Preliminary [C-11]{beta}{beta}CNT rodent distribution showed very high brain uptake (3% ID at 60 min) and localization (striat: fr cort: hypo: cer: blood, 11: 5: 4: 1: 06). {beta}CNT-PET studies in juvenile pigs (5-20 mCi, 20-35 kg) found rapid brain uptake, and prominent retention (85 min) in midbrain, anterior brainstem and striatum, followed by cortex and olfactory bulb. Paroxetine pretreatment (5HT uptake blocker, 2mg/kg), diminished retention in most brain areas; nomifensine (DA/NE uptake blocker, 6 mg/kg) reduced striatum selectively. Direct comparisons of [C-11]{beta}CNT with other PET transporter radioligands {beta}CFT, {beta}CIT, and {beta}CTT (RTI-32) in the same pig found {beta}CNT had highest overall brain uptake among the agents. These initial results suggest {beta}CNT has favorable properties for imaging both 5HT and DA transporters in vivo, and further evaluation of its potential as a human PET agent is warranted.

  3. Pigmented Villonodular Synovitis: Potential Pitfall on Oncologic 18F-FDG PET/CT.

    PubMed

    Broski, Stephen M; Murdoch, Nathan M; Skinner, John A; Wenger, Doris E

    2016-01-01

    This study evaluated the semiquantitative and qualitative appearance of pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCTTS) on 18F-FDG PET/CT. An institutional review board-approved retrospective review was performed for patients diagnosed with GCTTS, focal PVNS, or diffuse PVNS who underwent PET/CT from 2003 to 2013. SUVmax and SUVmax/SUVmean of the liver (SUVr) were determined for each lesion on all available PET/CTs. Relevant conventional imaging and patient records were reviewed. Fourteen patients (mean [SD] age, 52.8 [14.0] years; range, 26-74 years) were identified, 6 with 2 or more PET/CT examinations. The mean (SD) SUVmax and SUVr of all lesions were 8.7 (3.4; range, 4.0-14.5) and 3.9 (1.7; range, 2.0-7.1), respectively. There was no difference of the mean (SD) SUVmax (P = 0.10) or SUVr (P = 0.11) between focal PVNS (6.8 [3.0], 3.3 [1.9]), GCTTS (9.1 [3.0], 4.0 [1.2]), or diffuse PVNS (14.5, 7.1) subtypes. Of 29 comparison PET/CTs in 6 patients, 17 were performed after nontargeted chemotherapy and 12 without antecedent therapy. Significant SUVr fluctuations (>25%) occurred in 11 cases; no correlation existed between SUVr change and presence or absence of chemotherapy. Pigmented villonodular synovitis and GCTTS can be intensely hypermetabolic, mimicking musculoskeletal metastases on 18F-FDG PET/CT. They may have significant SUV fluctuations, both during nontargeted chemotherapy and between treatments. The diagnosis of PVNS/GCTTS should be considered for focal intra-articular or juxta-articular FDG-avid lesions, and MRI is useful in further evaluation given the often diagnostic imaging features with this modality.

  4. Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors.

    PubMed

    Wang, Changning; Moseley, Christian K; Carlin, Stephen M; Wilson, Colin M; Neelamegam, Ramesh; Hooker, Jacob M

    2013-06-01

    EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [(3)H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [(11)C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([(11)C]EMPA), and evaluation as a potential PET tracer for OX2 receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [(11)C]CH3I in the presence of cesium carbonate in DMSO at room temp afforded [(11)C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [(11)C]CH3I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [(11)C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.

  5. The Pearl of FDG PET/CT in Preoperative Assessment of Patients with Potentially Operable Non-Small-Cell Lung Cancer and its Clinical Impact

    PubMed Central

    Kung, Boom Ting; Yong, Ting Kun Au; Tong, Cheuk Man

    2017-01-01

    The aim of this retrospective study is to evaluate the clinical impact and efficacy of fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) on management decisions for patients suffering from clinically operable non–small-cell lung cancer (NSCLC). A retrospective review of 186 potentially operable NSCLC patients who underwent whole-body PET/CT examination in 2012 was performed. The patients were further analyzed via the electronic patient record (ePR) system for relevant findings. Overall change in management was assigned if a patient avoided unnecessary surgery due to disease upstaging or if a patient underwent further neoadjuvant treatment or investigation before the curative surgery. Of all 186 subjects, 65 (34.9%) became inoperable after PET/CT due to disease upstaging. The remaining 121 (65.1%) of patients remained operable after PET/CT examination. Nineteen out of 121 potentially operable patients did not receive curative surgery eventually, as 11 patients had poor clinical condition and 8 patients refused surgery. One hundred two out of 186 (54.8%) patients received curative operation following PET/CT. Among these 102 individuals, 97 patients (95%) proceeded to surgery without further neoadjuvant treatment or other investigatory procedures. Of the remaining 5 patients, 4 (3.9%) received neoadjuvant treatment and 1 (1.0%) had further investigation after PET/CT. Seventy of the 186 (37.6%) patients underwent changes in management plans after PET/CT study. Out of the 186 individuals, a subgroup of 141 (75.8%) patients underwent dedicated CT thorax before PET/CT examination. Forty-seven (33.3%) patients had avoided futile surgery due to disease upstaging. Fifty-one of the 141 (36.2%) patients underwent changes in management plans after PET/CT. PET/CT had great clinical impact, with significant reduction of futile curative surgery. PMID:28217015

  6. The Pearl of FDG PET/CT in Preoperative Assessment of Patients with Potentially Operable Non-Small-Cell Lung Cancer and its Clinical Impact.

    PubMed

    Kung, Boom Ting; Yong, Ting Kun Au; Tong, Cheuk Man

    2017-01-01

    The aim of this retrospective study is to evaluate the clinical impact and efficacy of fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) on management decisions for patients suffering from clinically operable non-small-cell lung cancer (NSCLC). A retrospective review of 186 potentially operable NSCLC patients who underwent whole-body PET/CT examination in 2012 was performed. The patients were further analyzed via the electronic patient record (ePR) system for relevant findings. Overall change in management was assigned if a patient avoided unnecessary surgery due to disease upstaging or if a patient underwent further neoadjuvant treatment or investigation before the curative surgery. Of all 186 subjects, 65 (34.9%) became inoperable after PET/CT due to disease upstaging. The remaining 121 (65.1%) of patients remained operable after PET/CT examination. Nineteen out of 121 potentially operable patients did not receive curative surgery eventually, as 11 patients had poor clinical condition and 8 patients refused surgery. One hundred two out of 186 (54.8%) patients received curative operation following PET/CT. Among these 102 individuals, 97 patients (95%) proceeded to surgery without further neoadjuvant treatment or other investigatory procedures. Of the remaining 5 patients, 4 (3.9%) received neoadjuvant treatment and 1 (1.0%) had further investigation after PET/CT. Seventy of the 186 (37.6%) patients underwent changes in management plans after PET/CT study. Out of the 186 individuals, a subgroup of 141 (75.8%) patients underwent dedicated CT thorax before PET/CT examination. Forty-seven (33.3%) patients had avoided futile surgery due to disease upstaging. Fifty-one of the 141 (36.2%) patients underwent changes in management plans after PET/CT. PET/CT had great clinical impact, with significant reduction of futile curative surgery.

  7. Cholinergic Modulation by Opioid Receptor Ligands: Potential Application to Alzheimer’s Disease

    PubMed Central

    Motel, William C.; Coop, Andrew; Cunningham, Christopher W.

    2013-01-01

    Morphinans have a storied history in medicinal chemistry as pain management drugs but have received attention as modulators of cholinergic signaling for the treatment of Alzheimer’s Disease (AD). Galantamine is a reversible, competitive acetylcholinesterase (AChE) inhibitor and allosteric potentiating ligand of nicotinic acetylcholine receptors (nAChR-APL) that shares many common structural elements with morphinan-based opioids. The structurally diverse opioids codeine and eseroline, like galantamine, are also nAChR-APL that have greatly diminished affinity for AChE, representing potential lead compounds for selective nAChR-APL development. In accordance with the emerging repurposing trend of evaluating known compounds for novel pharmacological activity, ongoing research on augmentation of cholinergic signaling that has been aided by the use of opioids will be reviewed. PMID:22931533

  8. Evaluation of Potential PET Imaging Probes for the Orexin 2 Receptors

    PubMed Central

    Wang, Changning; Wilson, Colin M.; Moseley, Christian K.; Carlin, Stephen M.; Hsu, Shirley; Arabasz, Grae; Schroeder, Frederick A.; Sander, Christin Y.; Hooker, Jacob M.

    2013-01-01

    A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are associated with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [11C]CW4 showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [11C]CW4 exhibited fast kinetics and high nonspecific binding, as determined after co-administration of [11C]CW4 and unlabeled CW4. These properties indicate that [11C]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors. PMID:23953751

  9. Structure-Based Virtual Screening for Dopamine D2 Receptor Ligands as Potential Antipsychotics.

    PubMed

    Kaczor, Agnieszka A; Silva, Andrea G; Loza, María I; Kolb, Peter; Castro, Marián; Poso, Antti

    2016-04-05

    Structure-based virtual screening using a D2 receptor homology model was performed to identify dopamine D2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D2 ligands were identified (47.6% success rate, among them D2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (Ki values) of the compounds ranged from 58 nm to about 24 μM. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D2 receptor over the D3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential.

    PubMed

    Zlotos, Darius P; Jockers, Ralf; Cecon, Erika; Rivara, Silvia; Witt-Enderby, Paula A

    2014-04-24

    Numerous physiological functions of the pineal gland hormone melatonin are mediated via activation of two G-protein-coupled receptors, MT1 and MT2. The melatonergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and TIK-301, are high-affinity nonselective MT1/MT2 agonists. A great number of MT2-selective ligands and, more recently, several MT1-selective agents have been reported to date. Herein, we review recent advances in the field focusing on high-affinity agonists and antagonists and those displaying selectivity toward MT1 and MT2 receptors. Moreover, the existing models of MT1 and MT2 receptors as well as the current status in the emerging field of melatonin receptor oligomerization are critically discussed. In addition to the already existing indications, such as insomnia, circadian sleep disorders, and depression, new potential therapeutic applications of melatonergic ligands including cardiovascular regulation, appetite control, tumor growth inhibition, and neurodegenerative diseases are presented.

  11. In vivo evaluation of PEGylated ⁶⁴Cu-liposomes with theranostic and radiotherapeutic potential using micro PET/CT.

    PubMed

    Petersen, Anncatrine Luisa; Henriksen, Jonas Rosager; Binderup, Tina; Elema, Dennis Ringkjøbing; Rasmussen, Palle Hedengran; Hag, Anne Mette; Kjær, Andreas; Andresen, Thomas Lars

    2016-05-01

    The objective of this study was to evaluate the potential of PEGylated (64)Cu-liposomes in clinical diagnostic positron emission tomography (PET) imaging and PEGylated (177)Lu-liposomes in internal tumor radiotherapy through in vivo characterization and dosimetric analysis in a human xenograft mouse model. Liposomes with 5 and 10 mol% PEG were characterized with respect to size, charge, and (64)Cu- and (177)Lu-loading efficiency. The tumor imaging potential of (64)Cu-loaded liposomes was evaluated in terms of in vivo biodistribution, tumor accumulation and tumor-to-muscle (T/M) ratios, using PET imaging. The potential of PEGylated liposomes for diagnostic and therapeutic applications was further evaluated through dosimetry analysis using OLINDA/EXM software. The (64)Cu-liposomes were used as biological surrogates to estimate the organ and tumor kinetics of (177)Lu-liposomes. High remote loading efficiency (>95 %) was obtained for both (64)Cu and (177)Lu radionuclides with PEGylated liposomes, and essentially no leakage of the encapsulated radionuclide was observed upon storage and after serum incubation for 24 h at 37 °C. The 10 mol% PEG liposomes showed higher tumor accumulation (6.2 ± 0.2 %ID/g) than the 5 mol% PEG liposomes, as evaluated by PET imaging. The dosimetry analysis of the (64)Cu-liposomes estimated an acceptable total effective dose of 3.3·10(-2) mSv/MBq for diagnostic imaging in patients. A high absorbed tumor dose (114 mGy/MBq) was estimated for the potential radiotherapeutic (177)Lu-liposomes. The overall preclinical profile of PEGylated (64)Cu-liposomes showed high potential as a new PET theranostic tracer for imaging in humans. Dosimetry results predicted that initial administered activity of 200 MBq of (64)Cu-liposomes should be acceptable in patients. Work is in progress to validate the utility of PEGylated (64)Cu-liposomes in a clinical research programme. The high absorbed tumor dose (114 mGy/MBq) estimated for (177)Lu-liposomes and

  12. Ethanol withdrawal-induced depressive symptoms in animals and therapeutic potential of sigma1 receptor ligands.

    PubMed

    Skuza, Grażyna

    2013-01-01

    Clinical evidence has indicated a high degree of comorbidity of alcoholism and depression. Manifestation of the depression symptoms during abstinence increases the likelihood of relapse and indicates a worse prognosis in terms of treatment outcome. The depressive symptoms may be alcohol independent or alcohol induced. In this paper, only the ethanol-related depression is the focus of interest. In preclinical studies, some models of depressive-like symptoms induced by chronic alcohol treatment and withdrawal were proposed. In this minireview, the results concerning the depression-like behavior and some accompanying biochemical changes induced by prolonged ethanol exposure and its cessation in rats and mice were summarized. Moreover, the therapeutic potential of sigma1 receptor ligands for the treatment of depression disorder induced by ethanol abuse and withdrawal is discussed.

  13. New organoruthenium complexes with bioactive thiosemicarbazones as co-ligands: potential anti-trypanosomal agents†

    PubMed Central

    Demoro, Bruno; Sarniguet, Cynthia; Sánchez-Delgado, Roberto; Rossi, Miriam; Liebowitz, Daniel; Caruso, Francesco; Olea-Azar, Claudio; Moreno, Virtudes; Medeiros, Andrea; Comini, Marcelo A.; Otero, Lucía; Gambino, Dinorah

    2012-01-01

    In the search for new therapeutic tools against neglected diseases produced by trypanosomatid parasites, and particularly against African Trypanosomiasis, whose etiological agent is Trypanosoma brucei, organoruthenium compounds with bioactive nitrofuran containing thiosemicarbazones (L) as co-ligands were obtained. Four ruthenium(ii) complexes with the formula [Ru2(p-cymene)2(L)2]X2, where X = Cl or PF6, were synthesized and the crystal structures of two of them were solved by X-ray diffraction methods. Two of the complexes show significant in vitro growth inhibition activity against Trypanosoma brucei brucei and are highly selective towards trypanosomal cells with respect to mammalian cells (J774 murine macrophages). These promising results make the title organoruthenium compounds good lead candidates for further developments towards potential antitrypanosomal organometallic drugs. PMID:22138896

  14. The heterodimeric sweet taste receptor has multiple potential ligand binding sites.

    PubMed

    Cui, Meng; Jiang, Peihua; Maillet, Emeline; Max, Marianna; Margolskee, Robert F; Osman, Roman

    2006-01-01

    The sweet taste receptor is a heterodimer of two G protein coupled receptors, T1R2 and T1R3. This discovery has increased our understanding at the molecular level of the mechanisms underlying sweet taste. Previous experimental studies using sweet receptor chimeras and mutants show that there are at least three potential binding sites in this heterodimeric receptor. Receptor activity toward the artificial sweeteners aspartame and neotame depends on residues in the amino terminal domain of human T1R2. In contrast, receptor activity toward the sweetener cyclamate and the sweet taste inhibitor lactisole depends on residues within the transmembrane domain of human T1R3. Furthermore, receptor activity toward the sweet protein brazzein depends on the cysteine rich domain of human T1R3. Although crystal structures are not available for the sweet taste receptor, useful homology models can be developed based on appropriate templates. The amino terminal domain, cysteine rich domain and transmembrane helix domain of T1R2 and T1R3 have been modeled based on the crystal structures of metabotropic glutamate receptor type 1, tumor necrosis factor receptor, and bovine rhodopsin, respectively. We have used homology models of the sweet taste receptors, molecular docking of sweet ligands to the receptors, and site-directed mutagenesis of the receptors to identify potential ligand binding sites of the sweet taste receptor. These studies have led to a better understanding of the structure and function of this heterodimeric receptor, and can act as a guide for rational structure-based design of novel non-caloric sweeteners, which can be used in the fighting against obesity and diabetes.

  15. Computational prediction and in vitro analysis of potential physiological ligands of the bile acid binding site in cytochrome c oxidase†

    PubMed Central

    Buhrow, Leann; Hiser, Carrie; Van Voorst, Jeffrey R.; Ferguson-Miller, Shelagh; Kuhn, Leslie A.

    2013-01-01

    A conserved bile acid site has been crystallographically defined in the membrane domain of mammalian and Rhodobacter sphaeroides cytochrome c oxidase (RsCcO). Diverse amphipathic ligands were shown previously to bind to this site and affect the electron transfer equilibrium between heme a and a3 cofactors by blocking the K proton uptake path. Current studies identify physiologically relevant ligands for the bile acid site using a novel three-pronged computational approach: ROCS comparison of ligand shape and electrostatics, SimSite3D comparison of ligand binding site features, and SLIDE screening of potential ligands by docking. Identified candidate ligands include steroids, nicotinamides, flavins, nucleotides, retinoic acid, and thyroid hormones, which are predicted to make key protein contacts with the residues involved in bile acid binding. In vitro oxygen consumption and ligand competition assays on RsCcO wildtype and its Glu101Ala mutant support regulatory activity and specificity of some of these ligands. An ATP analog and GDP inhibit RsCcO under low substrate conditions, while fusidic acid, cholesteryl hemisuccinate, retinoic acid, and T3 thyroid hormone are more potent inhibitors under both high and low substrate conditions. The sigmoidal kinetics of RsCcO inhibition in the presence of certain nucleotides is reminiscent of previously reported ATP inhibition of mammalian CcO, suggesting regulation involving the conserved core subunits of both mammalian and bacterial oxidases. Ligand binding to the bile acid site is non-competitive with respect to cytochrome c and appears to arrest CcO in a semi-oxidized state with some resemblance to the “resting” state of the enzyme. PMID:24073649

  16. Computational prediction and in vitro analysis of potential physiological ligands of the bile acid binding site in cytochrome c oxidase.

    PubMed

    Buhrow, Leann; Hiser, Carrie; Van Voorst, Jeffrey R; Ferguson-Miller, Shelagh; Kuhn, Leslie A

    2013-10-08

    A conserved bile acid site has been crystallographically defined in the membrane domain of mammalian and Rhodobacter sphaeroides cytochrome c oxidase (RsCcO). Diverse amphipathic ligands were shown previously to bind to this site and affect the electron transfer equilibrium between heme a and a3 cofactors by blocking the K proton uptake path. Current studies identify physiologically relevant ligands for the bile acid site using a novel three-pronged computational approach: ROCS comparison of ligand shape and electrostatics, SimSite3D comparison of ligand binding site features, and SLIDE screening of potential ligands by docking. Identified candidate ligands include steroids, nicotinamides, flavins, nucleotides, retinoic acid, and thyroid hormones, which are predicted to make key protein contacts with the residues involved in bile acid binding. In vitro oxygen consumption and ligand competition assays on RsCcO wildtype and its Glu101Ala mutant support regulatory activity and specificity of some of these ligands. An ATP analog and GDP inhibit RsCcO under low substrate conditions, while fusidic acid, cholesteryl hemisuccinate, retinoic acid, and T3 thyroid hormone are more potent inhibitors under both high and low substrate conditions. The sigmoidal kinetics of RsCcO inhibition in the presence of certain nucleotides is reminiscent of previously reported ATP inhibition of mammalian CcO, suggesting regulation involving the conserved core subunits of both mammalian and bacterial oxidases. Ligand binding to the bile acid site is noncompetitive with respect to cytochrome c and appears to arrest CcO in a semioxidized state with some resemblance to the "resting" state of the enzyme.

  17. Health effects in family pets and 2,3,7,8-TCDD contamination in Missouri: a look at potential animal sentinels

    SciTech Connect

    Schilling, R.J.; Stehr-Green, P.A.

    1987-05-01

    In 1971, waste oils containing 2,3,7,8:tetrachlorodibenzodioxin (TCDD) were sprayed in Missouri for dust control. To determine if pets could serve as sentinels of human health risks associated with this contamination, we asked pet owners in a pilot study of exposed human populations about their pets' illnesses. Of 13 pets with owner-reported illnesses, 8 had potential TCDD exposures and 5 did not (p less than .05 by Mantel-Haenzel chi-square analysis stratified by age). Owner-reported illnesses in 2 of 8 illness categories were associated with TCDD contamination after adjusting for age. Although these findings suggest that pets in TCDD-contaminated areas may have greater health risks, the small sample size, unlikely pathologic groupings, and unconfirmed nature of the data fail to support a relationship between pet illnesses and possible TCDD exposure and thus make extrapolation to human populations inappropriate. The limited validity found for owner-reported pet illnesses should caution against using such data in future environmental health studies.

  18. 18F-barbiturates are PET tracers with diagnostic potential in Alzheimer's disease.

    PubMed

    Calamai, Elisa; Dall'Angelo, Sergio; Koss, David; Domarkas, Juozas; McCarthy, Timothy J; Mingarelli, Marco; Riedel, Gernot; Schweiger, Lutz F; Welch, Andy; Platt, Bettina; Zanda, Matteo

    2013-01-28

    Three fluoro-barbiturates were synthesised, showing in vivo sedative efficacy. One of them, [(18)F], was synthesised in radiofluorinated form. PET/CT Imaging with [(18)F] identified β-amyloid over-expressing transgenic mice (βA mice) compared to wild type and tau lines. The fluorescent barbiturate 9 was able to label βA plaques in brain sections of βA mice, and co-localise with a fluorescent Zn(II) indicator.

  19. Benign fibrous dysplasia on [(11)C]choline PET: a potential mimicker of disease in patients with biochemical recurrence of prostate cancer.

    PubMed

    Gu, Chris N; Hunt, Christopher H; Lehman, Vance T; Johnson, Geoffrey B; Diehn, Felix E; Schwartz, Kara M; Eckel, Laurence J

    2012-08-01

    We present the case of a 74-year-old male with biochemical recurrence of prostate cancer who underwent [(11)C]choline PET/CT. The PET/CT demonstrated an intense focus of uptake within the skull base that was initially felt to potentially represent metastatic disease. Subsequent evaluation with MRI and dedicated thin-section CT revealed this area to be benign fibrous dysplasia of the bone. The focal uptake on PET/CT with [(11)C]choline in benign fibrous dysplasia represents a potential mimicker of metastatic disease. Due to recognizing this benign process, our patient was able to avoid systemic treatment and/or focal radiation and was treated with cryotherapy for biopsy-proven local recurrence within the prostate bed. While benign fibrous dysplasia can demonstrate increased radiotracer uptake on other modalities (i.e., bone scintigraphy, FDG PET/CT), its appearance on [(11)C]choline PET/CT has been largely overlooked in the literature. With the increasing use of [(11)C]choline PET/CT for biochemical recurrent prostate cancer evaluation, it is important to understand this potential mimicker of disease.

  20. Iodine-122-labeled amphetamine derivative with potential for PET brain blood-flow studies

    SciTech Connect

    Mathis, C.A.; Sargent, T. 3d.; Shulgin, A.T.

    1985-11-01

    The positron emitter SSI (t1/2 3.6 min) was collected from a xenon- SS/iodine- SS ( SSXe/ SSI) generator and incorporated into an amphetamine analog, 2,4-dimethoxy-N,N-dimethyl-5-( SSI)iodophenylisopropylamine (5-( SSI)-2,4-DNNA). The remote synthesis was achieved in 3 min with a 50% radioincorporation yield and a product radiopurity of greater than 98%. 5-( SSI)-2,4-DNNA was injected into a beagle dog and a brain section imaged with positron emission tomography (PET). The uptake and retention of 5-( SSI)-2,4-DNNA was compared to that of YSRb in the same animal. Dynamic PET activity data were obtained 0-20 min postinjection of 5-( SSI)-2,4-DNNA and showed rapid uptake by brain and good cerebral/extracerebral tissue distinction. A whole-body scan of a dog was also obtained with 5-123I-2,4-DNNA showing uptake in brain, lung, and other body organs. The feasibility of incorporating SSI into an extracted brain perfusion agent for use with PET is demonstrated.

  1. Potential of F-18 PET/CT in the Detection of Leptomeningeal Metastasis.

    PubMed

    Short, Ryan G; Bal, Susan; German, John P; Poelstra, Raymond J; Kardan, Arash

    2014-12-01

    Leptomeningeal metastasis (LM) is a rare but increasingly common condition in which malignant cells migrate to the meninges. The gold standard for diagnosing LM is detection of cancer cells in the cerebrospinal fluid (CSF). Contrast enhanced-magnetic resonance imaging (CE-MRI) is also used to diagnose LM. We describe a case of LM in which CE-MRI of the neuroaxis was initially negative for meningeal enhancement but F-18 fluorodeoxyglucose positron-emission tomography/computed tomography (F-18 FDG PET/CT) revealed hypermetabolism within the lumbar spinal canal. Positive F-18 FDG PET findings have rarely been reported in LM and, to our knowledge, have never been reported in the context of initially negative CE-MRI scanning of the neuroaxis. F-18 FDG PET/CT may represent an alternative modality for diagnosing LM in patients who are unable to undergo CE-MRI and/or LP or in patients for whom initial CE-MRI and/or LP are negative for LM.

  2. Read the Label First: Protect Your Pets

    EPA Pesticide Factsheets

    Learn about the importance of reading pet products labels before purchasing and using any product to insure the safety of your pets. Find tips for ways to reduce the changes of pets accessing potentially dangerous products.

  3. Organometallic Palladium Complexes with a Water-Soluble Iminophosphorane Ligand as Potential Anticancer Agents

    PubMed Central

    Carreira, Monica; Calvo-Sanjuán, Rubén; Sanaú, Mercedes; Marzo, Isabel; Contel, María

    2012-01-01

    The synthesis and characterization of a new water-soluble iminophosphorane ligand TPA=N-C(O)-2BrC6H4 (C,N-IM; TPA = 1,3,5-triaza-7-phosphaadamantane) 1 is reported. Oxidative addition of 1 to Pd2(dba)3 affords the orthopalladated dimer [Pd(μ-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) as a mixture of cis and trans isomers (1:1 molar ratio) where the iminophosphorane moeity behaves as a C,N-pincer ligand. By addition of different neutral or monoanionic ligands to 2, the bridging bromide can be cleaved and a variety of hydrophilic or water-soluble mononuclear organometallic palladium(II) complexes of the type [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L-L)] (L-L = acac (3); S2CNMe2 (4); 4,7-Diphenyl-1,10-phenanthrolinedisulfonic acid disodium salt C12H6N2(C6H4SO3Na)2 (5)); [Pd{C6H4(C(O)N=TPA-kC,N)-2}(L)Br] (L = P(mC6H4SO3Na)3 (6); P(3-Pyridyl)3 (7)) and, [Pd(C6H4(C(O)N=TPA)-2}(TPA)2Br] (8) are obtained as single isomers. All new complexes were tested as potential anticancer agents and their cytotoxicity properties were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells, normal T-lymphocytes (PBMC) and DU-145 human prostate cancer cells. Compounds [Pd(μ-Br){C6H4(C(O)N=TPA-kC,N)-2}]2 (2) and [Pd{C6H4(C(O)N=TPA-kC,N)-2}(acac)] 3 (which has been crystallographically characterized) display the higher cytotoxicity against the above mentioned cancer cell lines while being less toxic to normal T-lymphocytes (peripheral blood mononuclear cells: PBMC). In addition, 3 is very toxic to cisplatin resistant Jurkat shBak indicating a cell death pathway that may be different to that of cisplatin. The interaction of 2 and 3 with plasmid (pBR322) DNA is much weaker than that of cisplatin pointing to an alternative biomolecular target for these cytotoxic compounds. All the compounds show an interaction with human serum albumin (HSA) faster than that of cisplatin. PMID:23066172

  4. Macrophage Membrane Potential Changes Associated with γ 2b/γ 1 Fc Receptor-Ligand Binding

    NASA Astrophysics Data System (ADS)

    Young, John Ding-E; Unkeless, Jay C.; Kaback, H. Ronald; Cohn, Zanvil A.

    1983-03-01

    We have studied the effects of specific ligands of the receptor for the IgG Fc fragment (FcR) on the membrane potential (Δ Psi ) of the macrophage cell line J774 by the [3H]tetraphenylphosphonium ion equilibration technique. We observe a membrane depolarization with binding of FcR ligands that is dependent on the degree of receptor crosslinking. Binding of the FcR by monovalent ligands is not sufficient to induce a significant drop in Δ Psi , but a sustained depolarization lasting ≈ 20 min occurs with insoluble multivalent ligands. This FcR-mediated depolarization can be inhibited by substitution of Na+ from the cell incubation medium with monovalent choline cation, indicating that depolarization is due to Na+ influx into the cell. The extracellular Ca2+ does not play a significant role in membrane depolarization. The depolarization response is not triggered by monoclonal antibodies directed against three other major macrophage surface antigens. The cell depolarization mediated by FcR ligands is followed by a prolonged hyperpolarization that can be partially blocked by ouabain and quinine, indicating that the hyperpolarization response is a result of a combination of a Na+, K+-ATPase activity and a Ca2+-activated K+ conductance. These data support our hypothesis that the mouse macrophage IgG FcR is a ligand-dependent ion channel.

  5. Neural network evaluation of PET scans of the liver: a potentially useful adjunct in clinical interpretation.

    PubMed

    Preis, Ori; Blake, Michael A; Scott, James A

    2011-03-01

    To assess the performance of an artificial neural network in the evaluation of fluorine 18 fluorodeoxyglucose (FDG) uptake in the liver, compared with the results of expert interpretation of abdominal liver magnetic resonance (MR) images. The study was approved by the institutional human research committee and was HIPAA compliant, with waiver of informed consent. Digital data from positron emission tomographic (PET)/computed tomographic (CT) examinations, along with patient demographics, were obtained from 98 consecutive patients who underwent both whole-body PET/CT examinations and liver MR imaging examinations within 2 months. Interpretations of the scans from PET/CT examinations by trained neural networks were cross-classified with expert interpretations of the findings on images from MR examinations for intrahepatic benignity or malignancy. Receiver operating characteristic (ROC) curves were obtained for the designed networks. The significance of the difference between neural network ROC curves and the ROC curves detailing the performance of two expert blinded observers in the interpretation of liver FDG uptake was determined. A neural network incorporating lesion data demonstrated an ROC curve with an area under the curve (AUC) of 0.905 (standard error, 0.0370). A network independent of lesion data demonstrated an ROC curve with an AUC of 0.896 (standard error, 0.0386). These results compare favorably with results of expert blinded observers 1 and 2 who demonstrated ROCs with AUCs of 0.786 (standard error, 0.0522) and 0.796 (standard error, 0.0514), respectively. Following unblinding to network data, the AUCs for readers 1 and 2 improved to 0.924 (standard error, 0.0335) and 0.881 (standard error, 0.0409), respectively. Computers running artificial neural networks employing PET/CT scan data are sensitive and specific in the designation of the presence of intrahepatic malignancy, with comparison with interpretation by expert observers. When used in conjunction

  6. Paget Disease: A Potential Pitfall in PSMA PET for Prostate Cancer.

    PubMed

    Blazak, John Kenneth; Thomas, Paul

    2016-09-01

    We present a case of an 81-year-old man with multifocal Paget disease found on bone scan that was performed for incidentally diagnosed prostate cancer. The subsequent Ga-PSMA (HBED-CC) PET scan also displayed increased uptake in the same distribution. Multiple known tumors display increased Ga-PSMA uptake due to neovasculature. We postulate that increased Ga-PSMA uptake within the pagetoid bone relates to neovascularity known to occur in Paget disease. Such pagetic uptake could result in false-positive studies for bone metastases, particularly in the setting of less typical Paget disease.

  7. SiOx layer as functional barrier in polyethylene terephthalate (PET) bottles against potential contaminants from post-consumer recycled PET.

    PubMed

    Welle, Frank; Franz, Roland

    2008-06-01

    The barrier effect of a silicon oxide (SiOx) coating on the inner surface of PET bottles, in terms of the ability to reduce the migration of post-consumer compounds from the PET bottle wall into food simulants (3% acetic acid and 10% ethanol), was investigated. The barrier effect was examined by artificially introducing model substances (surrogates) into the PET bottle wall to represent a worst-case scenario. Test bottles with three different spiking levels up to approximately 1000 mg kg(-1) per surrogate were blown and coated on the inner surface. The SiOx-coated bottles and the non-coated reference bottles were filled with food simulants. From the specific migration of the surrogates with different bottles wall concentrations, the maximum surrogate concentrations in the bottle wall corresponding to migration of 10 microg l(-1) were determined. It was shown that the SiOx coating layer is an efficient barrier to post-consumer compounds. The maximum bottle wall concentrations of the surrogates corresponding to migration of 10 microg l(-1) were in the range of 200 mg kg(-1) for toluene and approximately 900 mg kg(-1) for benzophenone. Consequently, the SiOx coating allows use of conventionally recycled post-consumer PET flakes (without a super-clean recycling process) for packaging aqueous and low alcoholic foodstuffs (under cold-fill conditions) and protects food from migration of unwanted contaminants from post-consumer PET.

  8. Latest advances in novel cannabinoid CB(2) ligands for drug abuse and their therapeutic potential.

    PubMed

    Yang, Peng; Wang, Lirong; Xie, Xiang-Qun

    2012-02-01

    The field of cannabinoid (CB) drug research is experiencing a challenge as the CB(1) antagonist Rimonabant, launched in 2006 as an anorectic/anti-obesity drug, was withdrawn from the European market due to the complications of suicide and depression as side effects. There is interest in developing CB(2) drugs without CB(1) psychotropic side effects for drug-abuse treatment and therapeutic medication. The CB(1) receptor was discovered predominantly in the brain, whereas the CB(2) is mainly expressed in peripheral cells and tissues, and is involved in immune signal transduction. Conversely, the CB(2) receptor was recently detected in the CNS, for example, in the microglial cells and the neurons. While the CB(2) neurons activity remains controversial, the CB(2) receptor is an attractive therapeutic target for neuropathic pain, immune system, cancer and osteoporosis without psychoactivity. This review addresses CB drug abuse and therapeutic potential with a focus on the most recent advances on new CB(2) ligands from the literature as well as patents.

  9. Thoughts on interactions between PGRMC1 and diverse attested and potential hydrophobic ligands.

    PubMed

    Cahill, Michael A; Medlock, Amy E

    2017-07-01

    Progesterone Receptor Membrane Component 1 (PGRMC1) is located in many different subcellular locations with many different attested and probably location-specific functions. PGRMC1 was recently identified in the mitochondrial outer membrane where it interacts with ferrochelatase, the last enzyme in the heme synthetic pathway. It has been proposed that PGRMC1 may act as a chaperone to shuttle newly synthesized heme from the mitochondrion to cytochrome P450 (cyP450) enzymes. Here we consider potential roles that PGRMC1 may play in transferring heme, and other small hydrophobic ligands such as cholesterol and steroids, between the hydrophobic compartment of the membrane lipid bilayer interior to aqueous proteins, and perhaps to the membranes of other organelles. We review the synthesis and roles of especially PGRMC1- and cyP450-bound heme, the sources and transport of cholesterol, the involvement of PGRMC1 in cholesterol regulation, and the production of the first progestogen pregnenolone from cholesterol. We also show by clustering by inferred models of evolution (CLIME) analysis that PGRMC1 and related proteins exhibit co-evolution with a series of cyP450 enzymes, as well as a group of mitochondrial proteins lacking in several parasitic protist groups. Altogether, PGRMC1 is implicated with important roles in sterol synthesis and energy regulation that are dispensable in certain parasites. Some novel hypothetical models for PGRMC1 function are proposed to direct future investigative research. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. 4-Phenyl quinoline derivatives as potential serotonin receptor ligands with antiproliferative activity.

    PubMed

    Joshi, Pranaya V; Sayed, Alim A; RaviKumar, Ameeta; Puranik, Vedavati G; Zinjarde, Smita S

    2017-08-18

    Antagonists of signaling receptors are often effective non-toxic therapeutic agents. Over the years, there have been evidences describing the role of serotonin or 5-hydroxytryptamine (5-HT) in development of cancer. Although there are reports on the antiproliferative effects of some serotonin receptor antagonists, there are very few investigations related to understanding their structure-activity relationships. In this study, we report the screening of a library of 4-phenyl quinoline derivatives for their antiproliferative activities. Preliminary docking studies indicated that these ligands had the ability to bind to two of the serotonin receptors, 5-HT1B and 5-HT2B. The results of the in silico experiments were validated by performing in vitro studies on MCF-7 breast cancer cell line. The ethylpiperazine derivatives showed maximum toxicity against this cancer cell line. The compounds inhibited Calcium ion efflux (induced by serotonin) and ERK activation. One of the most active 4-phenyl quinoline derivatives (H3a) also induced apoptosis, thereby, suggesting the use of this scaffold as a potential anticancer drug. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Potential energy-driven spin manipulation via a controllable hydrogen ligand.

    PubMed

    Jacobson, Peter; Muenks, Matthias; Laskin, Gennadii; Brovko, Oleg; Stepanyuk, Valeri; Ternes, Markus; Kern, Klaus

    2017-04-01

    Spin-bearing molecules can be stabilized on surfaces and in junctions with desirable properties, such as a net spin that can be adjusted by external stimuli. Using scanning probes, initial and final spin states can be deduced from topographic or spectroscopic data, but how the system transitions between these states is largely unknown. We address this question by manipulating the total spin of magnetic cobalt hydride complexes on a corrugated boron nitride surface with a hydrogen-functionalized scanning probe tip by simultaneously tracking force and conductance. When the additional hydrogen ligand is brought close to the cobalt monohydride, switching between a correlated S = (1)/2 Kondo state, where host electrons screen the magnetic moment, and an S = 1 state with magnetocrystalline anisotropy is observed. We show that the total spin changes when the system is transferred onto a new potential energy surface that is defined by the position of the hydrogen in the junction. These results show how and why chemically functionalized tips are an effective tool to manipulate adatoms and molecules and a promising new method to selectively tune spin systems.

  12. Assessment of (10)B concentration in boron neutron capture therapy: potential of image-guided therapy using (18)FBPA PET.

    PubMed

    Shimosegawa, Eku; Isohashi, Kayako; Naka, Sadahiro; Horitsugi, Genki; Hatazawa, Jun

    2016-12-01

    In boron neutron capture therapy (BNCT) for cancer, the accurate estimation of (10)B tissue concentrations, especially in neighboring normal organs, is important to avoid adverse effects. The (10)B concentration in normal organs after loading with (10)B, however, has not been established in humans. In this study, we performed 4-borono-2-[(18)F]-fluoro-phenylalanine ((18)FBPA) PET in healthy volunteers and estimated the chronological changes in the (10)B concentrations of normal organs. In 6 healthy volunteers, whole-body (18)FBPA PET scans were repeated 7 times during 1 h, and the mean (18)FBPA distributions of 13 organs were measured. Based on the (18)FBPA PET data, we then estimated the changes in the (10)B concentrations of the organs when the injection of a therapeutic dose of (10)BPA-fructose complex ((10)BPA-fr; 30 g, 500 mg/kg body weight) was assumed. The maximum mean (18)FBPA concentrations were reached at 2-6 min after injection in all the organs except the brain and urinary bladder. The mean (18)FBPA concentration in normal brain plateaued at 24 min after injection. When the injection of a therapeutic dose of (10)BPA-fr was assumed, the estimated mean (10)B concentration in the kidney increased to 126.1 ± 24.2 ppm at 3 min after injection and then rapidly decreased to 30.9 ± 7.4 ppm at 53 min. The estimated mean (10)B concentration in the bladder gradually increased and reached 383.6 ± 214.7 ppm at 51 min. The mean (10)B concentration in the brain was estimated to be 7.6 ± 1.5 ppm at 57 min. (18)FBPA PET has a potential to estimate (10)B concentration of normal organs before neutron irradiation of BNCT when several assumptions are validated in the future studies.

  13. Radiobrominated m-tyrosine analog as potential CNS L-dopa PET tracer

    SciTech Connect

    De Jesus, O.T.; Mukherjee, J.

    1988-02-15

    Radiobrominated 6-bromo-m-tyrosine (6-BMT) was prepared and the time course of its localization in selected cerebral and peripheral organs in the mouse was determined. Since m-tyrosine is known to have L-dopa-like properties in vivo, our goal was to assess the utility of a radiolabeled analog as a tracer for cerebral L-dopa. Our preliminary results showed that substantial amounts of 6-BMT is extracted by the mouse brain and that the regional distribution and time course of the radiotracer is consistent with uptake in regions rich in dopamine neurons. Although a more thorough biochemical characterization of 6-BMT is necessary, this or other positron emitting analogs of m-tyrosine, such as an /sup 18/F labelled analog, may be useful PET tracers for the non-invasive study of dopamine turnover in humans.

  14. Trypsin-Ligand Binding Free Energies from Explicit and Implicit Solvent Simulations with Polarizable Potential

    PubMed Central

    Jiao, Dian; Zhang, Jiajing; Duke, Robert E.; Li, Guohui; Ren, Pengyu

    2009-01-01

    We have calculated the binding free energies of a series of benzamidine-like inhibitors to trypsin with a polarizable force field using both explicit and implicit solvent approaches. Free energy perturbation has been performed for the ligands in bulk water and in protein complex with molecular dynamics simulations. The calculated binding free energies are well within the accuracy of experimental measurement and the direction of change is predicted correctly in call cases. We analyzed the molecular dipole moments of the ligands in gas, water and protein environments. Neither binding affinity nor ligand solvation free energy in bulk water shows much dependence on the molecular dipole moments of the ligands. Substitution of the aromatic or the charged group in the ligand results in considerable change in the solvation energy in bulk water and protein whereas the binding affinity varies insignificantly due to cancellation. The effect of chemical modification on ligand charge distribution is mostly local. Replacing benzene with diazine has minimal impact on the atomic multipoles at the amidinium group. We have also utilized an implicit solvent based end-state approach to evaluate the binding free energies of these inhibitors. In this approach, the polarizable multipole model combined with Poisson-Boltzmann/surface area (PMPB/SA) provides the electrostatic interaction energy and the polar solvation free energy. Overall the relative binding free energies obtained from the PMPB/SA model are in good agreement with the experimental data. PMID:19399779

  15. Synthesis of fluorine-18 labeled rhodamine B: A potential PET myocardial perfusion imaging agent

    PubMed Central

    Heinrich, Tobias K.; Gottumukkala, Vijay; Snay, Erin; Dunning, Patricia; Fahey, Frederic H; Treves, S. Ted; Packard, Alan B.

    2009-01-01

    There is considerable interest in developing an 18F-labeled PET myocardial perfusion agent. Rhodamine dyes share several properties with 99mTc-MIBI, the most commonly used single-photon myocardial perfusion agent, suggesting that an 18F-labeled rhodamine dye might prove useful for this application. In addition to being lipophilic cations, like 99mTc-MIBI, rhodamine dyes are known to accumulate in the myocardium and are substrates for Pgp, the protein implicated in MDR1 multidrug resistance. As the first step in determining whether 18F-labeled rhodamines might be useful as myocardial perfusion agents for PET, our objective was to develop synthetic methods for preparing the 18F-labeled compounds so that they could be evaluated in vivo. Rhodamine B was chosen as the prototype compound for development of the synthesis because the ethyl substituents on the amine moieties of rhodamine B protect them from side reactions, thus eliminating the need to include (and subsequently remove) protecting groups. The 2′-[18F]fluoroethyl ester of rhodamine B was synthesized by heating rhodamine B lactone with [18F]fluoroethyltosylate in acetonitrile at 165°C for 30 min.using [18F]fluoroethyl tosylate, which was prepared by the reaction of ethyleneglycol ditosylate with Kryptofix 2.2.2, K2CO3, and [18F]NaF in acetonitrile for 10 min. at 90°C. The product was purified by semi-preparative HPLC to produce the 2′-[18F]-fluoroethylester in >97% radiochemical purity with a specific activity of 1.3 GBq/μmol, an isolated decay corrected yield of 35%, and a total synthesis time of 90 min. PMID:19783150

  16. A graphical method to compare the in vivo binding potential of PET radioligands in the absence of a reference region: application to [11C]PBR28 and [18F]PBR111 for TSPO imaging

    PubMed Central

    Guo, Qi; Owen, David R; Rabiner, Eugenii A; Turkheimer, Federico E; Gunn, Roger N

    2014-01-01

    Positron emission tomography (PET) radioligands for a reversible central nervous system (CNS) demand a high specific to nonspecific signal characterized by the binding potential (BPND). The quantification of BPND requires the determination of the nondisplaceable binding usually derived from a reference region devoid of the target of interest. However, for many CNS targets, there is no valid reference region available. In such cases, the total volume of distribution (VT) is often used as the outcome measure, which includes both the specific and nonspecific binding signals. Here we present a graphical method that allows for direct comparison of the binding potential of ligands using the regional VT data alone via linear regression. The method was first validated using literature data for five serotonin transporter ligands, for which a reference region exists, and then applied to two second generation 18 kDa translocator protein radioligands, namely [11C]PBR28 and [18F]PBR111. The analysis determined that [11C]PBR28 had a higher BPND than [18F]PBR111. PMID:24736889

  17. Accelerated flexible protein-ligand docking using Hamiltonian replica exchange with a repulsive biasing potential

    PubMed Central

    Ostermeir, Katja; Zacharias, Martin

    2017-01-01

    A molecular dynamics replica exchange based method has been developed that allows rapid identification of putative ligand binding sites on the surface of biomolecules. The approach employs a set of ambiguity restraints in replica simulations between receptor and ligand that allow close contacts in the reference replica but promotes transient dissociation in higher replicas. This avoids long-lived trapping of the ligand or partner proteins at nonspecific, sticky, sites on the receptor molecule and results in accelerated exploration of the possible binding regions. In contrast to common docking methods that require knowledge of the binding site, exclude solvent and often keep parts of receptor and ligand rigid the approach allows for full flexibility of binding partners. Application to peptide-protein, protein-protein and a drug-receptor system indicate rapid sampling of near-native binding regions even in case of starting far away from the native binding site outperforming continuous MD simulations. An application on a DNA minor groove binding ligand in complex with DNA demonstrates that it can also be used in explicit solvent simulations. PMID:28207811

  18. Optimization of pentadentate bispidines as bifunctional chelators for 64Cu positron emission tomography (PET).

    PubMed

    Comba, Peter; Hunoldt, Sebastian; Morgen, Michael; Pietzsch, Jens; Stephan, Holger; Wadepohl, Hubert

    2013-07-15

    Pentadentate bispidine ligands (3,7-diazabicyclo[3.3.1]nonanes) are optimized for maximum complex stability and facile functionalization with respect to their coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging). The pentadentate ligand with two tertiary amine donors, two p-methoxy substituted pyridines, and one unsubsituted pyridine group is shown to best fulfill important conditions for PET applications, i.e., fast complexation with Cu(II) and high in vivo stability, and this was predicted from the solution chemistry, in particular the Cu(II/I) redox potentials. Also, solvent partition experiments to model the lipophilicity of the Cu(II) complexes indicate that the bis p-methoxy substituted ligand leads to cationic complexes with an appreciable lipophilicity. This is supported by the biodistribution experiments that show that the complex with the p-methoxy substituted ligand is excreted very quickly and primarily via the renal route and therefore is ideally suited for the development of PET tracers with ligands of this type coupled to biomolecules.

  19. Bivalent peptidomimetic ligands of TrkC are biased agonists, selectively induce neuritogenesis, or potentiate neurotrophin-3 trophic signals

    PubMed Central

    Chen, Dianjun; Brahimi, Fouad; Angell, Yu; Li, Yu-Chin; Moscowicz, Jennifer; Saragovi, H. Uri; Burgess, Kevin

    2009-01-01

    This study was initiated to find small molecule ligands that would induce a functional response when docked with neurotrophin Trk receptors. “Minimalist” mimics of β-turns were designed for this purpose. These mimics are: (i) rigid, yet easily folded into turn-like conformations, and (ii) readily accessible from amino acids bearing most of the natural side chains. Gram quantities of sixteen of these turn mimics were prepared, then assembled into 152 fluorescein-labeled bivalent peptidomimetics via a solution-phase combinatorial method. Fluorescence-based screening of these molecules using cells transfected with the Trk receptors identified 10 potential ligands of TrkC, the receptor for neurotrophin-3 (NT-3). Analogs of these bivalent peptidomimetics with biotin replacing the fluorescein label were then prepared and tested to confirm that binding was not due to the fluorescein. Several assays were conducted to find the mode of action of these biotinylated compounds. Thus, direct binding, survival and neuritogenic, and biochemical signal transduction assays showed 8 of the original 10 hits were agonistic ligands binding to the ectodomain of TrkC. Remarkably, some peptidomimetics afford discrete signals leading to either cell survival or neuritogenic differentiation. The significance of this work is three fold. First, we succeeded in finding small, selective, proteolytically stable ligands for the TrkC receptor; there are very few of these in the literature. Second, we show that it is possible to activate distinct and biased signaling pathways with ligands binding at the ectodomain of wild type receptors. Third, the discovery that some peptidomimetics initiate different modes of cell signaling increases their potential as pharmacological probes and therapeutic leads. PMID:19735123

  20. Multitracer Molecular Imaging of Paget Disease Targeting Bone Remodeling, Fatty Acid Metabolism, and PSMA Expression on PET/CT.

    PubMed

    Derlin, Thorsten; Weiberg, Desiree; Sohns, Jan M

    2016-12-01

    Paget disease is a chronic disorder resulting in enlarged and misshapen bones, and is caused by disorganized bone remodeling. We present the case of an 85-year-old man with prostatic adenocarcinoma and known Paget disease of the right iliac bone who underwent Ga-prostate-specific membrane antigen ligand, C-acetate, and F-fluoride PET/CT for restaging of cancer. On all PET scans, increased tracer accumulation was observed in Paget disease of bone. Besides that Paget disease may mimic metastases on PET/CT using various radiotracers, including Ga-prostate-specific membrane antigen ligands and C-acetate, this case highlights the potential of multiparametric disease characterization on PET.

  1. [11C]PR04.MZ, a promising DAT ligand for low concentration imaging: synthesis, efficient 11C-0-methylation and initial small animal PET studies

    SciTech Connect

    Riss, P.J.; Hooker, J.; Alexoff, D.; Kim, Sung-Won; Fowler, J.S.; Roesch, F.

    2009-05-01

    PR04.MZ was designed as a highly selective dopamine transporter inhibitor, derived from natural cocaine. Its binding profile indicates that [{sup 11}C]PR04.MZ may be suited as a PET radioligand for the non-invasive exploration of striatal and extrastriatal DAT populations. As a key feature, its structural design facilitates both, labelling with fluorine-18 at its terminally fluorinated butynyl moiety and carbon-11 at its methyl ester function. The present report concerns the efficient [{sup 11}C]MeI mediated synthesis of [{sup 11}C]PR04.MZ from an O-desmethyl precursor trifluoroacetic acid salt with Rb{sub 2}CO{sub 3} in DMF in up to 95 {+-} 5% labelling yield. A preliminary {mu}PET-experiment demonstrates the reversible, highly specific binding of [{sup 11}C]PR04.MZ in the brain of a male Sprague-Dawley rat.

  2. Effect of temperature on the release of intentionally and non-intentionally added substances from polyethylene terephthalate (PET) bottles into water: chemical analysis and potential toxicity.

    PubMed

    Bach, Cristina; Dauchy, Xavier; Severin, Isabelle; Munoz, Jean-François; Etienne, Serge; Chagnon, Marie-Christine

    2013-08-15

    The purpose of this study was to investigate the impact of temperature on the release of PET-bottle constituents into water and to assess the potential health hazard using in vitro bioassays with bacteria and human cell lines. Aldehydes, trace metals and other compounds found in plastic packaging were analysed in PET-bottled water stored at different temperatures: 40, 50, and 60°C. In this study, temperature and the presence of CO2 increased the release of formaldehyde, acetaldehyde and antimony (Sb). In parallel, genotoxicity assays (Ames and micronucleus assays) and transcriptional-reporter gene assays for estrogenic and anti-androgenic activity were performed on bottled water extracts at relevant consumer exposure levels. As expected, and in accordance with the chemical formulations specified for PET bottles, neither phthalates nor UV stabilisers were present in the water extracts. However, 2,4-di-tert-butylphenol, a degradation compound of phenolic antioxidants, was detected. In addition, an intermediary monomer, bis(2-hydroxyethyl)terephthalate, was found but only in PET-bottled waters. None of the compounds are on the positive list of EU Regulation No. 10/2011. However, the PET-bottled water extracts did not induce any cytotoxic, genotoxic or endocrine-disruption activity in the bioassays after exposure. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. CpG oligodeoxynucleotide ligand potentiates the activity of the pVAX1-Sj26GST

    PubMed Central

    LU, JUN; JIANG, SHAN; YE, SONG; DENG, YUN; MA, SHUAI; LI, CHAO-PIN

    2013-01-01

    Schistosomiasis is considered one of the most important neglected tropical diseases and remains a major public health problem in endemic countries. Toll-like receptor (TLR) ligands have been investigated as potential vaccine adjuvants for tumor and virus immunotherapy. However, few TLR ligands affecting schistosoma vaccines have been characterized. In this study, we evaluated a TLR9 ligand (CpG oligodeoxynucleotide 1826, CpG) as an adjuvant for a partially protective DNA vaccine encoding a 26-kDa glutathione S-transferase of Schistosoma japonicum (pVAX1-Sj26GST). Vaccination with pVAX1-Sj26GST in combination with CpG inhibited Treg immunosuppressive function, upregulated the production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, IL-2 and IL-6, and decreased CD4+CD8+Foxp3+ expression in vitro, which may contribute to the escape from Treg-mediated suppression during vaccination, allowing expansion of antigen-specific T cells against pathogens. In conclusion, our data demonstrated that selective TLR ligand combination may increase protective efficacy against schistosomiasis, which may synergistically antagonize Treg-mediated suppression. PMID:24648995

  4. Detecting a dexmedetomidine-evoked reduction of noradrenaline release in the human brain with the alpha2C-adrenoceptor PET ligand [11C]ORM-13070.

    PubMed

    Lehto, Jussi; Scheinin, Annalotta; Johansson, Jarkko; Marjamäki, Päivi; Arponen, Eveliina; Scheinin, Harry; Scheinin, Mika

    2016-02-01

    PET imaging can for some neurotransmitters be used to measure synaptic neurotransmitter concentrations. The objective of this study was to test whether the receptor binding of the α2C -AR antagonist PET tracer [(11)C]ORM-13070 would increase in response to reductions in synaptic noradrenaline, evoked by dexmedetomidine as a sympatholytic drug challenge. Six subjects underwent a control PET scan and two dexmedetomidine PET scans. Dexmedetomidine was infused with target plasma concentrations of 0.6 and 0.2 ng/ml. Tracer binding was measured by voxel-based analysis of bound per free (B/F) images. ROI-based analysis was performed in the dorsal striatum and in the thalamus. Vital signs and drug concentrations in plasma were measured and the sedative effect was estimated with the visual analog scale. In the voxel-based analysis, dexmedetomidine administration was associated with a tendency to increased B/F tracer in the right thalamus (mean, +17%, P = 0.14, and +19%, P = 0.05, with the low and high dose, respectively). Tracer binding in the dorsal striatum was unaffected by dexmedetomidine. A cluster with significantly increased B/F tracer (+42%, P = 0.01) was seen in the right superior temporal gyrus with low-dose dexmedetomidine, but not after the high dose. Brain uptake of [(11)C]ORM-13070 has previously been shown to be reduced in conditions of increased synaptic noradrenaline concentrations. In this study, tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, but statistical significance was not reached.

  5. Biological redundancy of endogenous GPCR ligands in the gut and the potential for endogenous functional selectivity

    PubMed Central

    Thompson, Georgina L.; Canals, Meritxell; Poole, Daniel P.

    2014-01-01

    This review focuses on the existence and function of multiple endogenous agonists of the somatostatin and opioid receptors with an emphasis on their expression in the gastrointestinal tract. These agonists generally arise from the proteolytic cleavage of prepropeptides during peptide maturation or from degradation of peptides by extracellular or intracellular endopeptidases. In other examples, endogenous peptide agonists for the same G protein-coupled receptors can be products of distinct genes but contain high sequence homology. This apparent biological redundancy has recently been challenged by the realization that different ligands may engender distinct receptor conformations linked to different intracellular signaling profiles and, as such the existence of distinct ligands may underlie mechanisms to finely tune physiological responses. We propose that further characterization of signaling pathways activated by these endogenous ligands will provide invaluable insight into the mechanisms governing biased agonism. Moreover, these ligands may prove useful in the design of novel therapeutic tools to target distinct signaling pathways, thereby favoring desirable effects and limiting detrimental on-target effects. Finally we will discuss the limitations of this area of research and we will highlight the difficulties that need to be addressed when examining endogenous bias in tissues and in animals. PMID:25506328

  6. The scope and potentials of functional radionuclide imaging towards advancing personalized medicine in oncology: emphasis on PET-CT.

    PubMed

    Basu, Sandip

    2012-01-01

    Behavioral heterogeneity within a given patient cohort has been a major challenge in clinical practice and is probably most prominently observed in the field of oncology. This has been the prime impetus of the cutting-edge preclinical and clinical research studies over recent times, many of which seek to further stratify patients based on patients' genetic, proteomic, and metabolic profile (the three key components of "-omics" research), in order to select the appropriate therapy according to an individual's best-fit. Data from functional radionuclide imaging particularly that obtained from PET-CT, with regard to characterization of an individual's tumor phenotype, can play a very important role in answering some of the critical decision-making questions on an individual basis. The role of molecular imaging with PET, SPECT, and planar radionuclide technologies is not confined to early response assessment of administered therapeutics (which is its major benefit compared to conventional methods), rather it has a much broader perspective and encompasses multiple steps in decision making steps of patient management. The immense impact of the radionuclide-based molecular imaging techniques on the selection of an appropriate treatment (at initial diagnosis, during therapy, or after therapy) or in defining the tumor biology has been documented and increasingly recognized through both large and small-scale studies. However, there has been relatively less systematic effort towards the development of a successful and definitive clinical model of "personalized cancer medicine" (based on accurate disease triaging on an individual basis) by the medical community that would be suitable for routine adoption. In this paper, an endeavor has been made to explore the potential of this approach and underscore the areas that would require further critical evaluation to make this a reality.

  7. PSMA PET and Radionuclide Therapy in Prostate Cancer.

    PubMed

    Bouchelouche, Kirsten; Turkbey, Baris; Choyke, Peter L

    2016-11-01

    Prostate cancer (PCa) is the most common malignancy in men and a major cause of cancer death. Accurate imaging plays an important role in diagnosis, staging, restaging, detection of biochemical recurrence, and for therapy of patients with PCa. Because no effective treatment is available for advanced PCa, there is an urgent need to develop new and more effective therapeutic strategies. To optimize treatment outcome, especially in high-risk patients with PCa, therapy for PCa is moving rapidly toward personalization. Medical imaging, including positron emission tomography (PET)/computed tomography (CT), plays an important role in personalized medicine in oncology. In the recent years, much focus has been on prostate-specific membrane antigen (PSMA) as a promising target for imaging and therapy with radionuclides, as it is upregulated in most PCa. In the prostate, one potential role for PSMA PET imaging is to help guide focal therapy. Several studies have shown great potential of PSMA PET/CT for initial staging, lymph node staging, and detection of recurrence of PCa, even at very low prostate-specific antigen values after primary therapy. Furthermore, studies have shown that PSMA PET/CT has a higher detection rate than choline PET/CT. Radiolabeled PSMA ligands for therapy show promise in several studies with metastatic PCa and is an area of active investigation. The "image and treat" strategy, with radiolabeled PSMA ligands, has the potential to improve the treatment outcome of patients with PCa and is paving the way for precision medicine in PCa. The aim of this review is to give an overview of recent advancement in PSMA PET and radionuclide therapy for PCa.

  8. Potential Role of Pet Animals in Household Transmission of Methicillin-Resistant Staphylococcus aureus: A Narrative Review

    PubMed Central

    Bramble, Manuel; Morris, Daniel; Tolomeo, Pam

    2011-01-01

    Abstract In this narrative review, we found numerous reports suggesting that dogs and cats may play a role in household methicillin-resistant Staphylococcus aureus (MRSA) transmission and recurrent MRSA infection in human contacts. Future work should emphasize elucidating more clearly the prevalence of MRSA in household pets and characterize transmission dynamics of MRSA humans and pet animals. PMID:21142959

  9. Potential role of pet animals in household transmission of methicillin-resistant Staphylococcus aureus: a narrative review.

    PubMed

    Bramble, Manuel; Morris, Daniel; Tolomeo, Pam; Lautenbach, Ebbing

    2011-06-01

    In this narrative review, we found numerous reports suggesting that dogs and cats may play a role in household methicillin-resistant Staphylococcus aureus (MRSA) transmission and recurrent MRSA infection in human contacts. Future work should emphasize elucidating more clearly the prevalence of MRSA in household pets and characterize transmission dynamics of MRSA humans and pet animals.

  10. Herbo-mineral based Schiff base ligand and its metal complexes: Synthesis, characterization, catalytic potential and biological applications.

    PubMed

    Kareem, Abdul; Laxmi; Arshad, Mohammad; Nami, Shahab A A; Nishat, Nahid

    2016-07-01

    Schiff base ligand, (L), derived from condensation reaction of 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, (curcumin), with pyridine-3-carboxamide, (nicotinamide), and its complexes of Co(II), Ni(II) and Cu(II) ions, containing 1,10-phenanthroline as auxiliary ligand were synthesized and characterized by various physico-chemical techniques. From the micro analytical data, the stoichiometry of the complexes 1:1 (metal: ligand) was ascertained. The Co(II) and Cu(II) forms octahedral complexes, while the geometric structure around Ni(II) atom can be described as square planar. The catalytic potential of the metal complexes have been evaluated by recording the rate of decomposition of hydrogen peroxide. The results reveal that the percent decomposition of H2O2increases with time and the highest value (50.50%) was recorded for Co(II) complex. The ligand and its complexes were also screened for their in vitro antibacterial activity against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pyogenes and Pseudomonas aeruginosa. The relative order of antibacterial activity against S. Pyogenes, S. aureus and E. coli is Cu(II)>Ni(II)>Co(II)>(L); while with P. aeruginosa, K. pneumoniae the order of activity is Cu(II)>Co(II)>Ni(II)>(L). The anthelmintic screening was performed using Pheretima posthuma. The order of anthelmintic activity of ligand and its complexes is [(Phen)CuLCl2]>[(Phen)CoLCl2]>[(Phen)NiL]Cl2>(L).

  11. Combined TLR7/8 and TLR9 Ligands Potentiate the Activity of a Schistosoma japonicum DNA Vaccine

    PubMed Central

    Wang, Xuefeng; Dong, Liyang; Ni, Hongchang; Zhou, Sha; Xu, Zhipeng; Hoellwarth, Jason Shih; Chen, Xiaojun; Zhang, Rongbo; Chen, Qiaoyun; Liu, Feng; Wang, Jun; Su, Chuan

    2013-01-01

    Background Toll-like receptor (TLR) ligands have been explored as vaccine adjuvants for tumor and virus immunotherapy, but few TLR ligands affecting schistosoma vaccines have been characterized. Previously, we developed a partially protective DNA vaccine encoding the 26-kDa glutathione S-transferase of Schistosoma japonicum (pVAX1-Sj26GST). Methodology/Principal Findings In this study, we evaluated a TLR7/8 ligand (R848) and a TLR9 ligand (CpG oligodeoxynucleotides, or CpG) as adjuvants for pVAX1-Sj26GST and assessed their effects on the immune system and protection against S. japonicum. We show that combining CpG and R848 with pVAX1-Sj26GST immunization significantly increases splenocyte proliferation and IgG and IgG2a levels, decreases CD4+CD25+Foxp3+ regulatory T cells (Treg) frequency in vivo, and enhances protection against S. japonicum. CpG and R848 inhibited Treg-mediated immunosuppression, upregulated the production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, IL-2, and IL-6, and decreased Foxp3 expression in vitro, which may contribute to prevent Treg suppression and conversion during vaccination and allow expansion of antigen-specific T cells against pathogens. Conclusions Our data shows that selective TLR ligands can increase the protective efficacy of DNA vaccines against schistosomiasis, potentially through combined antagonism of Treg-mediated immunosuppression and conversion. PMID:23593527

  12. Synthesis, characterisation, spectral, thermal, XRD, molecular modelling and potential antibacterial study of metal complexes containing octadentate azodye ligands

    NASA Astrophysics Data System (ADS)

    Mahapatra, Bipin Bihari; Chaulia, Satyanarayan; Sarangi, Ashish Kumar; Dehury, Satyanarayan; Panda, Jnyanaranjan

    2015-05-01

    Twelve tetrametallic complexes of Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II) with two new octadentate azodye ligands, 4,4‧-bis(2‧,4‧-dihydroxy-5‧carboxyphenylazo) diphenylether (LH6) and 4,4‧-bis(2‧,4‧-dihydroxy-5‧-acylphenylazo) diphenylether (L‧H4) have been synthesised. The structural elucidation of the complexes was made basing upon analytical, conductance, magnetic susceptibility, IR, electronic spectra, ESR, NMR, ESI-MS, TG, DTG, DTA and X-ray diffraction (powder pattern) data. The cobalt (II) and nickel (II) complexes are found to be octahedral, copper (II) complexes are distorted octahedral and a tetrahedral stereochemistry has been suggested to zinc (II), cadmium (II) and mercury (II) complexes. The thermal analysis data provided the kinetic parameters as order of decomposition reaction, activation energy and frequency factor. The geometry of the ligands and their Co(II), Ni(II), Cu(II) and Zn(II) complexes were optimised and their physicochemical properties were calculated by using molecular modelling procedure. The ESI-MS determination supports the molecular formula and molecular weight of the ligands and the complexes. The Ni(II) complex is found to have a triclinic crystal system. The potential antibacterial study of the two ligands and eight metal complexes was made by cup-plate method against one gram positive and one gram negative bacteria. The results showed increase in the activity of some metal complexes as compare with azodye ligands.

  13. Potential for pet animals to harbour methicillin-resistant Staphylococcus aureus when residing with human MRSA patients.

    PubMed

    Morris, D O; Lautenbach, E; Zaoutis, T; Leckerman, K; Edelstein, P H; Rankin, S C

    2012-06-01

    Colonization by methicillin-resistant Staphylococcus aureus (MRSA) may be persistent in people and is horizontally transmissible. The scientific literature suggests that domestic pets may also participate in cross-transmission of MRSA within households. The objectives of this study were to evaluate the prevalence of and risk factors for MRSA carriage by pets residing in households with an MRSA-infected person. From 66 households in which an MRSA-infected patient resided, we screened 47 dogs and 52 cats using a swab protocol. Isolates from pets and humans were genotyped using two techniques and compared for concordance. Human participants completed a 22-question survey of demographic and epidemiologic data relevant to staphylococcal transmission. Eleven of 99 pets (11.5%) representing 9 (13.6%) of households were MRSA-positive, but in only six of these households were the human and animal-source strains genetically concordant. Human infection by strain USA 100 was significantly associated with pet carriage [OR = 11.4 (95% CI 1.7, 76.9); P = 0.013]. Yet, for each day of delay in sampling the pet after the person's MRSA diagnosis, the odds of isolating any type of MRSA from the pet decreased by 13.9% [(95% CI 2.6, 23.8); P = 0.017)]. It may be concluded that pets can harbour pandemic strains of MRSA while residing in a household with an infected person. However, the source of MRSA to the pet cannot always be attributed to the human patient. Moreover, the rapid attrition of the odds of obtaining a positive culture from pets over time suggests that MRSA carriage may be fleeting. © 2012 Blackwell Verlag GmbH.

  14. Potential for pet animals to harbor methicillin-resistant Staphylococcus aureus (MRSA) when residing with human MRSA patients

    PubMed Central

    Morris, Daniel O.; Lautenbach, Ebbing; Zaoutis, Theoklis; Leckerman, Kateri; Edelstein, Paul H.; Rankin, Shelley C.

    2011-01-01

    Summary Colonization by methicillin-resistant Staphylococcus aureus (MRSA) may be persistent in people, and is horizontally transmissible. The scientific literature suggests that domestic pets may also participate in cross-transmission of MRSA within households. The objectives of this study were to evaluate the prevalence of and risk factors for MRSA carriage by pets residing in households with an MRSA-infected person. From 66 households in which an MRSA infected patient resided, we screened 47 dogs and 52 cats using a swab protocol. Isolates from pets and humans were genotyped using two techniques, and compared for concordance. Human participants completed a 22-question survey of demographic and epidemiologic data relevant to staphylococcal transmission. Eleven of 99 pets (11.5%) representing 9 (13.6%) of households were MRSA-positive, but in only 6 of these households were the human and animal-source strains genetically concordant. Human infection by strain USA 100 was significantly associated with pet carriage [OR = 11.4 (95% C.I. 1.7, 76.9); p=0.013]. Yet, for each day of delay in sampling the pet after the person’s MRSA diagnosis, the odds of isolating any type of MRSA from the pet decreased by 13.9% [(95% C.I. 2.6%, 23.8%); p=0.017)]. It may be concluded that pets can harbor pandemic strains of MRSA while residing in a household with an infected person. However, the source of MRSA to the pet cannot always be attributed to the human patient. Moreover, the rapid attrition of the odds of obtaining a positive culture from pets over time suggests that MRSA carriage may be fleeting. PMID:22233337

  15. Strand breakage by decay of DNA-bound (124)I provides a basis for combined PET imaging and Auger endoradiotherapy.

    PubMed

    Lobachevsky, Pavel; Clark, George R; Pytel, Patrycja D; Leung, Brenda; Skene, Colin; Andrau, Laura; White, Jonathan M; Karagiannis, Tom; Cullinane, Carleen; Lee, Boon Q; Stuchbery, Andrew; Kibedi, Tibor; Hicks, Rodney J; Martin, Roger F

    2016-11-01

    Purpose DNA ligands labelled with (125)I induce cytotoxic DNA double-strand breaks (DSB), suggesting a potential for Auger endoradiotherapy. Since the 60-day half-life of (125)I is suboptimal for therapy, we have investigated another Auger-emitter (124)I, with shorter half-life (4.18 days), and the additional feature of positron-emission, enabling positron emission tomography (PET) imaging. The purpose of this study was to compare the two radionuclides on the basis of DNA DSB per decay. Materials and methods Using a (124)I- (or (125)I)-labelled minor groove binding DNA ligand, we investigated DNA breakage using the plasmid DNA assay. Biodistribution of the conjugate of the labelled ligand with transferrin was investigated in nude mice bearing a K562 human lymphoma xenograft. Results The probability of DSB per decay was 0.58 and 0.85 for (124)I and (125)I, respectively, confirming the therapeutic potential of the former. The crystal structure of the ligand DNA complex shows the iodine atom deep within the minor groove, consistent with the high efficiency of induced damage. Biodistribution studies, including PET imaging, showed distinctive results for the conjugate, compared to the free ligand and transferrin, consistent with receptor-mediated delivery of the ligand. Conclusions Conjugation of (124)I-labelled DNA ligands to tumor targeting peptides provides a feasible strategy for Auger endoradiotherapy, with the advantage of monitoring tumor targeting by PET imaging.

  16. Four-body atomic potential for modeling protein-ligand binding affinity: application to enzyme-inhibitor binding energy prediction

    PubMed Central

    2013-01-01

    Background Models that are capable of reliably predicting binding affinities for protein-ligand complexes play an important role the field of structure-guided drug design. Methods Here, we begin by applying the computational geometry technique of Delaunay tessellation to each set of atomic coordinates for over 1400 diverse macromolecular structures, for the purpose of deriving a four-body statistical potential that serves as a topological scoring function. Next, we identify a second, independent set of three hundred protein-ligand complexes, having both high-resolution structures and known dissociation constants. Two-thirds of these complexes are randomly selected to train a predictive model of binding affinity as follows: two tessellations are generated in each case, one for the entire complex and another strictly for the isolated protein without its bound ligand, and a topological score is computed for each tessellation with the four-body potential. Predicted protein-ligand binding affinity is then based on an empirically derived linear function of the difference between both topological scores, one that appropriately scales the value of this difference. Results A comparison between experimental and calculated binding affinity values over the two hundred complexes reveals a Pearson's correlation coefficient of r = 0.79 with a standard error of SE = 1.98 kcal/mol. To validate the method, we similarly generated two tessellations for each of the remaining protein-ligand complexes, computed their topological scores and the difference between the two scores for each complex, and applied the previously derived linear transformation of this topological score difference to predict binding affinities. For these one hundred complexes, we again observe a correlation of r = 0.79 (SE = 1.93 kcal/mol) between known and calculated binding affinities. Applying our model to an independent test set of high-resolution structures for three hundred diverse enzyme-inhibitor complexes

  17. RutheniumII complexes bearing fused polycyclic ligands: from fundamental aspects to potential applications.

    PubMed

    Troian-Gautier, Ludovic; Moucheron, Cécile

    2014-04-22

    In this review, we first discuss the photophysics reported in the literature for mononuclear ruthenium complexes bearing ligands with extended aromaticity such as dipyrido[3,2-a:2',3'-c]phenazine (DPPZ), tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]-phenazine (TPPHZ),  tetrapyrido[3,2-a:2',3'-c:3'',2''-h:2''',3'''-j]acridine (TPAC), 1,10-phenanthrolino[5,6-b]1,4,5,8,9,12-hexaazatriphenylene (PHEHAT) 9,11,20,22-tetraaza- tetrapyrido[3,2-a:2',3'-c:3'',2''-l:2''',3'''-n]pentacene (TATPP), etc. Photophysical properties of binuclear and polynuclear complexes based on these extended ligands are then reported. We finally develop the use of binuclear complexes with extended π-systems for applications such as photocatalysis.

  18. Synthesis and Characterization of a Tetramethyl Furanone Functionalized Diiminedioxime, A Potential Ligand for 64Cu Radiopharmaceuticals, and its Copper(II) and Nickel(II) Complexes

    PubMed Central

    Kiani, Salma; Staples, Richard J.; Treves, S. Ted; Packard, Alan B.

    2009-01-01

    As part of our on-going effort to develop 64Cu-based radiopharmaceuticals for PET (positron emission tomography) imaging of multidrug resistance in cancer, we prepared a tetramethylfuranone-functionalized diiminedioxime ligand, TMFPreH (TMFPreH = 4-[3-(4-Hydroxyimino-2,2,5,5-dimethyl-dihydro-furan-3-ylideneamino)-propylimino]-2,2,5,5-tetramethyl-dihydro-furan-3-one oxime) and its Cu(II) and Ni(II) complexes. When the copper(II) complex was prepared from Cu(ClO4)2 in ethanol, it was isolated as a Cu(II)-bridged dimer, but when it was prepared from Cu(OAc)2 and heated in acetone, an unusual example of an acetone adduct of the ligand is formed by reduction of one of the imine double bonds by the solvent. The Ni(II) complex is square pyramidal with the perchlorate counterion at the apex. PMID:20161333

  19. Targeting programmed cell death ligand 1 in osteosarcoma: an auto-commentary on therapeutic potential.

    PubMed

    Shen, Jacson K; Cote, Gregory M; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng

    Programmed cell death ligand 1 (PDL1) expression was recently shown to correlate with tumor-infiltrating lymphocytes (TILs) in a subset of osteosarcoma patients. Among clinical factors evaluated across human osteosarcoma samples, a pulmonary origin of metastases correlated with high PDL1 expression and prominent TILs. Considering that multiple agents targeting PD-1/PDL1 are under development, targeting this immune checkpoint may be a novel immunotherapeutic route for osteosarcoma in future clinical trials.

  20. Select corn coproducts from the ethanol industry and their potential as ingredients in pet foods.

    PubMed

    de Godoy, M R C; Bauer, L L; Parsons, C M; Fahey, G C

    2009-01-01

    The objectives of this study were to determine the chemical composition and nutritive value of corn protein product 1 (CPP 1), corn protein product 2 (CPP 2), and corn fiber (CF), novel coproducts of the ethanol industry, and compare these feed ingredients with standard plant protein ingredients [soybean meal (SBM), distillers dried grains with solubles (DDGS), corn gluten meal (CGlM), and corn germ meal (CGeM)], and to compare CF sources (CF control 1 and control 2) with standard fiber sources (peanut hulls, Solka-Floc, and beet pulp) commonly used in pet foods. Corn fiber, CPP 1, and CPP 2 were produced at a pilot-scale modified dry-grind plant, with CPP 2 having a greater degree of purification than CPP 1. Crude protein values for CPP 2 and CPP 1 were 57.3 and 49.7%, respectively. Total dietary fiber concentration was 29% for CPP 2 and 23.5% for CPP 1. Acid-hydrolyzed fat and GE concentrations were similar for these ingredients. In a protein efficiency ratio assay, no differences (P > 0.05) in feed intake, BW gain, or CP intake were noted for CPP 2, CPP 1, or CGlM. However, feeding CPP 2 resulted in a greater (P < 0.05) G:F ratio and protein efficiency ratio than CPP 1 and CGlM. In a cecectomized rooster assay, CGlM had numerically the greatest standardized total AA, total essential AA, and total nonessential AA digestibilities, but they were not different (P > 0.05) from CPP 1 or SBM values. Corn germ meal resulted in the least values, but they were not different from those for DDGS and CPP 1. The greatest values for true nitrogen-corrected ME were obtained with CGlM, followed by CPP 2, DDGS, CPP 1, SBM, and CGeM. Distillers dried grains with solubles and CPP 1 had similar true nitrogen-corrected ME values, and they were not different from values for CPP 2 and SBM. In vitro CP disappearance was greatest (P < 0.05) for CGlM (94.1%), intermediate for DDGS (76.8%) and CPP 1 (77.5%), and least for CPP 2 (74.1%) and CGeM (67.7%). Corn fibers contained predominantly

  1. Selective fluorescence sensing of Cu(II) and Zn(II) using a simple Schiff base ligand: Naked eye detection and elucidation of photoinduced electron transfer (PET) mechanism

    NASA Astrophysics Data System (ADS)

    Ganguly, Aniruddha; Ghosh, Soumen; Kar, Samiran; Guchhait, Nikhil

    2015-05-01

    A simple Schiff base compound 2-((cyclohexylmethylimino)-methyl)-naphthalen-1-ol (2CMIMN1O) has been synthesized and characterized by 1H NMR, 13C NMR and FT-IR spectroscopic techniques. A significantly low emission yield of the compound has been rationalized in anticipation with photo-induced electron transfer (PET) from the imine receptor moiety to the naphthalene fluorophore unit. Consequently, an evaluation of the transition metal ion-induced modification of the fluorophore-receptor communication reveals the promising prospect of the title compound to function as a chemosensor for Cu2+ and Zn2+ ions selectively, through remarkable fluorescence enhancement as well as visual changes. While perturbation of the PET process has been argued to be the plausible mechanism behind the fluorescence enhancement, the selectivity for these two metal ions has been interpreted on the grounds of an appreciably strong binding interaction. Particularly notable aspects regarding the chemosensory activity of the compound is its ability to detect the aforesaid transition metal ions down to the level of micromolar concentration (detection limit being 2.74 and 2.27 ppm respectively), along with a simple and efficient synthetic procedure.

  2. Whole body biodistribution and radiation dosimetry in humans of a new PET ligand, [(18)F]-FEPPA, to image translocator protein (18 kDa).

    PubMed

    Mizrahi, Romina; Rusjan, Pablo M; Vitcu, Irina; Ng, Alvina; Wilson, Alan A; Houle, Sylvain; Bloomfield, Peter M

    2013-06-01

    [(18)F]-FEPPA is a translocator protein (18 kDa, TSPO) positron emission tomography (PET) radiotracer. Radiation dosimetry was estimated from the whole body biodistribution, taking into consideration TSPO rs6971 (Ala147Thr) polymorphism. [(18)F]-FEPPA whole body PET scans were acquired for six healthy subjects. Time-activity curves were generated from regions of interest of nine organs, from which normalized accumulated activities were calculated and thus internal dose, using OLINDA/EXM 1.1. Genotyping of rs6971, associated with high- and low-affinity [(18)F]-FEPPA binding (high-affinity binder (HAB) and low-affinity binder (LAB)), was performed. Five subjects exhibited the C/C (HAB) allele, and the other carried the minor allele T/T (LAB). The LAB whole body biodistribution showed highest radioactivity accumulation in bladder, whereas in HABs, the spleen received the highest dose. The effective dose of the single LAB (16.3 μSv/MBq) was 23 % less than the mean of the HABs (21.0 ± 2.9 μSv/MBq). When including all subjects, the effective dose was 20.2 ± 3.0 μSv/MBq. [(18)F]-FEPPA radiation dose is consistent with other (18)F-labeled radioligands and the Ala147Thr genotype agreed with [(18)F]-FEPPA distribution.

  3. Bacillus Calmette-Guerin injections for melanoma immunotherapy: potential for a false-positive PET/CT.

    PubMed

    Sogge, Steven M; Fotos, Joseph S; Tulchinsky, Mark

    2015-04-01

    An 82-year-old woman presented for routine follow-up PET/CT after undergoing local melanoma resection in the left lower leg, isolated limb infusion chemotherapy, and immunomodulation therapy with Bacillus Calmette-Guérin (BCG) vaccine. Symmetric, bilateral, moderately intense FDG avid axillary and inguinal cutaneous nodules were observed that were new from the prior PET-CT. The patient had developed skin lesions at the BCG injection sites several months before the study. The case raises awareness to PET/CT appearance of local inflammatory response to BCG injection, which could be mistaken by an unaware reader for recurrent melanoma.

  4. Pet Health

    MedlinePlus

    ... Before getting a pet, think carefully about which animal is best for your family. What is each ... Does anyone have pet allergies? What type of animal suits your lifestyle and budget? Once you own ...

  5. Activation of gene transcription via CIM0216, a synthetic ligand of transient receptor potential melastatin-3 (TRPM3) channels.

    PubMed

    Rubil, Sandra; Thiel, Gerald

    2017-01-02

    Several compounds have been proposed to stimulate TRPM3 Ca(2+) channels. We recently showed that stimulation of TRPM3 channels with pregnenolone sulfate activated the transcription factor AP-1, while other proposed TRPM3 ligands (nifedipine, D-erythro-sphingosine) exhibited either no or TRPM3-independent effects on gene transcription. Here, we have analyzed the transcriptional activity of CIM0216, a synthetic TRPM3 ligand proposed to have a higher potency and affinity for TRPM3 than pregnenolone sulfate. The results show that CIM0216 treatment of HEK293 cells expressing TRPM3 channels activated AP-1 and stimulated the transcriptional activation potential of c-Jun and c-Fos, 2 basic region leucine zipper transcription factors that constitute AP-1. CIM0216-induced gene transcription was attenuated by knock-down of TRPM3 or treatment with mefenamic acid, a TRPM3 inhibitor. CIM0216 was similarly or less capable in activating TRPM3-mediated gene transcription, suggesting that pregnenolone sulfate is still the ligand of choice for changing the gene expression pattern via TRPM3.

  6. Triamidetriamine bearing macrobicyclic and macrotricyclic ligands: potential applications in the development of copper-64 radiopharmaceuticals.

    PubMed

    Tan, Kel Vin; Pellegrini, Paul A; Skelton, Brian W; Hogan, Conor F; Greguric, Ivan; Barnard, Peter J

    2014-01-06

    A versatile and straightforward synthetic approach is described for the preparation of triamide bearing analogues of sarcophagine hexaazamacrobicyclic cage ligands without the need for a templating metal ion. Reaction of 1,1,1-tris(aminoethyl)ethane (tame) with 3 equiv of 2-chloroacetyl chloride, yields the tris(α-chloroamide) synthetic intermediate 6, which when treated with either 1,1,1-tris(aminoethyl)ethane or 1,4,7-triazacyclononane furnished two novel triamidetriamine cryptand ligands (7 and 8 respectively). The Co(III) and Cu(II) complexes of cryptand 7 were prepared; however, cryptand 8 could not be metalated. The cryptands and the Co(III) complex 9 have been characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and X-ray crystallography. These studies confirm that the Co(III) complex 9 adopts an octahedral geometry with three facial deprotonated amido-donors and three facial amine donor groups. The Cu(II) complex 10 was characterized by elemental analysis, single crystal X-ray crystallography, cyclic voltammetry, and UV-visible absorption spectroscopy. In contrast to the Co(III) complex (9), the Cu(II) center adopts a square planar coordination geometry, with two amine and two deprotonated amido donor groups. Compound 10 exhibited a quasi-reversible, one-electron oxidation, which is assigned to the Cu(2+/3+) redox couple. These cryptands represent interesting ligands for radiopharmaceutical applications, and 7 has been labeled with (64)Cu to give (64)Cu-10. This complex showed good stability when subjected to L-cysteine challenge whereas low levels of decomplexation were evident in the presence of L-histidine.

  7. New lithium borates with bistetrazolato(2-) and pyrazinediolato(2-) ligands - potentially interesting lithium electrolyte additives.

    PubMed

    Finger, Lars H; Venker, Alexander; Schröder, Fabian G; Sundermeyer, Jörg

    2017-02-28

    We present a convenient synthesis of the first silylated bistetrazole via a catalyzed twin [2 + 3] cycloaddition of TMS-azide at cyanogen and its application to access bistetrazolatoborates, structurally characterized by a unique unsaturated ten-membered B2N4C4 heterocyclic system. Furthermore, new borate anions with two pyrazine-2,3-diolato ligands were synthesized from tetrafluoroborate salts and structurally characterized. Their organic cation can be exchanged for Li(+)via cation exchange. The conceptual relation of these new salts to lithium ion battery bisoxalalatoborate additive LiBOB, a prominent solid electrolyte interface (SEI) generator, is discussed.

  8. A Search for CD36 Ligands from Flavor Volatiles in Foods with an Aldehyde Moiety: Identification of Saturated Aliphatic Aldehydes with 9-16 Carbon Atoms as Potential Ligands of the Receptor.

    PubMed

    Tsuzuki, Satoshi; Amitsuka, Takahiko; Okahashi, Tatsuya; Kimoto, Yusaku; Inoue, Kazuo

    2017-08-09

    Volatile compounds with an aldehyde moiety such as (Z)-9-octadecenal are potential ligands for cluster of differentiation 36 (CD36), a transmembrane receptor that has recently been shown to play a role in mammalian olfaction. In this study, by performing an assay using a peptide mimic of human CD36, we aimed to discover additional ligands for the receptor from volatiles containing a single aldehyde group commonly found in human foods. Straight-chain, saturated aliphatic aldehydes with 9-16 carbons exhibited CD36 ligand activities, albeit to varying degrees. Notably, the activities of tridecanal and tetradecanal were higher than that of oleic acid, the most potent ligand among the fatty acids tested. Among the aldehydes other than aliphatic aldehydes, only phenylacetaldehyde showed a weak activity. These findings make a contribution to our knowledge of recognition mechanisms for flavor volatiles in foods with an aldehyde group.

  9. What Amyloid Ligands can tell us about Molecular Polymorphism and Disease

    PubMed Central

    LeVine, Harry; Walker, Lary C.

    2016-01-01

    Brain-penetrant PET imaging ligands selective for amyloid pathology in living subjects have sparked a revolution in presymptomatic biomarkers for Alzheimer’s disease progression. As additional chemical structures were investigated, the heterogeneity of ligand binding sites became apparent, as did discrepancies in binding of some ligands between human disease and animal models. These differences and their implications have received little attention. This review discusses the impact of different ligand binding sites and misfolded protein conformational polymorphism on the interpretation of imaging data acquired with different ligands. Investigation of the differences in binding in animal models may identify pathological processes informing improvements to these models for more faithful recapitulation of this uniquely human disease. The differential selectivity for binding of particular ligands to different conformational states could potentially be harnessed to better define disease progression and improve the prediction of clinical outcomes. PMID:27143437

  10. Pharmacologic perturbation as a potential tool to increase the sensitivity of FDG-PET in the evaluation of brain tumors

    SciTech Connect

    Wong, F.C.L.; Kim, E.E.; Yung, W.K.A.

    1994-05-01

    The usefulness of F-18 FDG PET in the study of brain tumors is limited by the high baseline cortical uptake which decreases the contrast of the tumor. Two alternatives to increase the tumor/background contrast have been reported: barbiturate-induced coma and postprandial state. This project evaluates the effects of sedation with diazepam or of oral glucose intake on the brain tumor/background contrast during F-18 FDG PET studies.

  11. PET/CT and High Resolution CT as potential imaging biomarkers associated with treatment outcomes in MDR-TB

    PubMed Central

    Chen, Ray Y.; Dodd, Lori E.; Lee, Myungsun; Paripati, Praveen; Hammoud, Dima A.; Mountz, James M.; Jeon, Doosoo; Zia, Nadeem; Zahiri, Homeira; Coleman, M. Teresa; Carroll, Matthew W.; Lee, Jong Doo; Jeong, Yeon Joo; Herscovitch, Peter; Lahouar, Saher; Tartakovsky, Michael; Rosenthal, Alexander; Somaiyya, Sandeep; Lee, Soyoung; Goldfeder, Lisa C.; Cai, Ying; Via, Laura E.; Park, Seung-Kyu; Cho, Sang-Nae; Barry, Clifton E.

    2017-01-01

    Definitive clinical trials of new chemotherapies for tuberculosis (TB) treatment require following subjects until at least six months after treatment discontinuation to assess for durable cure, making these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. In this study we prospectively assessed radiographic changes using 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at two months and six months (CT only) in a cohort of subjects with multidrug-resistant (MDR) TB who were treated with second-line TB therapy for two years and then followed for an additional six months. CT scans were read semi-quantitatively by radiologists and computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at six months assessed by readers were predictive of outcomes but not two months and changes in computed abnormal volumes were predictive at both time points. Quantitative changes in FDG uptake two months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging biomarkers as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed. PMID:25473034

  12. Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy.

    PubMed

    Eiber, Matthias; Fendler, Wolfgang P; Rowe, Steven P; Calais, Jeremie; Hofman, Michael S; Maurer, Tobias; Schwarzenboeck, Sarah M; Kratowchil, Clemens; Herrmann, Ken; Giesel, Frederik L

    2017-09-01

    The prostate-specific membrane antigen (PSMA) is highly expressed on most prostate cancer (PC) cells. Therefore, the targeting of PSMA has become increasingly important over the last decade. Glu-urea-based PSMA ligands used for both imaging and radioligand therapy are the mainstays of the current success. For PET imaging, both (68)Ga- and (18)F-labeled agents have been successfully translated to clinical applications. Mainly retrospective cohort studies have shown a high value in the setting of biochemical recurrence, with high detection rates even in the presence of low prostate-specific antigen levels. Preliminary data indicated that radioguided surgery with PSMA ligands may help to further improve patient outcomes because it facilitates the removal of small tumor deposits that are otherwise difficult to detect. For primary PC, PSMA ligand PET imaging has been shown to be superior to cross-sectional imaging for the detection of metastatic lymph nodes. In addition, it promises to also provide intraprostatic tumor localization, especially when used in combination with multiparametric MRI. Increasing numbers of studies have reported considerable changes in management resulting from PSMA ligand PET imaging for both biochemical recurrence and primary disease. The use of (177)Lu-PSMA-based radioligand therapy has demonstrated a reasonable response, mainly as defined by a prostate-specific antigen response of more than 50%, comparable to other recently introduced agents. Especially given the high level of safety of (177)Lu-PSMA radioligand therapy, with only minimal grade 3 and 4 toxicities reported so far, it has the potential to expand options for metastatic castration-resistant PC. This review is intended to provide a comprehensive overview of the current literature on low-molecular-weight PSMA ligands for both PET imaging and therapeutic approaches, with a focus on agents that have been clinically adopted. © 2017 by the Society of Nuclear Medicine and Molecular

  13. Fluorescent pirenzepine derivatives as potential bitopic ligands of the human M1 muscarinic receptor.

    PubMed

    Tahtaoui, Chouaib; Parrot, Isabelle; Klotz, Philippe; Guillier, Fabrice; Galzi, Jean-Luc; Hibert, Marcel; Ilien, Brigitte

    2004-08-12

    Following a recent description of fluorescence resonance energy transfer between enhanced green fluorescent protein (EGFP)-fused human muscarinic M1 receptors and Bodipy-labeled pirenzepine, we synthesized seven fluorescent derivatives of this antagonist in order to further characterize ligand-receptor interactions. These compounds carry Bodipy [558/568], Rhodamine Red-X [560/580], or Fluorolink Cy3 [550/570] fluorophores connected to pirenzepine through various linkers. All molecules reversibly bind with high affinity to M1 receptors (radioligand and energy transfer binding experiments) provided that the linker contains more than six atoms. The energy transfer efficiency exhibits modest variations among ligands, indicating that the distance separating EGFP from the fluorophores remains almost constant. This also supports the notion that the fluorophores may bind to the receptor protein. Kinetic analyses reveal that the dissociation of two Bodipy derivatives (10 or 12 atom long linkers) is sensitive to the presence of the allosteric modulator brucine, while that of all other molecules (15-24 atom long linkers) is not. The data favor the idea that these analogues might interact with both the acetylcholine and the brucine binding domains. Copyright 2004 American Chemical Society

  14. Potential New Ligand Systems for Binding Uranyl Ions in Seawater Environments

    SciTech Connect

    Arnold, John

    2014-12-13

    Work began this quarter on a new project involving a combined computational and biosynthetic approach to selective recognition of uranyl ion in aqueous solution. This project exploits the results of computational studies to discover new ligand classes. Synthetic studies will follow to generate target systems for uranyl binding and determination of binding constants. The process will be iterative, with results from computation informing synthesis, and vice versa. The theme of the ligand classes to be examined initially will be biologically based. New phosphonate-containing α-amino acid N-carboxyanhydride (NCA) monomers were used recently to prepare well-defined phosphonate-containing poly-peptides and block copolypeptides. Our first approach is to utilize these phosphate- and phosphonate-containing NCAs for the coordination of uranyl. The work includes the laboratory-scale preparation of a series of NCAs and the full thermodynamic and spectroscopic characterization of the resulting uranyl complexes. We are also evaluating the sequestering activity in different physiological and environmental conditions of these copolymers as well as their biodegradability.

  15. PET with radiolabeled aminoacid.

    PubMed

    Crippa, F; Alessi, A; Serafini, G L

    2012-04-01

    Since the clinical introduction of FDG, neuroimaging has been the first area of PET application in oncology. Later, while FDG-PET became progressively a key imaging modality in the management of the majority of malignancies outside the brain, its neuro-oncologic indications faced some limitations because of the unfavourable characteristics of FDG as brain tumor-seeking agent. PET applications in neuro-oncology have received new effectiveness by the advent of positron-emission labelled amino acids, so that it has been coined the term "Amino acid PET" to differentiate this imaging tool from FDG-PET. Radiolabeled amino acids are a very interesting class of PET tracers with great diagnostic potential in neuro-oncology because of their low uptake in normal brain and, conversely, high uptake in most brain tumors including low-grade gliomas. The present article surveys the results obtained using L-[methyl-11C]Methionine (MET), that has been the ancestor of PET amino acid tracers and is still the most popular amino acid imaging modality in oncology, and stresses the important role that this diagnostic modality can play in the evaluation of brain tumors. However, the use of MET is restricted to PET centers with an in-house cyclotron and radiochemistry facility, because of the short half-life (20 min) of 11C. The promising results of MET have stimulated the development of 18F-labelled aminoacid tracers, particularly O-(2-18F-fluoeoethyl1)-L-tyrosine (FET), that has the same properties of MET and, thanks to the longer half-life of 18F (about 110 min), allows a distribution strategy from a production tracer site to user satellite PET centers. Considering a more widespread use of Amino acid PET, together with the recent development of integrated PET-MRI imaging systems, and the oncoming clinical validation of other interesting PET tracers, i.e. FMISO or 18F-FAZA for hypoxia imaging and FLT for tumor proliferation imaging, it can be reasonably expected that metabolic imaging

  16. Potential clinical applications of bimodal PET-MRI or SPECT-MRI agents†

    PubMed Central

    de Rosales, Rafael T M

    2014-01-01

    The introduction to the clinic of positron emission tomography-magnetic resonance imaging scanners opens up the possibility to evaluate the real potential of bimodal imaging agents. In this mini-review, the limitations in the design and applications of these materials are summarised and the unique properties that may result in real clinical applications outlined. © 2013 The Authors. Labelled Compounds and Radiopharmaceuticals published by John Wiley. PMID:24395384

  17. A PET imaging agent with fast kinetics: synthesis and in vivo evaluation of the serotonin transporter ligand [11C]2-[2-dimethylaminomethylphenylthio)]-5-fluorophenylamine ([11C]AFA).

    PubMed

    Huang, Yiyun; Narendran, Raj; Bae, Sung-A; Erritzoe, David; Guo, Ningning; Zhu, Zhihong; Hwang, Dah-Ren; Laruelle, Marc

    2004-08-01

    A new serotonin transporter (SERT) ligand, [11C]2-[2-(dimethylaminomethylphenylthio)]-5-fluorophenylamine (10, [11C]AFA), was synthesized and evaluated as a candidate PET radioligand in pharmacological and pharmacokinetic studies. As a PET radioligand, AFA (8) can be labeled with either C-11 or F-18. In vitro, AFA displayed high affinity for SERT (Ki 1.46 +/- 0.15 nM) and lower affinity for norepinephrine transporter (NET, Ki 141.7 +/- 47.4 nM) or dopamine transporter (DAT, Ki > 10,000 nM). [11C]AFA (10) was prepared from its monomethylamino precursor 9 by reaction with high specific activity [11C]methyl iodide. Radiochemical yield was 43 +/- 20% based on [11C]methyl iodide at end of bombardment (EOB, n = 10) and specific activity was 2,129 +/- 1,369 Ci/mmol at end of synthesis (EOS, n = 10). Biodistribution studies in rats indicated that [11C]AFA accumulated in brain regions known to contain high concentrations of SERT. Binding in SERT-rich brain regions was reduced significantly by pretreatment with either the cold compound 8 or with the selective serotonin reuptake inhibitor (SSRI) citalopram, but not by the selective norepinephrine reuptake inhibitor nisoxetine, thus underlining its in vivo binding selectivity and specificity for SERT. Imaging experiments in baboons demonstrated that the uptake pattern of [11C]AFA in the baboon brain is consistent with the known distribution of SERT, with highest activity levels in the midbrain and thalamus, followed by striatum, hippocampus, and cortical regions. Activity levels in the baboon brain peaked at 15-40 min after radioligand injection, indicating a fast uptake kinetics for [11C]AFA. Pretreatment of the baboon with citalopram (4 mg/kg) significantly reduced the specific binding of [11C]AFA in all SERT-containing brain regions. Kinetic analysis revealed that the regional equilibrium specific to non-specific partition coefficients (V3") of [11C]AFA are similar to those of [11C]McN5652, but lower than those of [11C

  18. Evaluation of a potential generator-produced PET tracer for cerebral perfusion imaging: single-pass cerebral extraction measurements and imaging with radiolabeled Cu-PTSM.

    PubMed

    Mathias, C J; Welch, M J; Raichle, M E; Mintun, M A; Lich, L L; McGuire, A H; Zinn, K R; John, E K; Green, M A

    1990-03-01

    Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), copper(II) pyruvaldehyde bis(N4-dimethylthiosemicarbazone) (Cu-PTSM2), and copper(II) ethylglyoxal bis(N4-methylthiosemicarbazone) (Cu-ETSM), have been proposed as PET tracers for cerebral blood flow (CBF) when labeled with generator-produced 62Cu (t1/2 = 9.7 min). To evaluate the potential of Cu-PTSM for CBF PET studies, baboon single-pass cerebral extraction measurements and PET imaging were carried out with the use of 67Cu (t1/2 = 2.6 days) and 64Cu (t1/2 = 12.7 hr), respectively. All three chelates were extracted into the brain with high efficiency. There was some clearance of all chelates in the 10-50-sec time frame and Cu-PTSM2 continued to clear. Cu-PTSM and Cu-ETSM have high residual brain activity. PET imaging of baboon brain was carried out with the use of [64Cu]-Cu-PTSM. For comparison with the 64Cu brain image, a CBF (15O-labeled water) image (40 sec) was first obtained. Qualitatively, the H2(15)O and [64Cu]-Cu-PTSM images were very similar; for example, a comparison of gray to white matter uptake resulted in ratios of 2.42 for H2(15)O and 2.67 for Cu-PTSM. No redistribution of 64Cu was observed in 2 hr of imaging, as was predicted from the single-pass study results. Quantitative determination of blood flow using Cu-PTSM showed good agreement with blood flow determined with H2(15)O. This data suggests that [62Cu]-Cu-PTSM may be a useful generator-produced radiopharmaceutical for blood flow studies with PET.

  19. Pseudo-Mannosylated DC-SIGN Ligands as Potential Adjuvants for HIV Vaccines

    PubMed Central

    Berzi, Angela; Varga, Norbert; Sattin, Sara; Antonazzo, Patrizio; Biasin, Mara; Cetin, Irene; Trabattoni, Daria; Bernardi, Anna; Clerici, Mario

    2014-01-01

    The development of new and effective adjuvants may play a fundamental role in improving HIV vaccine efficacy. New classes of vaccine adjuvants activate innate immunity receptors, notably toll like receptors (TLRs). Adjuvants targeting the C-Type lectin receptor DC-SIGN may be alternative or complementary to adjuvants based on TRL activation. Herein we evaluate the ability of the glycomimetic DC-SIGN ligand Polyman 19 (PM 19) to modulate innate immune responses. Results showed that PM 19 alone, or in combination with TLR agonists, induces the expression of cytokines, β chemokines and co-stimulatory molecules that may, in turn, modulate adaptive immunity and exert anti-viral effects. These results indicate that the suitability of this compound as a vaccine adjuvant should be further evaluated. PMID:24473338

  20. (64)Cu-PSMA-617 PET/CT Imaging of Prostate Adenocarcinoma: First In-Human Studies.

    PubMed

    Grubmüller, Bernhard; Baum, Richard P; Capasso, Enza; Singh, Aviral; Ahmadi, Yasaman; Knoll, Peter; Floth, Andreas; Righi, Sergio; Zandieh, Shahin; Meleddu, Carlo; Shariat, Shahrokh F; Klingler, Hans Christoph; Mirzaei, Siroos

    2016-10-07

    The prostate-specific membrane antigen (PSMA) is a cell surface protein, which is overexpressed in nearly all cases of prostate cancer (PCa). PET imaging with (68)Ga-PSMA-HBED-CC has recently found widespread application in the diagnosis of recurrent PCa. In this study, the diagnostic potential of (64)Cu-labeled PSMA ligand (PSMA-617) PET in patients with PCa has been investigated. The study was conducted simultaneously at two nuclear medicine centers, Austria (Vienna, Center 1) and Germany (Bad Berka, Center 2). The patients (n = 29) included in this study were referred for PET (Center 1, 21 patients) or PET/CT (Center 2, 8 patients) imaging with either a high suspicion of recurrent disease or for possible surgical or PSMA radioligand therapy planning. PET images of the whole body were performed at 1 hour p.i. and additional images of the pelvis at 2 hours p.i. In 23 of 29 patients, at least one focus of pathological tracer uptake suspicious for primary disease in the prostate lobe or recurrent disease was detected. Among healthy organs, the salivary glands, kidneys, and liver showed the highest radiotracer uptake. Lesions suspicious for PCa were detected with excellent contrast as early as 1 hour p.i. with high detection rates even at low prostate-specific antigen (PSA) levels. The preliminary results of this study demonstrate the high potential of (64)Cu-PSMA ligand PET/CT imaging in patients with recurrent disease and in the primary staging of selected patients with progressive local disease. The acquired PET images showed an excellent resolution of the detected lesions with very high lesion-to- background contrast. Furthermore, the long half-life of (64)Cu allows distribution of the tracer to clinical PET centers that lack radiochemistry facilities for the preparation of (68)Ga-PSMA ligand (satellite concept).

  1. Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy.

    PubMed

    Rahaman, Obaidur; Estrada, Trilce P; Doren, Douglas J; Taufer, Michela; Brooks, Charles L; Armen, Roger S

    2011-09-26

    The performances of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for "step 2 discrimination" were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only "interacting" ligand atoms as the "effective size" of the ligand and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and 5-fold cross-validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new data set (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ data set where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of predicted ligand

  2. Evaluation of Several Two-Step Scoring Functions Based on Linear Interaction Energy, Effective Ligand Size, and Empirical Pair Potentials for Prediction of Protein-Ligand Binding Geometry and Free Energy

    PubMed Central

    Rahaman, Obaidur; Estrada, Trilce P.; Doren, Douglas J.; Taufer, Michela; Brooks, Charles L.; Armen, Roger S.

    2011-01-01

    The performance of several two-step scoring approaches for molecular docking were assessed for their ability to predict binding geometries and free energies. Two new scoring functions designed for “step 2 discrimination” were proposed and compared to our CHARMM implementation of the linear interaction energy (LIE) approach using the Generalized-Born with Molecular Volume (GBMV) implicit solvation model. A scoring function S1 was proposed by considering only “interacting” ligand atoms as the “effective size” of the ligand, and extended to an empirical regression-based pair potential S2. The S1 and S2 scoring schemes were trained and five-fold cross validated on a diverse set of 259 protein-ligand complexes from the Ligand Protein Database (LPDB). The regression-based parameters for S1 and S2 also demonstrated reasonable transferability in the CSARdock 2010 benchmark using a new dataset (NRC HiQ) of diverse protein-ligand complexes. The ability of the scoring functions to accurately predict ligand geometry was evaluated by calculating the discriminative power (DP) of the scoring functions to identify native poses. The parameters for the LIE scoring function with the optimal discriminative power (DP) for geometry (step 1 discrimination) were found to be very similar to the best-fit parameters for binding free energy over a large number of protein-ligand complexes (step 2 discrimination). Reasonable performance of the scoring functions in enrichment of active compounds in four different protein target classes established that the parameters for S1 and S2 provided reasonable accuracy and transferability. Additional analysis was performed to definitively separate scoring function performance from molecular weight effects. This analysis included the prediction of ligand binding efficiencies for a subset of the CSARdock NRC HiQ dataset where the number of ligand heavy atoms ranged from 17 to 35. This range of ligand heavy atoms is where improved accuracy of

  3. Future laser-accelerated proton beams at ELI-Beamlines as potential source of positron emitters for PET

    NASA Astrophysics Data System (ADS)

    Amato, E.; Italiano, A.; Margarone, D.; Pagano, B.; Baldari, S.; Korn, G.

    2016-04-01

    The development of novel compact PET radionuclide production systems is of great interest to promote the diffusion of PET diagnostics, especially in view of the continuous development of novel, fast and efficient, radiopharmaceutical methods of labeling. We studied the feasibility to produce clinically-relevant amounts of PET isotopes by means of laser-accelerated proton sources expected at the ELI-Beamlines facility where a PW, 30 fs, 10 Hz laser system will be available. The production yields of several positron emitters were calculated through the TALYS software, by taking into account three possible scenarios of broad proton spectra expected, with maximum energies ranging from about 8 MeV to 100 MeV. With the hypothesized proton fluencies, clinically-relevant amounts of radionuclides can be obtained, suitable to prepare single doses of radiopharmaceuticals exploiting modern fast and efficient labeling systems.

  4. The potential of positron emission tomography/computerized tomography (PET/CT) scanning as a detector of high-risk patients with oral infection during preoperative staging.

    PubMed

    Yamashiro, Keisuke; Nakano, Makoto; Sawaki, Koichi; Okazaki, Fumihiko; Hirata, Yasuhisa; Takashiba, Shogo

    2016-08-01

    It is sometimes difficult to determine during the preoperative period whether patients have oral infections; these patients need treatment to prevent oral infection-related complications from arising during medical therapies, such as cancer therapy and surgery. One of the reasons for this difficulty is that basic medical tests do not identify oral infections, including periodontitis and periapical periodontitis. In this report, we investigated the potential of positron emission tomography/computerized tomography (PET/CT) as a diagnostic tool in these patients. We evaluated eight patients during the preoperative period. All patients underwent PET/CT scanning and were identified as having the signs of oral infection, as evidenced by (18)F-fludeoxyglucose (FDG) localization in the oral regions. Periodontal examination and orthopantomogram evaluation showed severe infection or bone resorption in the oral regions. (18)F-FDG was localized in oral lesions, such as severe periodontitis, apical periodontitis, and pericoronitis of the third molar. The densities of (18)F-FDG were proportional to the degree of inflammation. PET/CT is a potential diagnostic tool for oral infections. It may be particularly useful in patients during preoperative staging, as they frequently undergo scanning at this time, and those identified as having oral infections at this time require treatment before cancer therapy or surgery. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Dual time-point imaging for post-dose binding potential estimation applied to a [(11)C]raclopride PET dose occupancy study.

    PubMed

    Alves, Isadora L; Willemsen, Antoon Tm; Dierckx, Rudi A; da Silva, Ana Maria M; Koole, Michel

    2017-03-01

    Receptor occupancy studies performed with PET often require time-consuming dynamic imaging for baseline and post-dose scans. Shorter protocol approximations based on standard uptake value ratios have been proposed. However, such methods depend on the time-point chosen for the quantification and often lead to overestimation and bias. The aim of this study was to develop a shorter protocol for the quantification of post-dose scans using a dual time-point approximation, which employs kinetic parameters from the baseline scan. Dual time-point was evaluated for a [(11)C]raclopride PET dose occupancy study with the D2 antagonist JNJ-37822681, obtaining estimates for binding potential and receptor occupancy. Results were compared to standard simplified reference tissue model and standard uptake value ratios-based estimates. Linear regression and Bland-Altman analysis demonstrated excellent correlation and agreement between dual time-point and the standard simplified reference tissue model approach. Moreover, the stability of dual time-point-based estimates is shown to be independent of the time-point chosen for quantification. Therefore, a dual time-point imaging protocol can be applied to post-dose [(11)C]raclopride PET scans, resulting in a significant reduction in total acquisition time while maintaining accuracy in the quantification of both the binding potential and the receptor occupancy.

  6. A novel ligand of calcitonin receptor reveals a potential new sensor that modulates programmed cell death

    PubMed Central

    Furness, SGB; Hare, DL; Kourakis, A; Turnley, AM; Wookey, PJ

    2016-01-01

    We have discovered that the accumulation of an anti-calcitonin receptor (anti-CTR) antibody conjugated to a fluorophore (mAb2C4:AF568) provides a robust signal for cells undergoing apoptotic programmed cell death (PCD). PCD is an absolute requirement for normal development of metazoan organisms. PCD is a hallmark of common diseases such as cardiovascular disease and tissue rejection in graft versus host pathologies, and chemotherapeutics work by increasing PCD. This robust signal or high fluorescent events were verified by confocal microscopy and flow cytometry in several cell lines and a primary culture in which PCD had been induced. In Jurkat cells, GBM-L2 and MG63 cells, the percentage undergoing PCD that were positive for both mAb2C4:AF568 and annexin V ranged between 70 and >90%. In MG63 cells induced for the preapoptotic cell stress response (PACSR), the normal expression of α-tubulin, a key structural component of the cytoskeleton, and accumulation of mAb2C4:AF568 were mutually exclusive. Our data support a model in which CTR is upregulated during PACSR and recycles to the plasma membrane with apoptosis. In cells committed to apoptosis (α-tubulin negative), there is accumulation of the CTR-ligand mAb2C4:AF568 generating a high fluorescent event. The reagent mAb2C4:AF568 effectively identifies a novel event linked to apoptosis. PMID:27777788

  7. Kinetics of protein-ligand unbinding via smoothed potential molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Mollica, Luca; Decherchi, Sergio; Zia, Syeda Rehana; Gaspari, Roberto; Cavalli, Andrea; Rocchia, Walter

    2015-06-01

    Drug discovery is expensive and high-risk. Its main reasons of failure are lack of efficacy and toxicity of a drug candidate. Binding affinity for the biological target has been usually considered one of the most relevant figures of merit to judge a drug candidate along with bioavailability, selectivity and metabolic properties, which could depend on off-target interactions. Nevertheless, affinity does not always satisfactorily correlate with in vivo drug efficacy. It is indeed becoming increasingly evident that the time a drug spends in contact with its target (aka residence time) can be a more reliable figure of merit. Experimental kinetic measurements are operatively limited by the cost and the time needed to synthesize compounds to be tested, to express and purify the target, and to setup the assays. We present here a simple and efficient molecular-dynamics-based computational approach to prioritize compounds according to their residence time. We devised a multiple-replica scaled molecular dynamics protocol with suitably defined harmonic restraints to accelerate the unbinding events while preserving the native fold. Ligands are ranked according to the mean observed scaled unbinding time. The approach, trivially parallel and easily implementable, was validated against experimental information available on biological systems of pharmacological relevance.

  8. Evaluation of N-Phenyl Homopiperazine Analogs as Potential Dopamine D3 Receptor Selective Ligands

    PubMed Central

    Li, Aixiao; Mishra, Yogesh; Malik, Maninder; Wang, Qi; Li, Shihong; Taylor, Michelle; Reichert, David E.; Luedtke, Robert R.; Mach, Robert H.

    2013-01-01

    A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had Ki values ranging from 0.7–3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D3 vs. D2 receptor. Calculated log P values (log P = 2.6–3.6) are within the desired range for passive transport across the blood brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that a) affinity at D2 and D3 dopamine receptors generally decreased, b) the D3 receptor binding selectivity (D2:D3 Ki value ratio) decreased and, c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased. PMID:23618707

  9. Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of Parkinson's disease.

    PubMed

    Jörg, Manuela; May, Lauren T; Mak, Frankie S; Lee, Kiew Ching K; Miller, Neil D; Scammells, Peter J; Capuano, Ben

    2015-01-22

    A relatively new strategy in drug discovery is the development of dual acting ligands. These molecules are potentially able to interact at two orthosteric binding sites of a heterodimer simultaneously, possibly resulting in enhanced subtype selectivity, higher affinity, enhanced or modified physiological response, and reduced reliance on multiple drug administration regimens. In this study, we have successfully synthesized a series of classical heterobivalent ligands as well as a series of more integrated and "drug-like" dual acting molecules, incorporating ropinirole as a dopamine D2 receptor agonist and ZM 241385 as an adenosine A2A receptor antagonist. The best compounds of our series maintained the potency of the original pharmacophores at both receptors (adenosine A2A and dopamine D2). In addition, the integrated dual acting ligands also showed promising results in preliminary blood-brain barrier permeability tests, whereas the classical heterobivalent ligands are potentially more suited as pharmacological tools.

  10. Use of concatemers of ligand-gated ion channel subunits to study mechanisms of steroid potentiation.

    PubMed

    Steinbach, Joe Henry; Akk, Gustav

    2011-12-01

    Synaptic receptors of the nicotinic receptor gene family are pentamers of subunits. This modular structure creates problems in studies of drug actions, related to the number of copies of a subunit that are present and their position. A separate issue concerns the mechanism of action of many anesthetics, which involves potentiation of responses to neurotransmitters. Potentiation requires an interaction between a transmitter and a potentiator, mediated through the target receptor. We have studied the mechanism by which neurosteroids potentiate transmitter responses, using concatemers of covalently linked subunits to control the number and position of subunits in the assembled receptor and to selectively introduce mutations into positionally defined copies of a subunit. We found that the steroid needs to interact with only one site to produce potentiation, that the native sites for steroid interaction have indistinguishable properties, and that steroid potentiation appears to result from a global effect on receptor function.

  11. Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning

    SciTech Connect

    Campbell, Belinda A.; Callahan, Jason; Bressel, Mathias; Simoens, Nathalie; Everitt, Sarah; Hofman, Michael S.; Hicks, Rodney J.; Burbury, Kate; MacManus, Michael

    2015-08-01

    Purpose: Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)–positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility. Methods and Materials: The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status. Results: Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age. Conclusions: This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required.

  12. Distribution Atlas of Proliferating Bone Marrow in Non-Small Cell Lung Cancer Patients Measured by FLT-PET/CT Imaging, With Potential Applicability in Radiation Therapy Planning.

    PubMed

    Campbell, Belinda A; Callahan, Jason; Bressel, Mathias; Simoens, Nathalie; Everitt, Sarah; Hofman, Michael S; Hicks, Rodney J; Burbury, Kate; MacManus, Michael

    2015-08-01

    Proliferating bone marrow is exquisitely sensitive to ionizing radiation. Knowledge of its distribution could improve radiation therapy planning to minimize unnecessary marrow exposure and avoid consequential prolonged myelosuppression. [18F]-Fluoro-3-deoxy-3-L-fluorothymidine (FLT)-positron emission tomography (PET) is a novel imaging modality that provides detailed quantitative images of proliferating tissues, including bone marrow. We used FLT-PET imaging in cancer patients to produce an atlas of marrow distribution with potential clinical utility. The FLT-PET and fused CT scans of eligible patients with non-small cell lung cancer (no distant metastases, no prior cytotoxic exposure, no hematologic disorders) were reviewed. The proportions of skeletal FLT activity in 10 predefined bony regions were determined and compared according to age, sex, and recent smoking status. Fifty-one patients were studied: 67% male; median age 68 (range, 31-87) years; 8% never smokers; 70% no smoking in the preceding 3 months. Significant differences in marrow distribution occurred between sex and age groups. No effect was detected from smoking in the preceding 3 months. Using the mean percentages of FLT uptake per body region, we created an atlas of the distribution of functional bone marrow in 4 subgroups defined by sex and age. This atlas has potential utility for estimating the distribution of active marrow in adult cancer patients to guide radiation therapy planning. However, because of interindividual variation it should be used with caution when radiation therapy risks ablating large proportions of active marrow; in such cases, individual FLT-PET scans may be required. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Synthesis and pre-clinical evaluation of a new class of high-affinity (18)F-labeled PSMA ligands for detection of prostate cancer by PET imaging.

    PubMed

    Kelly, James; Amor-Coarasa, Alejandro; Nikolopoulou, Anastasia; Kim, Dohyun; Williams, Clarence; Ponnala, Shashikanth; Babich, John W

    2017-04-01

    Current clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features (68)Ga-labeled tracers, notably [(68)Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer. Six triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [(18)F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [(18)F]fluoroethylazide. The (18)F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [(68)Ga]Ga-PSMA-HBED-CC and [(18)F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific. F-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20-40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC50) ranged from 3-36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6-14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [(68)Ga]Ga-PSMA-HBED-CC and [(18)F]DCFPyL was 5-6 %ID/g at 1-3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [(68)Ga]Ga-PSMA-HBED-CC. Six [(18)F]triazolylphenyl ureas were prepared in

  14. On the potential for RF heating in MRI to affect metabolic rates and (18) FDG signal in PET/MR: simulations of long-duration, maximum normal mode heating.

    PubMed

    Carluccio, Giuseppe; Ding, Yu-Shin; Logan, Jean; Collins, Christopher M

    2017-02-01

    To examine the possibility that MR-induced RF power deposition (SAR) and the resulting effects on temperature-dependent metabolic rates or perfusion rates might affect observed 18FDG signal in PET/MR. Using numerical simulations of the SAR, consequent temperature increase, effect on rates of metabolism or perfusion, and [18FDG] throughout the body, we simulated the potential effect of maximum-allowable whole-body SAR for the entire duration of an hour-long PET/MR scan on observed PET signal for two different 18FDG injection times: one hour before onset of imaging and concurrent with the beginning of imaging. This was all repeated three times with the head, the heart, and the abdomen (kidneys) at the center of the RF coil. Qualitatively, little effect of MR-induced heating is observed on simulated PET images. Maximum relative increases in PET signal (26% and 31% increase, respectively, for the uptake models based on metabolism and the perfusion) occur in regions of low baseline metabolic rate (also associated with low perfusion and, thus, greater potential temperature increase due to high local SAR), such that PET signal in these areas remains comparatively low. Maximum relative increases in regions of high metabolic rate (and also high perfusion: heart, thyroid, brain, etc.) are affected mostly by the relatively small increase in core body temperature and thus are not affected greatly (10% maximum increase). Even for worst-case heating, little effect of MR-induced heating is expected on 18FDG PET images during PET/MR for many clinically relevant applications. For quantitative, dynamic MR/PET studies requiring high SAR for extended periods, it is hoped that methods like those introduced here can help account for such potential effects in design of a given study, including selection of reference locations that should not experience notable increase in temperature. © 2016 American Association of Physicists in Medicine.

  15. A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands.

    PubMed

    Crowe, David L; Chandraratna, Roshantha A S

    2004-01-01

    Certain lipids have been shown to be ligands for a subgroup of the nuclear hormone receptor superfamily known as the peroxisome proliferator-activated receptors (PPARs). Ligands for these transcription factors have been used in experimental cancer therapies. PPARs heterodimerize and bind DNA with retinoid X receptors (RXRs), which have homology to other members of the nuclear receptor superfamily. Retinoids have been found to be effective in treating many types of cancer. However, many breast cancers become resistant to the chemotherapeutic effects of these drugs. Recently, RXR-selective ligands were discovered that inhibited proliferation of all-trans retinoic acid resistant breast cancer cells in vitro and caused regression of the disease in animal models. There are few published studies on the efficacy of combined therapy using PPAR and RXR ligands for breast cancer prevention or treatment. We determined the effects of selective PPAR and RXR ligands on established human breast cancer cell lines in vitro. PPAR-alpha and PPAR-gamma ligands induced apoptotic and antiproliferative responses in human breast cancer cell lines, respectively, which were associated with specific changes in gene expression. These responses were potentiated by the RXR-selective ligand AGN194204. Interestingly, RXR-alpha-overexpressing retinoic acid resistant breast cancer cell lines were more sensitive to the effects of the RXR-selective compound. RXR-selective retinoids can potentiate the antiproliferative and apoptotic responses of breast cancer cell lines to PPAR ligands.

  16. A retinoid X receptor (RXR)-selective retinoid reveals that RXR-α is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands

    PubMed Central

    Crowe, David L; Chandraratna, Roshantha AS

    2004-01-01

    Introduction Certain lipids have been shown to be ligands for a subgroup of the nuclear hormone receptor superfamily known as the peroxisome proliferator-activated receptors (PPARs). Ligands for these transcription factors have been used in experimental cancer therapies. PPARs heterodimerize and bind DNA with retinoid X receptors (RXRs), which have homology to other members of the nuclear receptor superfamily. Retinoids have been found to be effective in treating many types of cancer. However, many breast cancers become resistant to the chemotherapeutic effects of these drugs. Recently, RXR-selective ligands were discovered that inhibited proliferation of all-trans retinoic acid resistant breast cancer cells in vitro and caused regression of the disease in animal models. There are few published studies on the efficacy of combined therapy using PPAR and RXR ligands for breast cancer prevention or treatment. Methods We determined the effects of selective PPAR and RXR ligands on established human breast cancer cell lines in vitro. Results PPAR-α and PPAR-γ ligands induced apoptotic and antiproliferative responses in human breast cancer cell lines, respectively, which were associated with specific changes in gene expression. These responses were potentiated by the RXR-selective ligand AGN194204. Interestingly, RXR-α-overexpressing retinoic acid resistant breast cancer cell lines were more sensitive to the effects of the RXR-selective compound. Conclusion RXR-selective retinoids can potentiate the antiproliferative and apoptotic responses of breast cancer cell lines to PPAR ligands. PMID:15318936

  17. Negative electrostatic surface potential of protein sites specific for anionic ligands.

    PubMed Central

    Ledvina, P S; Yao, N; Choudhary, A; Quiocho, F A

    1996-01-01

    Determination of the crystal structure of an "open" unliganded active mutant (T141D) form of the Escherichia coli phosphate receptor for active transport has allowed calculation of the electrostatic surface potential for it and two other comparably modeled receptor structures (wild type and D137N). A discovery of considerable implication is the intensely negative potential of the phosphate-binding cleft. We report similar findings for a sulfate transport receptor, a DNA-binding protein, and, even more dramatically, redox proteins. Evidently, for proteins such as these, which rely almost exclusively on hydrogen bonding for anion interactions and electrostatic balance, a noncomplementary surface potential is not a barrier to binding. Moreover, experimental results show that the exquisite specificity and high affinity of the phosphate and sulfate receptors for unions are insensitive to modulations of charge potential, but extremely sensitive to conditions that leave a hydrogen bond donor or acceptor unpaired. Images Fig. 1 Fig. 2 Fig. 3 PMID:8692896

  18. Negative electrostatic surface potential of protein sites specific for anionic ligands.

    PubMed

    Ledvina, P S; Yao, N; Choudhary, A; Quiocho, F A

    1996-06-25

    Determination of the crystal structure of an "open" unliganded active mutant (T141D) form of the Escherichia coli phosphate receptor for active transport has allowed calculation of the electrostatic surface potential for it and two other comparably modeled receptor structures (wild type and D137N). A discovery of considerable implication is the intensely negative potential of the phosphate-binding cleft. We report similar findings for a sulfate transport receptor, a DNA-binding protein, and, even more dramatically, redox proteins. Evidently, for proteins such as these, which rely almost exclusively on hydrogen bonding for anion interactions and electrostatic balance, a noncomplementary surface potential is not a barrier to binding. Moreover, experimental results show that the exquisite specificity and high affinity of the phosphate and sulfate receptors for unions are insensitive to modulations of charge potential, but extremely sensitive to conditions that leave a hydrogen bond donor or acceptor unpaired.

  19. Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

    PubMed

    Farid, Karim; Hong, Young T; Aigbirhio, Franklin I; Fryer, Tim D; Menon, David K; Warburton, Elizabeth A; Baron, Jean-Claude

    2015-01-01

    Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1-6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD.

  20. Early-Phase 11C-PiB PET in Amyloid Angiopathy-Related Symptomatic Cerebral Hemorrhage: Potential Diagnostic Value?

    PubMed Central

    Aigbirhio, Franklin I.; Fryer, Tim D.; Menon, David K.; Warburton, Elizabeth A.; Baron, Jean-Claude

    2015-01-01

    Although late-phase (>35min post-administration) 11C-PiB-PET has good sensitivity in cerebral amyloid angiopathy (CAA), its specificity is poor due to frequently high uptake in healthy aged subjects. By detecting perfusion-like abnormalities, early-phase 11C-PiB-PET might add diagnostic value. Early-frame (1–6min) 11C-PiB-PET was obtained in 11 non-demented patients with probable CAA-related symptomatic lobar intracerebral haemorrhage (70±7yrs), 9 age-matched healthy controls (HCs) and 10 HCs <55yrs. There was a significant decrease in early-phase atrophy-corrected whole-cortex SUV relative to cerebellar vermis (SUVR) in the CAA vs age-matched HC group. None of the age-matched controls fell below the lower 95% confidence limit derived from the young HCs, while 6/11 CAA patients did (sensitivity = 55%, specificity = 100%). Combining both early- and late-phase 11C-PiB data did not change the sensitivity and specificity of late-phase PiB, but combined early- and late-phase positivity entails a very high suspicion of underlying Aβ-related clinical disorder, i.e., CAA or Alzheimer disease (AD). In order to clarify this ambiguity, we then show that the occipital/posterior cingulate ratio is markedly lower in CAA than in AD (N = 7). These pilot data suggest that early-phase 11C-PiB-PET may not only add to late-phase PiB-PET with respect to the unclear situation of late-phase positivity, but also help differentiate CAA from AD. PMID:26439113

  1. Low affinity glucocorticoid binding site ligands as potential anti-fibrogenics

    PubMed Central

    Marek, Carylyn J; Wallace, Karen; Durward, Elaine; Koruth, Matthew; Leel, Val; Leiper, Lucy J; Wright, Matthew C

    2009-01-01

    . Immunohistochemical analysis showed that rat liver myofibroblasts in vivo did not express rPGRMC1. Conclusion LAGS ligands inhibit HSC trans-differentiation and proliferation in vitro but show little efficacy in inhibiting liver fibrosis, in vivo. The reason(s) for this disparity is/are likely associated with an altered myofibroblast phenotype, in vitro, with expression of rPGMRC1 in vitro but not in vivo. These data emphasize the limitations of in vitro-derived myofibroblasts for predicting their activity in vivo, in studies of fibrogenesis. The data also demonstrate that the anti-fibrogenic effects of PCN in vivo are likely mediated entirely via the PXR. PMID:19432992

  2. In Vitro Evaluation of Guanidine Analogs as Sigma Receptor Ligands for Potential Anti-Stroke Therapeutics

    PubMed Central

    Behensky, Adam A.; Cortes-Salva, Michelle; Seminerio, Michael J.; Matsumoto, Rae R.; Antilla, Jon C.

    2013-01-01

    Currently, the only Food and Drug Administration–approved treatment of acute stroke is recombinant tissue plasminogen activator, which must be administered within 6 hours after stroke onset. The pan-selective σ-receptor agonist N,N′-di-o-tolyl-guanidine (o-DTG) has been shown to reduce infarct volume in rats after middle cerebral artery occlusion, even when administered 24 hours after stroke. DTG derivatives were synthesized to develop novel compounds with greater potency than o-DTG. Fluorometric Ca2+ imaging was used in cultured cortical neurons to screen compounds for their capacity to reduce ischemia- and acidosis-evoked cytosolic Ca2+ overload, which has been linked to stroke-induced neurodegeneration. In both assays, migration of the methyl moiety produced no significant differences, but removal of the group increased potency of the compound for inhibiting acidosis-induced [Ca2+]i elevations. Chloro and bromo substitution of the methyl moiety in the meta and para positions increased potency by ≤160%, but fluoro substitutions had no effect. The most potent DTG derivative tested was N,N′-di-p-bromo-phenyl-guanidine (p-BrDPhG), which had an IC50 of 2.2 µM in the ischemia assay, compared with 74.7 μM for o-DTG. Microglial migration assays also showed that p-BrDPhG is more potent than o-DTG in this marker for microglial activation, which is also linked to neuronal injury after stroke. Radioligand binding studies showed that p-BrDPhG is a pan-selective σ ligand. Experiments using the σ-1 receptor-selective antagonist 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) demonstrated that p-BrDPhG blocks Ca2+ overload via σ-1 receptor activation. The study identified four compounds that may be more effective than o-DTG for the treatment of ischemic stroke at delayed time points. PMID:23065135

  3. SU-D-9A-01: Listmode-Driven Optimal Gating (OG) Respiratory Motion Management: Potential Impact On Quantitative PET Imaging

    SciTech Connect

    Lee, K; Hristov, D

    2014-06-01

    Purpose: To evaluate the potential impact of listmode-driven amplitude based optimal gating (OG) respiratory motion management technique on quantitative PET imaging. Methods: During the PET acquisitions, an optical camera tracked and recorded the motion of a tool placed on top of patients' torso. PET event data were utilized to detect and derive a motion signal that is directly coupled with a specific internal organ. A radioactivity-trace was generated from listmode data by accumulating all prompt counts in temporal bins matching the sampling rate of the external tracking device. Decay correction for 18F was performed. The image reconstructions using OG respiratory motion management technique that uses 35% of total radioactivity counts within limited motion amplitudes were performed with external motion and radioactivity traces separately with ordered subset expectation maximization (OSEM) with 2 iterations and 21 subsets. Standard uptake values (SUVs) in a tumor region were calculated to measure the effect of using radioactivity trace for motion compensation. Motion-blurred 3D static PET image was also reconstructed with all counts and the SUVs derived from OG images were compared with SUVs from 3D images. Results: A 5.7 % increase of the maximum SUV in the lesion was found for optimal gating image reconstruction with radioactivity trace when compared to a static 3D image. The mean and maximum SUVs on the image that was reconstructed with radioactivity trace were found comparable (0.4 % and 4.5 % increase, respectively) to the values derived from the image that was reconstructed with external trace. Conclusion: The image reconstructed using radioactivity trace showed that the blurring due to the motion was reduced with impact on derived SUVs. The resolution and contrast of the images reconstructed with radioactivity trace were comparable to the resolution and contrast of the images reconstructed with external respiratory traces. Research supported by Siemens.

  4. Dissemination and serotype modification potential of pSFxv_2, an O-antigen PEtN modification plasmid in Shigella flexneri.

    PubMed

    Sun, Qiangzheng; Knirel, Yuriy A; Lan, Ruiting; Wang, Jianping; Senchenkova, Sof'ya N; Shashkov, Alexander S; Wang, Yan; Wang, Yiting; Luo, Xia; Xu, Jianguo

    2014-03-01

    The O-antigens of all Shigella flexneri serotypes, except serotype 6, share a linear tetrasaccharide repeat composed of one N-acetylglucosamine and three l-rhamnose residues, and differences between the serotypes are due to modification of various monosaccharide residues with glucosyl and/or O-acetyl and/or phosphoethanolamine (PEtN) groups. Plasmid-borne opt (formerly lpt-O) gene encoding a PEtN transferase which modifies the O-antigens of S. flexneri serotype X, 4a and Y strains and converts the hosts into MASF IV-1 (E1037) positive "variant" (v) Xv, 4av and Yv serotypes, respectively. In this study, we showed that the opt-carrying plasmid pSFxv_2 can transform strains of all S. flexneri serotypes (1-6) to confer them with the MASF IV-1 epitope recognized by monoclonal antibody MASF IV-1 and typing antiserum IV. The transformants possessed modified O-antigens with a PEtN group(s) at position 3 of one or two rhamnose residues. In some serotypes, the PEtN modification competed or/and interfered with glucosylation and O-acetylation at the same or its neighboring sugar residue. We also showed that the plasmid pSFxv_2 is mobilizable to other S. flexneri strains by conjugation. Although pSFxv_2-harboring S. flexneri strains found in clinical infections are restricted to serotypes Xv, 4av, Yv and, possibly, 6v, our results demonstrate a high potential of dissemination of this plasmid in S. flexneri and emergence of new S. flexneri serotypes.

  5. Potential influence of Gadolinium contrast on image segmentation in MR-based attenuation correction with Dixon sequences in whole-body 18F-FDG PET/MR.

    PubMed

    Ruhlmann, Verena; Heusch, Philipp; Kühl, Hilmar; Beiderwellen, Karsten; Antoch, Gerald; Forsting, Michael; Bockisch, Andreas; Buchbender, Christian; Quick, Harald H

    2016-04-01

    To evaluate the influence of Gadolinium contrast agent on image segmentation in magnetic resonance (MR)-based attenuation correction (AC) with four-segment dual-echo time Dixon-sequences in whole-body [18F]-fluorodeoxyglucose positron emission tomography (PET)/MR imaging, and to analyze the consecutive effect on standardized uptake value (SUV). Hybrid imaging with an integrated PET/MR system was performed in 30 oncological patients. AC was based on MR imaging with a Dixon sequence with subsequent automated image segmentation. AC maps (µmaps) were acquired and reconstructed prior to (µmap-gd) and after (µmap+gd) Gd-contrast agent application. For quantification purposes, the SUV of organs and tumors based on both µmaps were compared. Tissue classification based on µmap-gd was correct in 29/30 patients; based on µmap+gd, the brain was falsely classified as fat in 12/30 patients with significant underestimation of SUV. In all cancerous lesions, tissue segmentation was correct. All concordant µmaps-gd/+gd resulted in no significant difference in SUV. In PET/MR, Gd-contrast agent potentially influences fat/water separation in Dixon-sequences of the head with above-average false tissue segmentation and an associated underestimation of SUV. Thus, MR-based AC should be acquired prior to Gd-contrast agent application. Additionally, integrating the MR-based AC maps into the reading-routine in PET/MR is recommended to avoid interpretation errors in cases where tissue segmentation fails.

  6. PET/CT in radiation oncology

    SciTech Connect

    Pan, Tinsu; Mawlawi, Osama

    2008-11-15

    PET/CT is an effective tool for the diagnosis, staging and restaging of cancer patients. It combines the complementary information of functional PET images and anatomical CT images in one imaging session. Conventional stand-alone PET has been replaced by PET/CT for improved patient comfort, patient throughput, and most importantly the proven clinical outcome of PET/CT over that of PET and that of separate PET and CT. There are over two thousand PET/CT scanners installed worldwide since 2001. Oncology is the main application for PET/CT. Fluorine-18 deoxyglucose is the choice of radiopharmaceutical in PET for imaging the glucose uptake in tissues, correlated with an increased rate of glycolysis in many tumor cells. New molecular targeted agents are being developed to improve the accuracy of targeting different disease states and assessing therapeutic response. Over 50% of cancer patients receive radiation therapy (RT) in the course of their disease treatment. Clinical data have demonstrated that the information provided by PET/CT often changes patient management of the patient and/or modifies the RT plan from conventional CT simulation. The application of PET/CT in RT is growing and will become increasingly important. Continuing improvement of PET/CT instrumentation will also make it easier for radiation oncologists to integrate PET/CT in RT. The purpose of this article is to provide a review of the current PET/CT technology, to project the future development of PET and CT for PET/CT, and to discuss some issues in adopting PET/CT in RT and potential improvements in PET/CT simulation of the thorax in radiation therapy.

  7. A 3-D QSAR-BASED IDENTIFICATION ALGORITHM FOR POTENTIAL ESTROGEN RECEPTOR LIGANDS

    EPA Science Inventory

    Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

  8. A 3-D QSAR-BASED IDENTIFICATION ALGORITHM FOR POTENTIAL ESTROGEN RECEPTOR LIGANDS

    EPA Science Inventory

    Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

  9. Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential

    PubMed Central

    Paterni, Ilaria; Granchi, Carlotta; Katzenellenbogen, John A.; Minutolo, Filippo

    2014-01-01

    Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathological conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications. PMID:24971815

  10. Recycled-PET fibre based panels for building thermal insulation: environmental impact and improvement potential assessment for a greener production.

    PubMed

    Ingrao, Carlo; Lo Giudice, Agata; Tricase, Caterina; Rana, Roberto; Mbohwa, Charles; Siracusa, Valentina

    2014-09-15

    A screening of Life Cycle Assessment for the evaluation of the damage arising from the production of 1 kg of recycled Polyethylene Terephthalate (RPET) fibre-based panel for building heat insulation was carried out according to the ISO 14040:2006 and 14044:2006. All data used were collected on site based on observations during site visits, review of documents and interviews with technical personnel and management. These data were processed by using SimaPro 7.3.3, accessing the Ecoinvent v.2.2 database and using the Impact 2002+ method. The study showed damage to be equal to 0.000299 points mostly due to the: 1) PET thermo-bonding fibre supply from China by means of a freight-equipped intercontinental aircraft; 2) production of bottle-grade granulate PET; 3) medium voltage electricity consumption during the manufacturing of RPET fibre panel. It was also highlighted that there were environmental benefits due to recycling through mainly avoiding significant emissions and reduced resource consumption. An improvement assessment was carried out to find solutions aimed at reducing the damage coming from the most impacting phases. Furthermore, the environmental impacts due to the production of the analysed RPET fibre-based panel were compared to other materials with the same insulating function, such as polystyrene foam, rock wool and cork slab. Finally, the environmental benefits of the recycling of PET bottles for flake production were highlighted compared to other treatment scenarios such as landfill and municipal incineration.

  11. Adsorbents made from waste ashes and post-consumer PET and their potential utilization in wastewater treatment.

    PubMed

    Zhang, Fu-Shen; Itoh, Hideaki

    2003-08-01

    This study was carried out to prepare low-cost adsorbents from different types of waste ashes and post-consumer PET for use in industrial wastewater treatment. PET was melted and blended with ashes. The mixture was then carbonized to form different types of adsorbents. Heavy metal leaching from the adsorbents was greatly reduced compared to leaching from the bulk ashes. The BET surface area of the adsorbents ranged from 115 to 485m(2)/g. The acidic sites on the adsorbents varied from 0.84 to 1.56meq./g, higher than that of the PET carbon. The adsorption of methylene blue (MB) or heavy metals on the adsorbents was not in accordance with their surface areas because acidic sites reaction, affinity adsorption and cation exchange all contribute to the adsorption of the adsorbents. The isotherm for MB adsorption on the adsorbents can be well described by the Langmuir or Freundlich equation but heavy metal adsorption cannot. It is believed that the adsorbents produced in this manner can be used in wastewater treatments for discoloration and heavy metal removal.

  12. P2Y Receptors in the Mammalian Nervous System: Pharmacology, Ligands and Therapeutic Potential

    PubMed Central

    Weisman, Gary A.; Woods, Lucas T.; Erb, Laurie; Seye, Cheikh I.

    2015-01-01

    P2Y receptors for extracellular nucleotides are coupled to activation of a variety of G proteins and stimulate diverse intracellular signaling pathways that regulate functions of cell types that comprise the central nervous system (CNS). There are 8 different subtypes of P2Y receptor expressed in cells of the CNS that are activated by a select group of nucleotide agonists. Here, the agonist selectivity of these 8 P2Y receptor subtypes is reviewed with an emphasis on synthetic agonists with high potency and resistance to degradation by extracellular nucleotidases that have potential applications as therapeutic agents. In addition, the recent identification of a wide variety of subtype-selective antagonists is discussed, since these compounds are critical for discerning cellular responses mediated by activation of individual P2Y receptor subtypes. The functional expression of P2Y receptor subtypes in cells that comprise the CNS is also reviewed and the role of each subtype in the regulation of physiological and pathophysiological responses is considered. Other topics include the role of P2Y receptors in the regulation of blood-brain barrier integrity and potential interactions between different P2Y receptor subtypes that likely impact tissue responses to extracellular nucleotides in the CNS. Overall, current research suggests that P2Y receptors in the CNS regulate repair mechanisms that are triggered by tissue damage, inflammation and disease and thus P2Y receptors represent promising targets for the treatment of neurodegenerative diseases. PMID:22963441

  13. Performance of 11C-Pittsburgh Compound B PET Binding Potential Images in the Detection of Amyloid Deposits on Equivocal Static Images.

    PubMed

    Hosokawa, Chisa; Ishii, Kazunari; Kimura, Yuichi; Hyodo, Tomoko; Hosono, Makoto; Sakaguchi, Kenta; Usami, Kimio; Shimamoto, Kenji; Yamazoe, Yuzuru; Murakami, Takamichi

    2015-12-01

    The goal of this study was to clarify whether binding potential (BP) images using (11)C-Pittsburgh compound B ((11)C-PiB) and dynamic PET can reliably detect cortical amyloid deposits for patients whose (11)C-PiB PET static images are ambiguous and whether visual ratings are affected by white matter retention. Static and BP images were constructed for 85 consecutive patients with cognitive impairment after (11)C-PiB dynamic PET. Cortical uptake was visually assessed as positive, negative, or equivocal for both types of images. Quantitatively, the standardized uptake value ratio (SUVR) from the static image, the nondisplaceable BP from the dynamic image for mean gray matter uptake, and the ratio of gray matter uptake to white matter retention were compared among (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. Forty-three scans were visually assessed as (11)C-PiB-positive in both the static and the BP images. Ten scans were (11)C-PiB-equivocal in the static images. In 8 of them, the BP images were (11)C-PiB-positive, whereas the other 2 were (11)C-PiB-equivocal. Thirty-two scans were assessed as (11)C-PiB-negative in the static images. In the BP images, 4 were (11)C-PiB-positive and 2 were (11)C-PiB-equivocal. The mean gray matter uptake of (11)C-PiB in SUVR and nondisplaceable BP, respectively, showed statistically significant differences among the (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. The ratio of gray matter uptake to white matter retention was lower in the BP images than static images from the (11)C-PiB-negative and (11)C-PiB-equivocal groups, whereas it was higher in the (11)C-PiB-positive group. (11)C-PiB PET BP images can clarify visual interpretation of clinical static (11)C-PiB-equivocal images by reducing the interference of nonspecific white matter retention. We conclude that (11)C-PiB-equivocal PET findings on static images reflect cortical amyloid deposits, which can be verified using BP images

  14. Reproducibility of quantitative measures of binding potential in rat striatum: A test re-test study using DTBZ dynamic PET studies

    SciTech Connect

    Avendaño-Estrada, A. Lara-Camacho, V. M. Ávila-García, M. C. Ávila- Rodríguez, M. A.

    2014-11-07

    There is great interest in the study of dopamine (DA) pathways due to the increasing number of patients with illnesses related to the dopaminergic system and molecular imaging based in Positron Emission Tomography (PET) has been proven helpful for this task. Among the different radiopharmaceuticals available to study DA interaction, [{sup 11}C]Dihydrotetrabenazine (DTBZ) has a high affinity for the vesicular monoamine transporter type 2 (VMAT2) and its binding potential (BP) is a marker of DA terminal integrity. This paper reports on the intersubject reproducibility of BP measurements in rat striatum with [11C]DTBZ using the Logańs method.

  15. Reproducibility of quantitative measures of binding potential in rat striatum: A test re-test study using DTBZ dynamic PET studies

    NASA Astrophysics Data System (ADS)

    Avendaño-Estrada, A.; Lara-Camacho, V. M.; Ávila-García, M. C.; Ávila-Rodríguez, M. A.

    2014-11-01

    There is great interest in the study of dopamine (DA) pathways due to the increasing number of patients with illnesses related to the dopaminergic system and molecular imaging based in Positron Emission Tomography (PET) has been proven helpful for this task. Among the different radiopharmaceuticals available to study DA interaction, [11C ]Dihydrotetrabenazine (DTBZ) has a high affinity for the vesicular monoamine transporter type 2 (VMAT2) and its binding potential (BP) is a marker of DA terminal integrity. This paper reports on the intersubject reproducibility of BP measurements in rat striatum with [11C]DTBZ using the Logańs method.

  16. Early-Late Heterobimetallic Complexes Linked by Phosphinoamide Ligands. Tuning Redox Potentials and Small Molecule Activation

    SciTech Connect

    Thomas, Christine M.

    2015-08-01

    Recent attention in the chemical community has been focused on the energy efficient and environmentally benign conversion of abundant small molecules (CO2, H2O, etc.) to useful liquid fuels. This project addresses these goals by examining fundamental aspects of catalyst design to ultimately access small molecule activation processes under mild conditions. Specifically, Thomas and coworkers have targetted heterobimetallic complexes that feature metal centers with vastly different electronic properties, dictated both by their respective positions on the periodic table and their coordination environment. Unlike homobimetallic complexes featuring identical or similar metals, the bonds between metals in early/late heterobimetallics are more polarized, with the more electron-rich late metal center donating electron density to the more electron-deficient early metal center. While metal-metal bonds pose an interesting strategy for storing redox equivalents and stabilizing reactive metal fragments, the polar character of metal-metal bonds in heterobimetallic complexes renders these molecules ideally poised to react with small molecule substrates via cleavage of energy-rich single and double bonds. In addition, metal-metal interactions have been shown to dramatically affect redox potentials and promote multielectron redox activity, suggesting that metal-metal interactions may provide a mechanism to tune redox potentials and access substrate reduction/activation at mild overpotentials. This research project has provided a better fundamental understanding of how interactions between transition metals can be used as a strategy to promote and/or control chemical transformations related to the clean production of fuels. While this project focused on the study of homogeneous systems, it is anticipated that the broad conclusions drawn from these investigations will be applicable to heterogeneous catalysis as well, particularly on heterogeneous processes that occur at interfaces in

  17. A study of DNA/BSA interaction and catalytic potential of oxidovanadium(v) complexes with ONO donor ligands.

    PubMed

    Dash, Subhashree P; Panda, Alok K; Dhaka, Sarita; Pasayat, Sagarika; Biswas, Ashis; Maurya, Mannar R; Majhi, Paresh Kumar; Crochet, Aurélien; Dinda, Rupam

    2016-11-15

    The study of DNA/BSA interaction and the catalytic potential of four mononuclear oxidoalkoxido vanadium(v) [V(V)O(L(1-4))OEt] (1-4) and one dinuclear oxidoalkoxido mixed-ligand vanadium(v) [{VO(L(2))OEt}2(Q)]{Q = 4,4'-bipyridine}(5) complexes, with tridentate binegative aroylazine ligands are reported [where H2L(1) = anthranylhydrazone of 2-hydroxy-1-napthaldehyde, H2L(2) = salicylhydrazone of 2-hydroxy-1-napthaldehyde, H2L(3) = benzoylhydrazone of 2-hydroxy-1-acetonaphthone, H2L(4) = anthranylhydrazone of 2-hydroxy-1-acetonaphthone]. All the complexes are characterized by elemental analysis as well as various spectroscopic techniques. Single crystal X-ray diffraction crystallography of 2 reveals that the metal centre is in distorted square pyramidal geometry with O4N coordination spheres, whereas 5 exhibits a distorted octahedral geometry around the metal center. In addition, all the complexes (1-5) show moderate DNA binding propensity which is investigated using UV-vis absorption titration, circular dichroism, thermal denaturation and fluorescence spectral studies. The experimental results show that the complexes effectively interact with CT-DNA through both minor and major groove binding modes, with binding constants ranging from 10(4)-10(5) M(-1). Among 1-5, complexes 3 and 4 show higher binding affinity towards CT-DNA than others and at the same time also exhibit negative ΔTm values of about ∼1.5 and 1.0 °C which resembles the properties shown by cisplatin. All complexes show moderate photo-induced cleavage of pUC19 supercoiled plasmid DNA with complex 3 showing the highest photo induced DNA cleavage activity of ∼48%. In coherence with the DNA interaction studies, 3 and 4 also exhibit good binding affinity towards BSA in the range of 10(10)-10(11) M(-1), which is also supported by their ability to quench the tryptophan fluorescence emission spectra of BSA. All the complexes show remarkable photo-induced BSA cleavage activity (>90%) at a complex

  18. Development of PET and SPECT Probes for Glutamate Receptors

    PubMed Central

    Nakayama, Morio

    2015-01-01

    l-Glutamate and its receptors (GluRs) play a key role in excitatory neurotransmission within the mammalian central nervous system (CNS). Impaired regulation of GluRs has also been implicated in various neurological disorders. GluRs are classified into two major groups: ionotropic GluRs (iGluRs), which are ligand-gated ion channels, and metabotropic GluRs (mGluRs), which are coupled to heterotrimeric guanosine nucleotide binding proteins (G-proteins). Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of GluRs could provide a novel view of CNS function and of a range of brain disorders, potentially leading to the development of new drug therapies. Although no satisfactory imaging agents have yet been developed for iGluRs, several PET ligands for mGluRs have been successfully employed in clinical studies. This paper reviews current progress towards the development of PET and SPECT probes for GluRs. PMID:25874256

  19. APRIL, a proliferation-inducing ligand, as a potential marker of lupus nephritis

    PubMed Central

    2012-01-01

    Introduction BLyS and APRIL are cytokines from the tumor necrosis factor family which play an important role in systemic lupus erythematosus (SLE). Previous works suggested an association between both molecules and SLE disease activity although their correlation with lupus nephritis is not known. We therefore assessed serum BLyS and APRIL in active lupus nephritis patients. Methods Serum samples from active lupus nephritis and at 6 months post-treatment were obtained. Serum levels of BLyS and APRIL (n = 47) as well as renal mRNA expression were measured. Serum levels of both molecules and clinical data (n = 27) were available at 6 months follow-up. All biopsy-proven lupus nephritis patients were treated with similar immunosuppressive drugs. Results Serum levels of APRIL were associated with proteinuria (Rs = 0.44, P value < 0.01) and degree of histological activity (Rs = 0.34; P value < 0.05) whereas BLyS levels were associated with complement levels (Rs = 0.46; P value < 0.01) and dosage of immunosuppressant. Interestingly, serum APRIL as well as its intrarenal mRNA levels were associated with resistance to treatment. From the receiver operating characteristic (ROC) analysis, high levels (> 4 ng/mL) of serum APRIL predicted treatment failure with a positive predictive value of 93 percent. Conclusion APRIL could be a potential biomarker for predicting difficult-to-treat cases of lupus nephritis. PMID:23171638

  20. Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents.

    PubMed

    Patch, Raymond J; Huang, Hui; Patel, Sharmila; Cheung, Wing; Xu, Guozhang; Zhao, Bao-Ping; Beauchamp, Derek A; Rentzeperis, Dionisios; Geisler, John G; Askari, Hossein B; Liu, Jianying; Kasturi, Jyotsna; Towers, Meghan; Gaul, Micheal D; Player, Mark R

    2017-09-29

    Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  1. Progress in developing cholecystokinin (CCK)/gastrin receptor ligands which have therapeutic potential

    PubMed Central

    Berna, Marc J.; Tapia, Jose A.; Sancho, Veronica; Jensen, Robert T.

    2007-01-01

    Summary Gastrin and CCK are two of the oldest hormones and within the last 15 years there has been an exponential increase in knowledge of their pharmacology, cell biology, receptors (CCK1R, CCK2R) and roles in physiology and pathological conditions. Despite these advances there is no approved disease indication for CCK receptor antagonists and only minor use of agonists. In this review the important factors determining this slow therapeutic development are reviewed. To assess this it is necessary to briefly review what is known about the roles of CCK receptors (CCK1R, CCK2R) in normal human physiology, their role in pathologic conditions, the selectivity of available potent CCKR agonists/antagonists as well as review their use in human conditions to date and the results. Despite extensive studies in animals and some in humans, recent studies suggest that monotherapy with CCK1R agonists will not be effective in obesity, nor CCK2R antagonists in panic disorders or CCK2R antagonists to inhibit growth of pancreatic cancer. Areas that require more study include the use of CCK2R agonists for imaging tumors and radiotherapy, CCK2R antagonists in hypergastrinemic states especially with long term PPI use and for potentiation of analgesia as well as use of CCK1R antagonists for a number of gastrointestinal disorders [motility disorders (irritable bowel syndrome, dyspepsia, constipation) and pancreatitis (acute, chronic)]. PMID:17997137

  2. PET/CT in the thorax: pitfalls.

    PubMed

    Truong, Mylene T; Viswanathan, Chitra; Carter, Brett W; Mawlawi, Osama; Marom, Edith M

    2014-01-01

    PET/CT is widely used in the staging and assessment of therapeutic response in patients with malignancies. Accurate interpretation of PET/CT requires knowledge of the normal physiologic distribution of [18F]-fluoro-2-deoxy-d-glucose, artifacts due to the use of CT for attenuation correction of the PET scan and potential pitfalls due to malignancies that are PET negative and benign conditions that are PET positive. Awareness of these artifacts and potential pitfalls is important in preventing misinterpretation that can alter patient management. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. PET scan

    MedlinePlus

    ... The PET detects signals from the tracer. A computer changes the signals into 3D pictures. The images ... urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. follows ...

  4. Senior Pets

    MedlinePlus

    ... does a pet become “old”? It varies, but cats and small dogs are generally considered “senior” at ... at roughly the same rate as humans, while cats have a somewhat lower rate. Contrary to popular ...

  5. Pet rabbits.

    PubMed

    Hillyer, E V

    1994-01-01

    Pet rabbits are becoming more common, and rabbit owners are demanding quality veterinary care. This article provides a broad overview of pet rabbit medicine, which is a relatively new field compared to laboratory and farm rabbit medicine. The most common differential diagnoses for presenting complaints are summarized in table form. Disease conditions are reviewed individually in the text. Sources of further information on veterinary care of rabbits are listed throughout the text, in an appendix, and in the references.

  6. Potential impact of atelectasis and primary tumor glycolysis on F-18 FDG PET/CT on survival in lung cancer patients.

    PubMed

    Hasbek, Zekiye; Yucel, Birsen; Salk, Ismail; Turgut, Bulent; Erselcan, Taner; Babacan, Nalan Akgul; Kacan, Turgut

    2014-01-01

    Atelectasis is an important prognostic factor that can cause pleuritic chest pain, coughing or dyspnea, and even may be a cause of death. In this study, we aimed to investigate the potential impact of atelectasis and PET parameters on survival and the relation between atelectasis and PET parameters. The study consisted of patients with lung cancer with or without atelectasis who underwent (18)F-FDG PET/CT examination before receiving any treatment. (18)F-FDG PET/CT derived parameters including tumor size, SUVmax, SUVmean, MTV, total lesion glycosis (TLG), SUV mean of atelectasis area, atelectasis volume, and histological and TNM stage were considered as potential prognostic factors for overall survival. Fifty consecutive lung cancer patients (22 patients with atelectasis and 28 patients without atelectasis, median age of 65 years) were evaluated in the present study. There was no relationship between tumor size and presence or absence of atelectasis, nor between presence/absence of atelectasis and TLG of primary tumors. The overall one-year survival rate was 83% and median survival was 20 months (n=22) in the presence of atelectasis; the overall one-year survival rate was 65.7% (n=28) and median survival was 16 months (p=0.138) in the absence of atelectasis. With respect to PFS; the one-year survival rate of AT+ patients was 81.8% and median survival was 19 months; the one-year survival rate of AT- patients was 64.3% and median survival was 16 months (p=0.159). According to univariate analysis, MTV, TLG and tumor size were significant risk factors for PFS and OS (p<0.05). However, SUVmax was not a significant factor for PFS and OS (p>0.05). The present study suggested that total lesion glycolysis and metabolic tumor volume were important predictors of survival in lung cancer patients, in contrast to SUVmax. In addition, having a segmental lung atelectasis seems not to be a significant factor on survival.

  7. A COMPUTATIONALLY-BASED IDENTIFICATION ALGORITHM FOR POTENTIAL ESTROGEN RECEPTOR LIGANDS, PART II. AN EVALUATION OF A HUMAN RECEPTOR-BASED MODEL

    EPA Science Inventory

    The objective of this study was to evaluate the capability of an expert system described in the previous paper (Bradbury et al., 2000; Toxicol. Sci.) to identify the potential for chemicals to act as ligands of mammalian estrogen receptors (ERs). The basis of that algorithm was a...

  8. Comparison of 18F-FDG PET/CT and PET/MRI in patients with multiple myeloma

    PubMed Central

    Sachpekidis, Christos; Hillengass, Jens; Goldschmidt, Hartmut; Mosebach, Jennifer; Pan, Leyun; Schlemmer, Heinz-Peter; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

    2015-01-01

    PET/MRI represents a promising hybrid imaging modality with several potential clinical applications. Although PET/MRI seems highly attractive in the diagnostic approach of multiple myeloma (MM), its role has not yet been evaluated. The aims of this prospective study are to evaluate the feasibility of 18F-FDG PET/MRI in detection of MM lesions, and to investigate the reproducibility of bone marrow lesions detection and quantitative data of 18F-FDG uptake between the functional (PET) component of PET/CT and PET/MRI in MM patients. The study includes 30 MM patients. All patients initially underwent 18F-FDG PET/CT (60 min p.i.), followed by PET/MRI (120 min p.i.). PET/CT and PET/MRI data were assessed and compared based on qualitative (lesion detection) and quantitative (SUV) evaluation. The hybrid PET/MRI system provided good image quality in all cases without artefacts. PET/MRI identified 65 of the 69 lesions, which were detectable with PET/CT (94.2%). Quantitative PET evaluations showed the following mean values in MM lesions: SUVaverage=5.5 and SUVmax=7.9 for PET/CT; SUVaverage=3.9 and SUVmax=5.8 for PET/MRI. Both SUVaverage and SUVmax were significantly higher on PET/CT than on PET/MRI. Spearman correlation analysis demonstrated a strong correlation between both lesional SUVaverage (r=0.744) and lesional SUVmax (r=0.855) values derived from PET/CT and PET/MRI. Regarding detection of myeloma skeletal lesions, PET/MRI exhibited equivalent performance to PET/CT. In terms of tracer uptake quantitation, a significant correlation between the two techniques was demonstrated, despite the statistically significant differences in lesional SUVs between PET/CT and PET/MRI. PMID:26550538

  9. Encapsulation of Nod1 and Nod2 receptor ligands into poly(lactic acid) nanoparticles potentiates their immune properties.

    PubMed

    Pavot, Vincent; Rochereau, Nicolas; Primard, Charlotte; Genin, Christian; Perouzel, Eric; Lioux, Thierry; Paul, Stéphane; Verrier, Bernard

    2013-04-10

    Most successful vaccines are able to induce persistent antibody responses that can last a lifetime. Emerging evidences indicate that activation of immune cells through pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) or Nod-like receptors (NLRs) may be critical mechanisms. Among PRRs, the use of TLR ligands as adjuvants is already largely described whereas the use of NLRs ligands remains largely unexplored. As activation of intracytoplasmic NLRs is able to induce proinflammatory molecules, the added value of encapsulation of Nod1 and Nod2 receptor ligands into Poly(Lactic Acid) (PLA) biodegradable nanocarriers to modulate their immune properties on human dendritic cells (DCs) maturation has been evaluated. Their ability to induce systemic immune responses in mice was also measured and compared to free ligands and the Alum adjuvant. Nod ligands encapsulated into PLA NPs were efficiently taken up by DCs and subsequently induced a strong up-regulation of maturation markers and the enhancement of proinflammatory cytokine secretion by DCs. Furthermore, co-injection of encapsulated Nod-ligands with PLA particles carrying Gag p24 HIV-1 antigen allowed a 100 fold increase in antibody responses in comparison to Alum. These results suggest that encapsulation of Nod ligands into PLA-NPs could be an effective way to improve vaccine efficiency.

  10. Physico-chemical characterization of a novel group of dopamine D(3)/D(2) receptor ligands, potential atypical antipsychotic agents.

    PubMed

    Deák, Katalin; Takács-Novák, Krisztina; Kapás, Margit; Vastag, Mónika; Tihanyi, Károly; Noszál, Béla

    2008-11-04

    The fundamental physico-chemical properties such as ionization and lipophilicity of twelve alkyl-aryl-piperidine and aryl-piperazine derivatives have been determined. Compounds are members of a recently identified, new class of potent dopamine D(3)/D(2) receptor ligands as potential atypical antipsychotic agents and were used in the development of a promising drug candidate (RGH-188) being present currently in clinical phase II investigations. The ionization constant (pK(a)) and the partition coefficient in octanol/water (logP(oct)) and cyclohexane/water systems (logP(ch)) were measured by validated analytical methods. Based on the highly precise physico-chemical data the structure-property relationships (SPR) were studied. The effect of the polar and apolar heteroatoms as well as polar and apolar surface areas on the partition in the two solvent systems was investigated by linear regression and multivariate linear regression analyses. Brain/blood concentration ratios (BB values) as a function of time were determined by HPLC analyses on plasma and brain homogenates of Wistar rats. A linear relationship has been found between DeltalogP values (logP(oct)-logP(ch)) and experimental logBB values, verifying that physico-chemical data can predict pharmacokinetic behaviour.

  11. Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel

    PubMed Central

    Basak, Sandip; Schmandt, Nicolaus; Gicheru, Yvonne; Chakrapani, Sudha

    2017-01-01

    Desensitization in pentameric ligand-gated ion channels plays an important role in regulating neuronal excitability. Here, we show that docosahexaenoic acid (DHA), a key ω−3 polyunsaturated fatty acid in synaptic membranes, enhances the agonist-induced transition to the desensitized state in the prokaryotic channel GLIC. We determined a 3.25 Å crystal structure of the GLIC-DHA complex in a potentially desensitized conformation. The DHA molecule is bound at the channel-periphery near the M4 helix and exerts a long-range allosteric effect on the pore across domain-interfaces. In this previously unobserved conformation, the extracellular-half of the pore-lining M2 is splayed open, reminiscent of the open conformation, while the intracellular-half is constricted, leading to a loss of both water and permeant ions. These findings, in combination with spin-labeling/EPR spectroscopic measurements in reconstituted-membranes, provide novel mechanistic details of desensitization in pentameric channels. DOI: http://dx.doi.org/10.7554/eLife.23886.001 PMID:28262093

  12. Exploring avidity: understanding the potential gains in functional affinity and target residence time of bivalent and heterobivalent ligands

    PubMed Central

    Vauquelin, Georges; Charlton, Steven J

    2013-01-01

    Bivalent ligands are increasingly important therapeutic agents. Although the naturally occurring antibodies are predominant, it is becoming more common to combine different antibody fragments or even low molecular weight compounds to generate heterobivalent ligands. Such ligands exhibit markedly increased affinity (i.e. avidity) and target residence time when both pharmacophores can bind simultaneously to their target sites. This is because binding of one pharmacophore forces the second tethered one to stay close to its corresponding site. This ‘forced proximity’ favours its binding and rebinding (once dissociated) to that site. However, rebinding will also take place when the diffusion of freshly dissociated ligands is merely slowed down. The present differential equation-based simulations explore the way both situations affect ligand binding. Both delay the attainment of binding equilibrium (resulting in steep saturation curves) and also increase the target residence time. Competitive ligands are able to interfere in a concentration-dependent manner, although much higher concentrations are required in the ‘forced proximity’ situation. Also, it is only in that situation that the ligand shows increased affinity. These simulations shed light on two practical consequences. Depending on the pharmacokinetic half-life of the bivalent ligand in the body, it may not have sufficient time to achieve equilibrium with the target. This will result in lower potency than expected, although it would have significant advantages in terms of residence time. In in vitro experiments, the manifestation of steep saturation curves and of accelerated dissociation in the presence of competitive ligands could mistakenly be interpreted as evidence for non-competitive, allosteric interactions. PMID:23330947

  13. Positron Emission Tomography (PET)

    SciTech Connect

    Welch, M.J.

    1990-01-01

    Positron emission tomography (PET) assesses biochemical processes in the living subject, producing images of function rather than form. Using PET, physicians are able to obtain not the anatomical information provided by other medical imaging techniques, but pictures of physiological activity. In metaphoric terms, traditional imaging methods supply a map of the body's roadways, its, anatomy; PET shows the traffic along those paths, its biochemistry. This document discusses the principles of PET, the radiopharmaceuticals in PET, PET research, clinical applications of PET, the cost of PET, training of individuals for PET, the role of the United States Department of Energy in PET, and the futures of PET. 22 figs.

  14. Positron Emission Tomography (PET)

    DOE R&D Accomplishments Database

    Welch, M. J.

    1990-01-01

    Positron emission tomography (PET) assesses biochemical processes in the living subject, producing images of function rather than form. Using PET, physicians are able to obtain not the anatomical information provided by other medical imaging techniques, but pictures of physiological activity. In metaphoric terms, traditional imaging methods supply a map of the body's roadways, its, anatomy; PET shows the traffic along those paths, its biochemistry. This document discusses the principles of PET, the radiopharmaceuticals in PET, PET research, clinical applications of PET, the cost of PET, training of individuals for PET, the role of the United States Department of Energy in PET, and the futures of PET.

  15. System with potential dual modes of metal-ligand cooperation: highly catalytically active pyridine-based PNNH-Ru pincer complexes.

    PubMed

    Fogler, Eran; Garg, Jai Anand; Hu, Peng; Leitus, Gregory; Shimon, Linda J W; Milstein, David

    2014-11-24

    Metal-ligand cooperation (MLC) plays an important role in catalysis. Systems reported so far are generally based on a single mode of MLC. We report here a system with potential for MLC by both amine-amide and aromatization-dearomatization ligand transformations, based on a new class of phosphino-pyridyl ruthenium pincer complexes, bearing sec-amine coordination. These pincer complexes are effective catalysts under unprecedented mild conditions for acceptorless dehydrogenative coupling of alcohols to esters at 35 °C and hydrogenation of esters at room temperature and 5 atm H2. The likely actual catalyst, a novel, crystallographically characterized monoanionic de-aromatized enamido-Ru(II) complex, was obtained by deprotonation of both the N-H and the methylene proton of the N-arm of the pincer ligand.

  16. Improving Cerebral Blood Flow Through Liposomal Delivery of Angiogenic Peptides: Potential of ¹⁸F-FDG PET Imaging in Ischemic Stroke Treatment.

    PubMed

    Hwang, Hyosook; Jeong, Hwan-Seok; Oh, Phil-Sun; Na, Kyung-Suk; Kwon, JeongIl; Kim, Jeonghun; Lim, SeokTae; Sohn, Myung-Hee; Jeong, Hwan-Jeong

    2015-07-01

    Strategies to promote angiogenesis can benefit cerebral ischemia. We determined whether liposomal delivery of angiogenic peptides with a known biologic activity of vascular endothelial growth factor benefitted cerebral ischemia. Also, the study examined the potential of (18)F-FDG PET imaging in ischemic stroke treatment. Male Sprague-Dawley rats (n = 40) underwent 40 min of middle cerebral artery occlusion. After 15 min of reperfusion, the rats (n = 10) received angiogenic peptides incorporated into liposomes. Animals receiving phosphate-buffered solution or liposomes without peptides served as controls. One week later, (18)F-FDG PET imaging was performed to examine regional changes in glucose utilization in response to the angiogenic therapy. The following day, (99m)Tc-hexamethylpropyleneamine oxime autoradiography was performed to determine changes in cerebral perfusion after angiogenic therapy. Corresponding changes in angiogenic markers, including von Willebrand factor and angiopoietin-1 and -2, were determined by immunostaining and polymerase chain reaction analysis, respectively. A 40-min period of middle cerebral artery occlusion decreased blood perfusion in the ipsilateral ischemic cortex of the brain, compared with that in the contralateral cortex, as measured by (99m)Tc-hexamethylpropyleneamine oxime autoradiography. Liposomal delivery of angiogenic peptides to the ischemic hemisphere of the brain attenuated the cerebral perfusion defect compared with controls. Similarly, vascular density evidenced by von Willebrand factor-positive staining was increased in response to angiogenic therapy, compared with that of controls. This increase was accompanied by an early increase in angiopoietin-2 expression, a gene participating in angiogenesis. (18)F-FDG PET imaging measured at 7 d after treatment revealed that liposomal delivery of angiogenic peptides facilitated glucose utilization in the ipsilateral ischemic cortex of the brain, compared with that in the

  17. Competitive advantage of PET/MRI.

    PubMed

    Jadvar, Hossein; Colletti, Patrick M

    2014-01-01

    Multimodality imaging has made great strides in the imaging evaluation of patients with a variety of diseases. Positron emission tomography/computed tomography (PET/CT) is now established as the imaging modality of choice in many clinical conditions, particularly in oncology. While the initial development of combined PET/magnetic resonance imaging (PET/MRI) was in the preclinical arena, hybrid PET/MR scanners are now available for clinical use. PET/MRI combines the unique features of MRI including excellent soft tissue contrast, diffusion-weighted imaging, dynamic contrast-enhanced imaging, fMRI and other specialized sequences as well as MR spectroscopy with the quantitative physiologic information that is provided by PET. Most evidence for the potential clinical utility of PET/MRI is based on studies performed with side-by-side comparison or software-fused MRI and PET images. Data on distinctive utility of hybrid PET/MRI are rapidly emerging. There are potential competitive advantages of PET/MRI over PET/CT. In general, PET/MRI may be preferred over PET/CT where the unique features of MRI provide more robust imaging evaluation in certain clinical settings. The exact role and potential utility of simultaneous data acquisition in specific research and clinical settings will need to be defined. It may be that simultaneous PET/MRI will be best suited for clinical situations that are disease-specific, organ-specific, related to diseases of the children or in those patients undergoing repeated imaging for whom cumulative radiation dose must be kept as low as reasonably achievable. PET/MRI also offers interesting opportunities for use of dual modality probes. Upon clear definition of clinical utility, other important and practical issues related to business operational model, clinical workflow and reimbursement will also be resolved. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  18. The Effect of the Prosthetic Group on the Pharmacologic Properties of 18F-labeled Rhodamine B, a Potential Myocardial Perfusion Agent for PET

    PubMed Central

    Bartholomä, Mark D.; Gottumukkala, Vijay; Zhang, Shaohui; Baker, Amanda; Dunning, Patricia; Fahey, Frederic H.; Treves, S. Ted; Packard, Alan B.

    2013-01-01

    We recently reported the development of the 2-[18F]fluoroethyl ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging. This compound, which was prepared using a [18F]fluoroethyl prosthetic group, has significant uptake in the myocardium in rats, but also demonstrates relatively high liver uptake and is rapidly hydrolyzed in vivo in mice. We have now prepared 18F-labeled rhodamine B using three additional prosthetic groups (propyl, diethylene glycol, and triethylene glycol) and found that the prosthetic group has a significant effect on the in vitro and in vivo properties of these compounds. Of the esters prepared to date, the diethylene glycol ester is superior in terms of in vitro stability and pharmacokinetics. These observations suggest that the prosthetic group plays a significant role in determining the pharmacological properties of 18F-labeled compounds. They also support the value of continued investigation of 18F-labeled rhodamines as PET radiopharmaceuticals for myocardial perfusion imaging. PMID:23210516

  19. Glutamate receptor ligands attenuate allodynia and hyperalgesia and potentiate morphine effects in a mouse model of neuropathic pain.

    PubMed

    Osikowicz, Maria; Mika, Joanna; Makuch, Wioletta; Przewlocka, Barbara

    2008-09-30

    Recent studies have indicated that metabotropic glutamate receptors mGluR5, mGluR2/3 and mGluR7 are present in the regions of central nervous system important for nociceptive transmission, but their involvement in neuropathic pain has not been well established. We demonstrated that acute and chronic administration of MPEP (mGluR5 antagonist), LY379268 (mGluR2/3 agonist), and AMN082 (mGluR7 agonist) attenuated allodynia (von Frey test) and hyperalgesia (cold plate test) as measured in Swiss albino mice on day seven after chronic constriction injury (CCI) to the sciatic nerve. Moreover, single administration of MPEP (30 mg/kg; i.p.) or LY379268 (10mg/kg; i.p.) injected 30 min before morphine potentiated morphine's effects (20mg/kg; i.p.) in the mouse CCI model, as measured by both the tests mentioned above. However, a single administration of AMN082 (3mg/kg; i.p.) potentiated the effects of a single morphine injection (20mg/kg; i.p.) in the von Frey test only. Chronic administration (7 days) of low doses of MPEP, LY379268 or AMN082 (all drugs at 3mg/kg; i.p.) potentiated the effects of single doses of morphine (3, 10, and 20mg/kg; i.p.) administered on day seven; however, AMN082 only potentiated the effect in the cold plate test. Additionally, the same doses of MPEP and LY379268 (but not AMN082) chronically co-administered with morphine (40 mg/kg; i.p.) attenuated the development of morphine tolerance in CCI-exposed mice. Our data suggest that mGluR5, mGluR2/3, and mGluR7 are involved in injury-induced plastic changes in nociceptive pathways and that the mGluR5 and mGluR2/3 ligands enhanced morphine's effectiveness in neuropathy, which could have therapeutic implications.

  20. Symposium on research advances in clinical PET. Final performance report

    SciTech Connect

    J. Michael McGehee

    1992-01-01

    The Institute for Clinical PET and the U.S. Department of Energy (DOE) co-sponsored a symposium entitled 'Research in PET: International and Institutional Perspectives' that highlighted the activities of many leading investigators in the U.S. and throughout the world. Research programs at the DOE were discussed as were potential directions of PET research. International as well as institutional perspectives on PET research were presented. This symposium was successful in reaching those interested in research advances of clinical PET.

  1. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel.

    PubMed

    Hilf, Ricarda J C; Dutzler, Raimund

    2009-01-01

    The X-ray structure of a pentameric ligand-gated ion channel from Erwinia chrysanthemi (ELIC) has recently provided structural insight into this family of ion channels at high resolution. The structure shows a homo-pentameric protein with a barrel-stave architecture that defines an ion-conduction pore located on the fivefold axis of symmetry. In this structure, the wide aqueous vestibule that is encircled by the extracellular ligand-binding domains of the five subunits narrows to a discontinuous pore that spans the lipid bilayer. The pore is constricted by bulky hydrophobic residues towards the extracellular side, which probably serve as barriers that prevent the diffusion of ions. This interrupted pore architecture in ELIC thus depicts a non-conducting conformation of a pentameric ligand-gated ion channel, the thermodynamically stable state in the absence of bound ligand. As ligand binding promotes pore opening in these ion channels and the specific ligand for ELIC has not yet been identified, we have turned our attention towards a homologous protein from the cyanobacterium Gloebacter violaceus (GLIC). GLIC was shown to form proton-gated channels that are activated by a pH decrease on the extracellular side and that do not desensitize after activation. Both prokaryotic proteins, ELIC and GLIC form ion channels that are selective for cations over anions with poor discrimination among monovalent cations, characteristics that resemble the conduction properties of the cation-selective branch of the family that includes acetylcholine and serotonin receptors. Here we present the X-ray structure of GLIC at 3.1 A resolution. The structure reveals a conformation of the channel that is distinct from ELIC and that probably resembles the open state. In combination, both structures suggest a novel gating mechanism for pentameric ligand-gated ion channels where channel opening proceeds by a change in the tilt of the pore-forming helices.

  2. Tuning redox potentials of bis(imino)pyridine cobalt complexes: an experimental and theoretical study involving solvent and ligand

    SciTech Connect

    Moyses Araujo, C.; Doherty, Mark D.; Konezny, Steven J.; Luca, Oana R.; Usyatinsky, Alex; Grade, Hans; Lobkovsky, Emil; Soloveichik, Grigorii L.; Crabtree, Robert H.; Batista, Victor S.

    2012-01-01

    The structure and electrochemical properties of a series of bis(imino)pyridine CoII complexes (NNN)CoX₂ and [(NNN)₂Co][PF₆]₂ (NNN = 2,6-bis[1-(4-R-phenylimino)ethyl]pyridine, with R = CN, CF₃, H, CH₃, OCH₃, N(CH₃)₂; NNN = 2,6-bis[1-(2,6-(iPr)₂-phenylimino)ethyl]pyridine and X = Cl, Br) were studied using a combination of electrochemical and theoretical methods. Cyclic voltammetry measurements and DFT/B3LYP calculations suggest that in solution (NNN)CoCl₂ complexes exist in equilibrium with disproportionation products [(NNN)₂Co]²⁺ [CoCl₄]²⁻ with the position of the equilibrium heavily influenced by both the solvent polarity and the steric and electronic properties of the bis(imino)pyridine ligands. In strong polar solvents (e.g., CH₃CN or H₂O) or with electron donating substituents (R = OCH₃ or N(CH₃)₂) the equilibrium is shifted and only oxidation of the charged products [(NNN)₂Co]²⁺ and [CoCl₄]²⁻ is observed. Conversely, in nonpolar organic solvents such as CH₂Cl₂ or with electron withdrawing substituents (R = CN or CF₃), disproportionation is suppressed and oxidation of the (NNN)CoCl₂ complexes leads to 18e⁻ CoIII complexes stabilized by coordination of a solvent moiety. In addition, the [(NNN)₂Co][PF₆]₂ complexes exhibit reversible CoII/III oxidation potentials that are strongly dependent on the electron withdrawing/donating nature of the N-aryl substituents, spanning nearly 750 mV in acetonitrile. The resulting insight on the regulation of redox properties of a series of bis(imino)pyridine cobalt(II) complexes should be particularly valuable to tune suitable conditions for reactivity.

  3. Evaluation of the genotoxic potential of three phenyltetrahydropyridinyl butylazole-derived sigma-receptor ligand drug candidates.

    PubMed

    Guzmán, Antonio; García, Concepción; Marín, Ana-Paz; Proudlock, Raymond J; Fernández de Henestrosa, Antonio R; Ruiz, Maria Teresa; Tortajada, Araceli; Lloyd, Mel; Marcos, Ricard

    2008-05-31

    Three structurally related phenyltetrahydropyridinyl butylazole (PTHPB)-derived drug candidates with sigma receptor-binding properties were evaluated for genotoxic potential in the ICH standard battery of genetic toxicology assays. These comprised an Ames test, a mouse-lymphoma assay, and a mouse bone-marrow micronucleus test. The maximum test concentrations in the in vitro assays were determined by the solubility and/or the cytotoxicity of the compounds. In the mouse micronucleus assay, the compounds were administered orally at three levels up to the maximum tolerated dose (MTD). Negative results were obtained for all three drug candidates in the Ames test and in the mouse-lymphoma assay, both in the absence or presence of metabolic activation. In the mouse micronucleus test, there was no effect on the frequency of micronucleated polychromatic erythrocytes (MNPCE) in bone marrow after oral administration of any of the three test compounds, at any dose level or sampling time (24 and 48h). Administration of all three compounds at the MTD induced a clear decrease in mouse body-temperature of 3.1-4.8 degrees C below normal; the temperature returned to normal within 8h of dose administration. The produced mild hypothermia and absence of micronucleus induction was in contrast to the induction of MNPCE secondary to marked hypothermia reported for a structurally similar PTHPB-derived sigma-receptor ligand, the antipsychotic compound E-5842. The results obtained in the current series of studies suggest that exposure to the three tested PTHPB-derived drug candidates would not pose a genotoxic risk under clinical conditions.

  4. ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

    PubMed Central

    Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

    2014-01-01

    Background and Purpose Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. Experimental Approach We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. Key Results ADN-1184 exhibits substantial 5-HT6/5-HT7/5-HT2A/D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg−1 i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg−1 i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg−1 ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg−1 i.p.). Conclusions and Implications ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. PMID:24199650

  5. Characterizing the Peroxisome Proliferator-Activated Receptor (PPARγ) Ligand Binding Potential of Several Major Flame Retardants, Their Metabolites, and Chemical Mixtures in House Dust

    PubMed Central

    Fang, Mingliang; Webster, Thomas F.; Ferguson, P. Lee

    2014-01-01

    Background: Accumulating evidence has shown that some environmental contaminants can alter adipogenesis and act as obesogens. Many of these contaminants act via the activation of the peroxisome proliferator-activated receptor γ (PPARγ) nuclear receptor. Objectives: Our goal was to determine the PPARγ ligand binding potency of several major flame retardants, including polybrominated diphenyl ethers (PBDEs), halogenated phenols and bisphenols, and their metabolites. Ligand binding activity of indoor dust and its bioactivated extracts were also investigated. Methods: We used a commercially available fluorescence polarization ligand binding assay to investigate the binding potency of flame retardants and dust extracts to human PPARγ ligand-binding domain. Rosiglitazone was used as a positive control. Results: Most of the tested compounds exhibited dose-dependent binding to PPARγ. Mono(2-ethylhexyl) tetrabromophthalate, halogenated bisphenols and phenols, and hydroxylated PBDEs were found to be potent PPARγ ligands. The most potent compound was 3-OH-BDE-47, with an IC50 (concentration required to reduce effect by 50%) of 0.24 μM. The extent of halogenation and the position of the hydroxyl group strongly affected binding. In the dust samples, 21 of the 24 samples tested showed significant binding potency at a concentration of 3 mg dust equivalent (DEQ)/mL. A 3–16% increase in PPARγ binding potency was observed following bioactivation of the dust using rat hepatic S9 fractions. Conclusion: Our results suggest that several flame retardants are potential PPARγ ligands and that metabolism may lead to increased binding affinity. The PPARγ binding activity of house dust extracts at levels comparable to human exposure warrants further studies into agonistic or antagonistic activities and their potential health effects. Citation: Fang M, Webster TF, Ferguson PL, Stapleton HM. 2015. Characterizing the peroxisome proliferator-activated receptor (PPARγ) ligand binding

  6. Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors

    PubMed Central

    2013-01-01

    Background The level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination of N-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [18F]1 and [18F]2 as CB2 receptor PET imaging agents. Results High binding affinity and specificity towards CB2 receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of 1 and 2. Aliphatic and aromatic radiofluorinations were optimized, and [18F]1 and [18F]2 were achieved in radiochemical yields of ≥30% with radiochemical purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood–brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [18F]1 and [18F]2 accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [18F]2 could be identified as the free acid [18F]10, which has no affinity towards the CB1 and CB2 receptors but can cross the BBB. Conclusions N-aryl-oxadiazolyl-propionamides can successfully be radiolabelled with 18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promising in vitro behavior, a rather rapid peripheral metabolism of [18F]1 and [18F

  7. Competitive antagonism between the nicotinic allosteric potentiating ligand galantamine and kynurenic acid at alpha7* nicotinic receptors.

    PubMed

    Lopes, Cristiane; Pereira, Edna F R; Wu, Hui-Qiu; Purushottamachar, Puranik; Njar, Vincent; Schwarcz, Robert; Albuquerque, Edson X

    2007-07-01

    Galantamine, a drug used to treat Alzheimer's disease, is a nicotinic allosteric potentiating ligand, and kynurenic acid (KYNA), a neuroactive metabolite of the kynurenine pathway, is an endogenous noncompetitive inhibitor of alpha7* nicotinic receptors (nAChRs) [the asterisk next to the nAChR subunit is intended to indicate that the exact subunit composition of the receptor is not known (Pharmacol Rev 51:397-401, 1999)]. Here, possible interactions between KYNA and galantamine at alpha7* nAChRs were examined in vitro and in vivo. In the presence of tetrodotoxin (TTX), approximately 85% of cultured hippocampal neurons responded to choline (0.3-30 mM) with alpha7* nAChR-subserved whole-cell (type IA) currents. In the absence of TTX and in the presence of glutamate receptor antagonists, choline triggered inhibitory postsynaptic currents (IPSCs) by activating alpha7* nAChRs on GABAergic neurons synapsing onto the neurons under study. Galantamine (1-10 microM) potentiated, whereas KYNA (10 nM-1 mM) inhibited, choline-triggered responses. Galantamine (1 microM), applied before KYNA, shifted to the right the concentration-response relationship for KYNA to inhibit type IA currents, increasing the IC(50) of KYNA from 13.9 +/- 8.3 to 271 +/- 131 microM. Galantamine, applied before or after KYNA, antagonized inhibition of choline-triggered IPSCs by KYNA. Local infusion of KYNA (100 nM) in the rat striatum reduced extracellular dopamine levels in vivo. This effect resulted from alpha7* nAChR inhibition and was blocked by coapplied galantamine (1-5 microM). It is concluded that galantamine competitively antagonizes the actions of KYNA on alpha7* nAChRs. Reducing alpha7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased alpha7* nAChR activity in the brain.

  8. Recent development in PET instrumentation.

    PubMed

    Peng, By Hao; Levin, Craig S

    2010-09-01

    Positron emission tomography (PET) is used in the clinic and in vivo small animal research to study molecular processes associated with diseases such as cancer, heart disease, and neurological disorders, and to guide the discovery and development of new treatments. This paper reviews current challenges of advancing PET technology and some of newly developed PET detectors and systems. The paper focuses on four aspects of PET instrumentation: high photon detection sensitivity; improved spatial resolution; depth-of-interaction (DOI) resolution and time-of-flight (TOF). Improved system geometry, novel non-scintillator based detectors, and tapered scintillation crystal arrays are able to enhance the photon detection sensitivity of a PET system. Several challenges for achieving high resolution with standard scintillator-based PET detectors are discussed. Novel detectors with 3-D positioning capability have great potential to be deployed in PET for achieving spatial resolution better than 1 mm, such as cadmium-zinc-telluride (CZT) and position-sensitive avalanche photodiodes (PSAPDs). DOI capability enables a PET system to mitigate parallax error and achieve uniform spatial resolution across the field-of-view (FOV). Six common DOI designs, as well as advantages and limitations of each design, are discussed. The availability of fast scintillation crystals such as LaBr(3), and the silicon photomultiplier (SiPM) greatly advances TOF-PET development. Recent instrumentation and initial results of clinical trials are briefly presented. If successful, these technology advances, together with new probe molecules, will substantially enhance the molecular sensitivity of PET and thus increase its role in preclinical and clinical research as well as evaluating and managing disease in the clinic.

  9. Recent Developments in PET Instrumentation

    PubMed Central

    Peng, Hao; Levin, Craig S.

    2013-01-01

    Positron emission tomography (PET) is used in the clinic and in vivo small animal research to study molecular processes associated with diseases such as cancer, heart disease, and neurological disorders, and to guide the discovery and development of new treatments. This paper reviews current challenges of advancing PET technology and some of newly developed PET detectors and systems. The paper focuses on four aspects of PET instrumentation: high photon detection sensitivity; improved spatial resolution; depth-of-interaction (DOI) resolution and time-of-flight (TOF). Improved system geometry, novel non-scintillator based detectors, and tapered scintillation crystal arrays are able to enhance the photon detection sensitivity of a PET system. Several challenges for achieving high resolution with standard scintillator-based PET detectors are discussed. Novel detectors with 3-D positioning capability have great potential to be deployed in PET for achieving spatial resolution better than 1 mm, such as cadmium-zinc-telluride (CZT) and position-sensitive avalanche photodiodes (PSAPDs). DOI capability enables a PET system to mitigate parallax error and achieve uniform spatial resolution across the field-of-view (FOV). Six common DOI designs, as well as advantages and limitations of each design, are discussed. The availability of fast scintillation crystals such as LaBr3, and the silicon photomultiplier (SiPM) greatly advances TOF-PET development. Recent instrumentation and initial results of clinical trials are briefly presented. If successful, these technology advances, together with new probe molecules, will substantially enhance the molecular sensitivity of PET and thus increase its role in preclinical and clinical research as well as evaluating and managing disease in the clinic. PMID:20497121

  10. Design, synthesis, characterisation and chemical reactivity of mixed-ligand platinum(II) oxadiazoline complexes with potential cytotoxic properties.

    PubMed

    Wagner, Gabriele; Marchant, Anthony; Sayer, James

    2010-09-07

    A series of mixed ligand platinum(II) oxadiazoline complexes bearing 7-nitro-1,3,5-triazaadamantane (7-NO(2)TAA) as a labile and reactive nitrogen ligand has been synthesised from easily accessible starting materials. [2+3] cycloaddition of nitrones R(1)R(2)C-N(+)(Me)O(-) to only one of the nitrile ligands in trans-[PtX(2)(PhCN)(2)] (X = Cl, Br) results in the selective formation of mono-oxadiazoline complexes trans-[PtX(2)(PhCN){N=C(Ph)-O-N(Me)-CR(1)R(2)}] from which the remaining nitrile can be replaced by 7-NO(2)TAA. The resulting complexes trans-[PtX(2)(7-NO(2)TAA) {N=C(Ph)-O-N(Me)-CR(1)R(2)}] and their precursors were characterised by elemental analysis, IR and multinuclear NMR spectroscopy.The suitability of the target complexes as anticancer agents was extrapolated from their general chemical reactivity. They are stable in DMSO, but react with thiols and undergo aquation of a chloro ligand. In the absence of a competing ligand, the coordinated 7-NO(2)TAA ligand slowly hydrolyses in an aqueous medium under release of formaldehyde, and this could induce bioactivity independent of the one typically found with platinum compounds. With nitrogen heterocycles such as pyridine a slow exchange of the 7-NO(2)TAA ligand occurs. A combined DFT/AIM study confirms the reaction observed in the experiment and predicts that other nitrogen heterocycles such as DNA nucleobases should react in the same way. Moreover, the 7-NO(2)TAA should be even more labile in an aqueous medium where protonation of the remaining amines can occur. A PM6 molecular modelling study suggests that the PtCl(oxadiazoline) fragment formed after release of one chloro and the labile 7-NO(2)TAA ligand fits well into the DNA groove and is able to form d(GpG) intrastrand crosslinks similar to the ones observed with cisplatin.

  11. High performance polyester concrete using recycled PET

    SciTech Connect

    Rebeiz, K.S.

    1995-10-01

    Recycled polyethylene terephthalate (PET) plastic wastes could be used in production of unsaturated polyester resins. In turn, these resins could be mixed with inorganic aggregates to produce polymer concrete (PC). Unsaturated polyesters based on recycled PET might be a potentially lower source cost of resins for producing useful PC based-products. The advantage of recycling PET in PC is that the PET materials do not have to be purified, including removal of colors, to the same extent as other PET recycling applications, which should facilitate the recycling operation and minimize its cost. The recycling of PET in PC could also help save energy and allow the long term disposal of the PET waste, an important advantage in recycling applications.

  12. Pet Therapy.

    ERIC Educational Resources Information Center

    Kavanagh, Kim

    1994-01-01

    This resource guide presents information on a variety of ways that animals can be used as a therapeutic modality with people having disabilities. Aspects addressed include: pet ownership and selection criteria; dogs (including service dogs, hearing/signal dogs, seeing leader dogs, and social/specialty dogs); horseriding for both therapy and fun;…

  13. Epileptic Activity Increases Cerebral Amino Acid Transport Assessed by 18F-Fluoroethyl-l-Tyrosine Amino Acid PET: A Potential Brain Tumor Mimic.

    PubMed

    Hutterer, Markus; Ebner, Yvonne; Riemenschneider, Markus J; Willuweit, Antje; McCoy, Mark; Egger, Barbara; Schröder, Michael; Wendl, Christina; Hellwig, Dirk; Grosse, Jirka; Menhart, Karin; Proescholdt, Martin; Fritsch, Brita; Urbach, Horst; Stockhammer, Guenther; Roelcke, Ulrich; Galldiks, Norbert; Meyer, Philipp T; Langen, Karl-Josef; Hau, Peter; Trinka, Eugen

    2017-01-01

    O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET) PET is a well-established method increasingly used for diagnosis, treatment planning, and monitoring in gliomas. Epileptic activity, frequently occurring in glioma patients, can influence MRI findings. Whether seizures also affect (18)F-FET PET imaging is currently unknown. The aim of this retrospective analysis was to investigate the brain amino acid metabolism during epileptic seizures by (18)F-FET PET and to elucidate the pathophysiologic background.

  14. The Heme-Based Oxygen Sensor Rhizobium etli FixL: Influence of Auxiliary Ligands on Heme Redox Potential and Implications on the Enzyme Activity.

    PubMed

    Honorio-Felício, Nathalie; Carepo, Marta S P; de F Paulo, Tércio; de França Lopes, Luiz Gonzaga; Sousa, Eduardo H S; Diógenes, Izaura C N; Bernhardt, Paul V

    2016-11-01

    Conformational changes associated to sensing mechanisms of heme-based protein sensors are a key molecular event that seems to modulate not only the protein activity but also the potential of the Fe(III/II) redox couple of the heme domain. In this work, midpoint potentials (Em) assigned to the Fe(III/II) redox couple of the heme domain of FixL from Rhizobium etli (ReFixL) in the unliganded and liganded states were determined by spectroelectrochemistry in the presence of inorganic mediators. In comparison to the unliganded ReFixL protein (+19mV), the binding to ligands that switch off the kinase activity induces a negative shift, i. e. Em=-51, -57 and -156mV for O2, imidazole and CN(-), respectively. Upon binding to CO, which does not affect the kinase active, Em was observed at +21mV. The potential values observed for Fe(III/II) of the heme domain of ReFixL upon binding to CO and O2 do not follow the expected trend based on thermodynamics, assuming that positive potential shift would be expected for ligands that bind to and therefore stabilize the Fe(II) state. Our results suggest that the conformational changes that switch off kinase activity upon O2 binding have knock-on effects to the local environment of the heme, such as solvent rearrangement, destabilize the Fe(II) state and counterbalances the Fe(II)-stabilizing influence of the O2 ligand. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. (68)Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter.

    PubMed

    Fellner, M; Biesalski, B; Bausbacher, N; Kubícek, V; Hermann, P; Rösch, F; Thews, O

    2012-10-01

    Bone metastases are a serious aggravation for patients suffering from cancer. Therefore, early recognition of bone metastases is of great interest for further treatment of patients. Bisphosphonates are widely used for scintigraphy of bone lesions with (99m)Tc. Using the (68)Ge/(68)Ga generator together with a macroyclic bisphosphonate a comparable PET-tracer comes into focus. The bisphosphonate DOTA-conjugated ligand BPAMD was labelled with (68)Ga. [(68)Ga]BPAMD was evaluated in vitro concerning binding to hydroxyapatite and stability. The tracer's in vivo accumulation was determined on healthy rats and bone metastases bearing animals by μ-PET. BPAMD was labelled efficiently with (68)Ga after 10 min at 100°C. [(68)Ga]BPAMD showed high in vitro stability within 3h and high binding to hydroxyapatite. Consequently, μ-PET experiments revealed high accumulation of [(68)Ga]BPAMD in regions of pronounced remodelling activity like bone metastases. (68)Ga BPAMD reveals great potential for diagnosis of bone metastases via PET/CT. The straight forward (68)Ga-labelling could be transferred to a kit-preparation of a cyclotron-independent PET tracer instantaneously available in many clinical sites using the (68)Ge/(68)Ga generator. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Pet Allergy Quiz

    MedlinePlus

    ... triggered by allergens such as pet dander or dust mites. Question 7 Which of these will not necessarily help minimize symptoms if you are allergic to pets? Try not to hug or kiss pets Keep your pets out of bedrooms Use a double or micro-filter bag in your vacuum cleaner Keep your pets ...

  17. Deoxyfluoro-D-trehalose (FDTre) analogues as potential PET probes for imaging mycobacterial infection: rapid synthesis and purification, conformational analysis, and uptake by mycobacteria

    PubMed Central

    Rundell, Sarah R.; Wagar, Zachary L.; Meints, Lisa M.; Olson, Claire D.; O’Neill, Mara K.; Piligian, Brent F.; Poston, Anne W.; Hood, Robin J.; Woodruff, Peter J.

    2016-01-01

    Mycobacterium tuberculosis, the etiological agent of human tuberculosis, requires the non-mammalian disaccharide trehalose for growth and virulence. Recently, detectable trehalose analogues have gained attention as probes for studying trehalose metabolism and as potential diagnostic imaging agents for mycobacterial infections. Of particular interest are deoxy-[18F]fluoro-D-trehalose (18F-FDTre) analogues, which have been suggested as possible positron emission tomography (PET) probes for in vivo imaging of M. tuberculosis infection. Here, we report progress toward this objective, including the synthesis and conformational analysis of four non-radioactive deoxy-[19F]fluoro-D-trehalose (19F-FDTre) analogues, as well as evaluation of their uptake by M. smegmatis. The rapid synthesis and purification of several 19F-FDTre analogues was accomplished in high yield using a one-step chemoenzymatic method. Conformational analysis of the 19F-FDTre analogues using NMR and molecular modeling methods showed that fluorine substitution had a negligible effect on the conformation of the native disaccharide, suggesting that fluorinated analogues may be successfully recognized and processed by trehalose metabolic machinery in mycobacteria. To test this hypothesis and to evaluate a possible route for delivery of FDTre probes specifically to mycobacteria, we showed that 19F-FDTre analogues are actively imported into M. smegmatis via the trehalose-specific transporter SugABC-LpqY. Finally, to demonstrate the applicability of these results to the efficient preparation and use of short-lived 18F-FDTre PET radiotracers, we carried out 19F-FDTre synthesis, purification, and administration to M. smegmatis in 1 hour. PMID:27560008

  18. Higher Pre-treatment 5-HT1A Receptor Binding Potential in Bipolar Disorder Depression is Associated with Treatment Remission: A Naturalistic Treatment Pilot PET Study

    PubMed Central

    Lan, Martin J; Hesselgrave, Natalie; Ciarleglio, Adam; Ogden, R Todd; Sullivan, Gregory M; Mann, J John; Parsey, Ramin V

    2013-01-01

    Bipolar Disorder is a major cause of disability and a high risk for suicide. The pathophysiology of the disorder remains largely unknown. Medication choice for bipolar depression patients involves trial and error. Our group reported previously that brain serotonin 1A (5HT1A) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5HT1A levels correlates with antidepressant medication outcome. 41 medication-free DSM-IV diagnosed, bipolar patients in a major depressive episode (MDE) had brain PET scans performed using [11C]WAY-100635 and a metabolite corrected arterial input function. The patients then received naturalistic psychopharmacologic treatment as outpatients and a follow up Hamilton Depression Rating Scale (HDRS) after 3 months of treatment. Patients with 24 item HDRS scores less than 10 were considered to have remitted. A linear mixed effects model was used to compare BPF (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and non-remitters. 34 patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and non-remitters did not differ in age, sex or recent medication history with serotonergic medications. Remitters had higher [11C]WAY-100635 BPF across all brain regions compared with non-remitters (p=0.02). Higher pre-treatment brain 5HT1A receptor binding was associated with remission after 3 months of pharmacological treatment in bipolar depression. Prospective treatment studies are warranted to determine whether this test predicts outcome of specific types of treatment. PMID:23720414

  19. Higher pretreatment 5-HT1A receptor binding potential in bipolar disorder depression is associated with treatment remission: a naturalistic treatment pilot PET study.

    PubMed

    Lan, Martin J; Hesselgrave, Natalie; Ciarleglio, Adam; Ogden, R Todd; Sullivan, Gregory M; Mann, J John; Parsey, Ramin V

    2013-11-01

    Bipolar disorder is a major cause of disability and a high risk for suicide. The pathophysiology of the disorder remains largely unknown. Medication choice for bipolar depression patients involves trial and error. Our group reported previously that brain serotonin 1A (5-HT(1A)) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5-HT(1A) levels correlates with antidepressant medication outcome. Forty-one medication-free DSM-IV diagnosed, bipolar patients in a major depressive episode had brain PET scans performed using [(11)C]WAY-100635 and a metabolite corrected arterial input function. The patients then received naturalistic psychopharmacologic treatment as outpatients and a follow up Hamilton Depression Rating Scale (HDRS) after 3 months of treatment. Patients with 24 item HDRS scores less than 10 were considered to have remitted. A linear mixed effects model was used to compare BP(F) (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and nonremitters. Thirty-four patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and nonremitters did not differ in age, sex, or recent medication history with serotonergic medications. Remitters had higher [(11)C]WAY-100635 BP(F) across all brain regions compared with nonremitters (P = 0.02). Higher pretreatment brain 5-HT(1A) receptor binding was associated with remission after 3 months of pharmacological treatment in bipolar depression. Prospective treatment studies are warranted to determine whether this test predicts outcome of specific types of treatment. Copyright © 2013 Wiley Periodicals, Inc.

  20. PET-positive fibrous dysplasia--a potentially misleading incidental finding in a patient with intimal sarcoma of the pulmonary artery.

    PubMed

    Strobel, Klaus; Bode, Beata; Lardinois, Didier; Exner, Ulrich

    2007-06-01

    Benign bone tumors can show an increased FDG uptake in FDG-PET/CT investigations. In the presented case, an incidentally detected PET-positive asymptomatic fibrous dysplasia was initially misinterpreted as a metastasis in a patient with intimal sarcoma of the pulmonary artery.

  1. Some metal complexes of three new potentially heptadentate (N4O3) tripodal Schiff base ligands; synthesis, characterizatin and X-ray crystal structure of a novel eight coordinate Gd(III) complex

    NASA Astrophysics Data System (ADS)

    Golbedaghi, Reza; Moradi, Somaeyh; Salehzadeh, Sadegh; Blackman, Allan G.

    2016-03-01

    The symmetrical and asymmetrical potentially heptadentate (N4O3) tripodal Schiff base ligands (H3L1-H3L3) were synthesized from the condensation reaction of three tripodal tetraamine ligands tpt (trpn), tris (3-aminopropyl) amine; ppe (abap), (2-aminoethyl)bis(3-aminopropyl)amine, and tren, tris(2-aminoethyl)amine, with 5-methoxysalicylaldehyde. Then, the reaction of Ln(III) (Ln = Gd, La and Sm), Al(III), and Fe(III) metal ions with the above ligands was investigated. The resulting compounds were characterized by IR, mass spectrometry and elemental analysis in all cases and NMR spectroscopy in the case of the Schiff base ligands. The X-ray crystal structure of the Gd complex of H3L3 ligand showed that in addition to all donor atoms of the ligand one molecule of H2O is also coordinated to the metal ion and a neutral eight-coordinate complex is formed.

  2. Mixed-Affinity Binding in Humans with 18-kDa Translocator Protein Ligands

    PubMed Central

    Owen, David R.J.; Gunn, Roger N.; Rabiner, Eugenii A.; Bennacef, Idriss; Fujita, Masahiro; Kreisl, William C.; Innis, Robert B.; Pike, Victor W.; Reynolds, Richard; Matthews, Paul M.; Parker, Christine A.

    2011-01-01

    11C-PBR28 PET can detect the 18-kDa translocator protein (TSPO) expressed within macrophages. However, quantitative evaluation of the signal in brain tissue from donors with multiple sclerosis (MS) shows that PBR28 binds the TSPO with high affinity (binding affinity [Ki], ~4 nM), low affinity (Ki, ~200 nM), or mixed affinity (2 sites with Ki, ~4 nM and ~300 nM). Our study tested whether similar binding behavior could be detected in brain tissue from donors with no history of neurologic disease, with TSPO-binding PET ligands other than 11C-PBR28, for TSPO present in peripheral blood, and with human brain PET data acquired in vivo with 11C-PBR28. Methods The affinity of TSPO ligands was measured in the human brain post-mortem from donors with a history of MS (n = 13), donors without any history of neurologic disease (n = 20), and in platelets from healthy volunteers (n = 13). Binding potential estimates from thirty-five 11C-PBR28 PET scans from an independent sample of healthy volunteers were analyzed using a gaussian mixture model. Results Three binding affinity patterns were found in brains from subjects without neurologic disease in similar proportions to those reported previously from studies of MS brains. TSPO ligands showed substantial differences in affinity between subjects classified as high-affinity binders (HABs) and low-affinity binders (LABs). Differences in affinity between HABs and LABs are approximately 50-fold with PBR28, approximately 17-fold with PBR06, and approximately 4-fold with DAA1106, DPA713, and PBR111. Where differences in affinity between HABs and LABs were low (~4-fold), distinct affinities were not resolvable in binding curves for mixed-affinity binders (MABs), which appeared to express 1 class of sites with an affinity approximately equal to the mean of those for HABs and LABs. Mixed-affinity binding was detected in platelets from an independent sample (HAB, 69%; MAB, 31%), although LABs were not detected. Analysis of 11C-PBR28 PET

  3. Synthesis of new C-25 and C-26 steroidal acids as potential ligands of the nuclear receptors DAF-12, LXR and GR.

    PubMed

    Dansey, María V; Del Fueyo, María C; Veleiro, Adriana S; Di Chenna, Pablo H

    2017-05-01

    A new methodology to obtain C-25 and C-26 steroidal acids starting from pregnenolone is described. Construction of the side chain was achieved by applying the Mukaiyama aldol reaction with a non-hydrolytic work-up to isolate the trapped silyl enol ether with higher yields. Using this methodology we synthesized three new steroidal acids as potential ligands of DAF-12, Liver X and Glucocorticoid nuclear receptors and studied their activity in reporter gene assays. Our results show that replacement of the 21-CH3 by a 20-keto group in the side chains of the cholestane scaffold of DAF-12 or Liver X receptors ligands causes the loss of the activity.

  4. Mixed-metal supramolecular complexes coupling phosphine-containing Ru(II) light absorbers to a reactive Pt(II) through polyazine bridging ligands.

    PubMed

    Swavey, Shawn; Fang, Zhenglai; Brewer, Karen J

    2002-05-06

    Supramolecular bimetallic Ru(II)/Pt(II) complexes [(tpy)Ru(PEt(2)Ph)(BL)PtCl(2)](2+) and their synthons [(tpy)Ru(L)(BL)](n)()(+) (where L = Cl(-), CH(3)CN, or PEt(2)Ph; tpy = 2,2':6',2''-terpyridine; and BL = 2,2'-bipyrimidine (bpm) or 2,3-bis(2-pyridyl)pyrazine (dpp)) have been synthesized and studied by cyclic voltammetry, electronic absorption spectroscopy, mass spectral analysis, and (31)P NMR. The mixed-metal bimetallic complexes couple phosphine-containing Ru chromophores to a reactive Pt site. These complexes show how substitution of the monodentate ligand on the [(tpy)RuCl(BL)](+) synthons can tune the properties of these light absorbers (LA) and incorporate a (31)P NMR tag by addition of the PEt(2)Ph ligand. The redox potentials for the Ru(III/II) couples occur at values greater than 1.00 V versus the Ag/AgCl reference electrode and can be tuned to more positive potentials on going from Cl(-) to CH(3)CN or PEt(2)Ph (E(1/2) = 1.01, 1.55, and 1.56 V, respectively, for BL = bpm). The BL(0/-) couple at -1.03 (bpm) and -1.05 V (dpp) for [(tpy)Ru(PEt(2)Ph)(BL)](2+) shifts dramatically to more positive potentials upon the addition of the PtCl(2) moiety to -0.34 (bpm) and -0.50 V (dpp) for the [(tpy)Ru(PEt(2)Ph)(BL)PtCl(2)](2+) bridged complex. The lowest energy electronic absorption for these complexes is assigned as the Ru(d pi) --> BL(pi*) metal-to-ligand charge transfer (MLCT) transition. These MLCT transitions are tuned to higher energy in the monometallic synthons when Cl(-) is replaced by CH(3)CN or PEt(2)Ph (516, 452, and 450 nm, for BL = bpm, respectively) and to lower energy when Pt(II)Cl(2) is coordinated to the bridging ligand (560 and 506 nm for BL = bpm or dpp). This MLCT state displays a broad emission at room temperature for all the dpp systems with the [(tpy)Ru(PEt(2)Ph)(dpp)PtCl(2)](2+) system exhibiting an emission centered at 750 nm with a lifetime of 56 ns. These supramolecular complexes [(tpy)Ru(PEt(2)Ph)(BL)PtCl(2)](2+) represent the

  5. Functional selectivity in CB(2) cannabinoid receptor signaling and regulation: implications for the therapeutic potential of CB(2) ligands.

    PubMed

    Atwood, Brady K; Wager-Miller, James; Haskins, Christopher; Straiker, Alex; Mackie, Ken

    2012-02-01

    Receptor internalization increases the flexibility and scope of G protein-coupled receptor (GPCR) signaling. CB(1) and CB(2) cannabinoid receptors undergo internalization after sustained exposure to agonists. However, it is not known whether different agonists internalize CB(2) to different extents. Because CB(2) is a promising therapeutic target, understanding its trafficking in response to different agonists is necessary for a complete understanding of its biology. Here we profile a number of cannabinoid receptor ligands and provide evidence for marked functional selectivity of cannabinoid receptor internalization. Classic, aminoalkylindole, bicyclic, cannabilactone, iminothiazole cannabinoid, and endocannabinoid ligands varied greatly in their effects on CB(1) and CB(2) trafficking. Our most striking finding was that (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212-2) (and other aminoalkylindoles) failed to promote CB(2) receptor internalization, whereas 5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol (CP55,940) robustly internalized CB(2) receptors. Furthermore, WIN55,212-2 competitively antagonized CP55,940-induced CB(2) internalization. Despite these differences in internalization, both compounds activated CB(2) receptors as measured by extracellular signal-regulated kinase 1/2 phosphorylation and recruitment of β-arrestin(2) to the membrane. In contrast, whereas CP55,940 inhibited voltage-gated calcium channels via CB(2) receptor activation, WIN55,212-2 was ineffective on its own and antagonized the effects of CP55,940. On the basis of the differences we found between these two ligands, we also tested the effects of other cannabinoids on these signaling pathways and found additional evidence for functional selectivity of CB(2) ligands. These novel data highlight that WIN55,212-2 and other cannabinoids show strong functional selectivity at CB(2

  6. The effects of sigma ligands on protein release from lacrimal acinar cells: a potential agonist/antagonist assay.

    PubMed

    Schoenwald, R D; Barfknecht, C F; Shirolkar, S; Xia, E

    1995-03-03

    Sigma receptor antagonists have been proposed as leading clinical candidates for use in various psychotic disorders. Prior to clinical testing, it is imperative that a new agent be correctly identified as an antagonist and not an agonist since the latter may worsen the psychosis. For sigma-ligands many behavioral and pharmacological assays have been developed in an attempt to classify agonist/antagonist activity. These assays evaluate a response or a behavior in an animal model that can be related to clinical efficacy. However, is the action by the presumed antagonist a consequence of sigma-receptor activity? Previously we have identified sigma-receptors in acinar cells of the main lacrimal gland of the New Zealand white rabbit and have measured protein release after the addition of various N,N-disubstituted phenylalkylamine derivatives known to be sigma-ligands by receptor binding studies. Although protein release from acinar cells has been attributed to either muscarinic or alpha-adrenergic stimulation, protein release from sigma-receptor stimulation was also confirmed. In the reported studies here, we isolated and incubated acinar cells with varying concentrations of known sigma-ligands and measured protein concentration. A knowledge of the receptor profile for the disubstituted phenylalkylamines permitted experiments to be designed in which various alpha, muscarinic, serotonergic, and dopaminergic antagonists could be added in equimolar concentrations. Under the conditions of these experiments, statistically significant increases in protein release for sigma-ligands could be attributed to stimulation of sigma-receptors. Haloperidol, an apparent sigma-antagonist, caused a statistically significant decrease in protein release and also inhibited protein release when tested with a known sigma-ligand, AF2975 [N,N-dimethyl-2-phenylethylamine]. In this system, stimulation and inhibition of protein release were defined as agonist and antagonist behavior, respectively

  7. Efficiency gains in tracer identification for nuclear imaging: can in vivo LC-MS/MS evaluation of small molecules screen for successful PET tracers?

    PubMed

    Joshi, Elizabeth M; Need, Anne; Schaus, John; Chen, Zhaogen; Benesh, Dana; Mitch, Charles; Morton, Stuart; Raub, Thomas J; Phebus, Lee; Barth, Vanessa

    2014-12-17

    Positron emission tomography (PET) imaging has become a useful noninvasive technique to explore molecular biology within living systems; however, the utility of this method is limited by the availability of suitable radiotracers to probe specific targets and disease biology. Methods to identify potential areas of improvement in the ability to predict small molecule performance as tracers prior to radiolabeling would speed the discovery of novel tracers. In this retrospective analysis, we characterized the brain penetration or peak SUV (standardized uptake value), binding potential (BP), and brain exposure kinetics across a series of known, nonradiolabeled PET ligands using in vivo LC-MS/MS (liquid chromatography coupled to mass spectrometry) and correlated these parameters with the reported PET ligand performance in nonhuman primates and humans available in the literature. The PET tracers studied included those reported to label G protein-coupled receptors (GPCRs), intracellular enzymes, and transporters. Additionally, data for each tracer was obtained from a mouse brain uptake assay (MBUA), previously published, where blood-brain barrier (BBB) penetration and clearance parameters were assessed and compared against similar data collected on a broad compound set of central nervous system (CNS) therapeutic compounds. The BP and SUV identified via nonradiolabeled LC-MS/MS, while different from the published values observed in the literature PET tracer data, allowed for an identification of initial criteria values we sought to facilitate increased potential for success from our early discovery screening paradigm. Our analysis showed that successful, as well as novel, clinical PET tracers exhibited BP of greater than 1.5 and peak SUVs greater than approximately 150% at 5 min post dose in rodents. The brain kinetics appeared similar between both techniques despite differences in tracer dose, suggesting linearity across these dose ranges. The assessment of tracers in a

  8. Synthesis and characterisation of new 4-oxo-N-(substituted-thiazol-2-yl)-4H-chromene-2-carboxamides as potential adenosine receptor ligands

    NASA Astrophysics Data System (ADS)

    Cagide, Fernando; Borges, Fernanda; Gomes, Ligia R.; Low, John Nicolson

    2015-06-01

    Chromones are 4H-benzopyran-4-one heterocycles that have been thoroughly studied due to their interesting biological activities. Thiazole based compounds have been used in therapeutics as antimicrobial, antiviral and as antifungal agents for a long time but, in the past decades, they have been identified as potent and selective ligands for adenosine receptor. In continuation of our project related to the syntheses of pharmacologically important heterocycles, a new series of chromone-thiazole hybrids have been designed as potential ligands for human adenosine receptors. In this context, new 4-oxo-N-(substituted-thiazol-2-yl)-4H-chromene-2-carboxamides were synthesized from chromone-2-carboxylic acid by two different amidation methods. The development of dissimilar synthetic approaches provided the possibility of working with diverse reaction conditions, namely with conventional heating and/or microwave irradiation. The structure of the compounds has been established on the basis of NMR and MS spectroscopy and X-ray crystallography. Relevant data related to the molecular geometry and conformation of the chromone-thiazole hybrids has been acquired which can be of the utmost importance to understand ligand-receptor binding.

  9. [Pet ownership and health status of pets from immunocompromised children, with emphasis in zoonotic diseases].

    PubMed

    Abarca V, Katia; López Del P, Javier; Peña D, Anamaría; López G, J Carlos

    2011-06-01

    To characterize pet ownership and pet health status in families of immunocompromised (IS) children, with emphasis in zoonotic diseases. Families of IS children from two hospitals in Santiago, Chile, were interviewed and their pets were evaluated by veterinary examination, coproparasitologic and skin dermatophytes test. In specific cases, other laboratory tests were performed in IS children or their relatives. 47 out of 70 contacted families had pets, 42 participated in the study. Several risk factors for IS children were observed, as having a turtle as a pet and to clean cat or turtle faeces. Lack of adequate veterinary control, immunizations and deparasitation of pets were observed. Some animals showed zoonotic diseases or agents, as Brucella canis, Cryptosporidium sp, Giardia intestinalis, Toxocara canis and scabies. 44% of dogs had ticks and 37% had fleas, both potential vectors of infections. Our results suggest that policies to provide safer pet contact in IS children are needed.

  10. Human health implications of Salmonella-contaminated natural pet treats and raw pet food.

    PubMed

    Finley, Rita; Reid-Smith, Richard; Weese, J Scott

    2006-03-01

    Human salmonellosis occurs mainly as a result of handling or consuming contaminated food products, with a small percentage of cases being related to other, less well-defined exposures, such as contact with companion animals and natural pet treats. The increasing popularity of raw food diets for companion animals is another potential pet-associated source of Salmonella organisms; however, no confirmed cases of human salmonellosis have been associated with these diets. Pets that consume contaminated pet treats and raw food diets can be colonized with Salmonella organisms without exhibiting clinical signs, making them a possible hidden source of contamination in the household. Pet owners can reduce their risk of acquiring Salmonella organisms by not feeding natural pet treats and raw food diets to their pets, whereas individuals who investigate cases of salmonellosis or interpret surveillance data should be aware of these possible sources of Salmonella organisms.

  11. The potential pool of Co, Ni, Cu, Pb and Cd organic complexing ligands in coastal and urban rain waters

    NASA Astrophysics Data System (ADS)

    Nimmo, Malcolm; Fones, Gary R.

    The detection of dissolved ACSV (adsorptive cathodic stripping voltammetry) Co, Ni, Cu, Cd and Pb in rain waters collected from an urban and a coastal site in the northwest of England is described. The presence of metal complexing organic ligands in rain waters is indicated with an overall percentage of ACSV non - labile dissolved metal of the total dissolved metal fraction ( = %ACSV nl/t) being 33 (33); 28 (35); 26 (32); 33 (25); 27 (34): for Co, Ni, Cu, Cd and Pb, respectively, for the urban site (and coastal site). ACSV metal lability is theoretically defined and is dependent upon the a-coefficient ( β' MAL [AL]) of the added ACSV ligand (AL). No major differences were observed between %ACSV nl/t metal fractions in rain waters collected at the two contrasting sites for all the metals considered. As Cu, Pb, Cd and Ni had values greater than 10 for their Ef crust (crustal enrichment factor), rain water collected from both sites had predominantly anthropic chemical characteristics. The commonality of the aerosol chemical characteristics at the two sites may account for the observed similar (relative to total metal concentrations) proportions of metal organic complexation at the two different sites. The general order of increasing organic associations was Cu = Pb = Ni < Co < Cd, although the analytical log α-coefficients ( β' MAL [AL]) for each metal were different (9.62—Ni; 9.27—Cu; 5.29—Co; 2.15—Pb; 1.13—Cd). Significant correlations were encountered between ACSV non - labile and total dissolved trace metal concentrations of the pooled data from both sites, again an indication of the similarity of the chemical characteristics of the scavenged soluble organic ligands associated with background aerosol material.

  12. Pet Bonding and Pet Bereavement among Adolescents.

    ERIC Educational Resources Information Center

    Brown, Brenda H.; And Others

    1996-01-01

    Studied adolescent-pet bonding and bereavement following pet loss (n=55). Hypothesized that highly-bonded adolescents experience more intense grief when a pet dies than do those less bonded; degree of bonding is greater for girls than for boys; and intensity of bereavement is greater for girls than for boys. Results supported the hypotheses. (RB)

  13. Pet Problems at Home: Pet Problems in the Community.

    ERIC Educational Resources Information Center

    Soltow, Willow

    1984-01-01

    Discusses problems of pets in the community, examining the community's role related to disruptive pets and pet overpopulation. Also discusses pet problems at home, offering advice on selecting a pet, meeting a pet's needs, and disciplining pets. Includes a list of books, films/filmstrips, teaching materials, and various instructional strategies.…

  14. Pet Problems at Home: Pet Problems in the Community.

    ERIC Educational Resources Information Center

    Soltow, Willow

    1984-01-01

    Discusses problems of pets in the community, examining the community's role related to disruptive pets and pet overpopulation. Also discusses pet problems at home, offering advice on selecting a pet, meeting a pet's needs, and disciplining pets. Includes a list of books, films/filmstrips, teaching materials, and various instructional strategies.…

  15. A comparative study of zwitterionic ligands-mediated mineralization and the potential of mineralized zwitterionic matrices for bone tissue engineering

    PubMed Central

    Liu, Pingsheng; Emmons, Erin

    2014-01-01

    Cationic and anionic residues of the extracellular matrices (ECM) of bone play synergistic roles in recruiting precursor ions and templating the nucleation, growth and crystalline transformations of calcium apatite in natural biomineralization. We previously reported that zwitterionic sulfobetaine ligands can template extensive 3-dimensional (3-D) hydroxyapaptite (HA)-mineralization of photo-crosslinked polymethacrylatehydrogels. Here, we compared the potency of two other major zwitterionic ligands, phosphobetaine and carboxybetaine, with that of the sulfobetaine in mediating 3-D mineralization using the crosslinked polymethacrylate hydrogel platform. We confirmed that all three zwitterionic hydrogels were able to effectively template 3-D mineralization, supporting the general ability of zwitterions to mediate templated mineralization. Among them, however, sulfobetaine and phosphobetaine hydrogels templated denser 3-D mineralizationthan the carboxybetaine hydrogel, likely due to their higher free water fractions and better maintenance of zwitterionic nature throughout the pH-changes during the in vitro mineralization process. We further demonstrated that the extensively mineralized zwitterionic hydrogels could be exploited for efficient retention (e.g. 99% retention after 24-h incubation in PBS) of osteogenic growth factor recombinant bone morphogenetic protein-2 (rhBMP-2) and subsequent sustained local release with retained bioactivity. Combined with the excellent cytocompatibility of all three zwitterionic hydrogels and the significantly improved cell adhesive properties of their mineralized matrices, these materials could find promising applications in bone tissue engineering. PMID:25558374

  16. Low energy cyclotron production of multivalent transition metals for PET imaging and therapy

    NASA Astrophysics Data System (ADS)

    Avila-Rodriguez, Miguel Angel

    Recent advances in high-resolution tomographs for small animals require the production of nonconventional long-lived positron emitters to label novel radiopharmaceuticals for PET-based molecular imaging. Radioisotopes with an appropriate half life to match the kinetics of slow biological processes will allow to researchers to study the phamacokinetics of PET ligands over several hours, or even days, on the same animal, with the injection of a single dose. In addition, radionuclides with a suitable half life can potentially be distributed from a central production site making them available in PET facilities that lack an in-house cyclotron. In the last few years there has been a growing interest in the use of PET ligands labeled with radiometals, particularly isotopes of copper, yttrium and zirconium. Future clinical applications of these tracers will require them to be produced reliably and efficiently. This thesis work deals with implementing and optimizing the production of the multivalent transition metals 61,64Cu, 86Y and 89Zr for molecular PET imaging and therapy. Our findings in the production of these radionuclides at high specific activity on an 11 MeV proton-only cyclotron are presented. Local applications of these tracers, including Cu-ATSM for in vivo quantification of hypoxia, synthesis of targeted radiopharmaceuticals using activated esters of DOTA, and a novel development of positron emitting resin microspheres, are also be discussed. As a result of this thesis work, metallic radionuclides are now efficiently produced on a weekly basis in sufficient quality and quantity for collaborating scientists at UW-Madison and external users in other Universities across the country.

  17. Advances in time-of-flight PET

    PubMed Central

    Surti, Suleman; Karp, Joel S.

    2016-01-01

    This paper provides a review and an update on time-of-flight PET imaging with a focus on PET instrumentation, ranging from hardware design to software algorithms. We first present a short introduction to PET, followed by a description of TOF PET imaging and its history from the early days. Next, we introduce the current state-of-art in TOF PET technology and briefly summarize the benefits of TOF PET imaging. This is followed by a discussion of the various technological advancements in hardware (scintillators, photo-sensors, electronics) and software (image reconstruction) that have led to the current widespread use of TOF PET technology, and future developments that have the potential for further improvements in the TOF imaging performance. We conclude with a discussion of some new research areas that have opened up in PET imaging as a result of having good system timing resolution, ranging from new algorithms for attenuation correction, through efficient system calibration techniques, to potential for new PET system designs. PMID:26778577

  18. Advances in time-of-flight PET.

    PubMed

    Surti, Suleman; Karp, Joel S

    2016-01-01

    This paper provides a review and an update on time-of-flight PET imaging with a focus on PET instrumentation, ranging from hardware design to software algorithms. We first present a short introduction to PET, followed by a description of TOF PET imaging and its history from the early days. Next, we introduce the current state-of-art in TOF PET technology and briefly summarize the benefits of TOF PET imaging. This is followed by a discussion of the various technological advancements in hardware (scintillators, photo-sensors, electronics) and software (image reconstruction) that have led to the current widespread use of TOF PET technology, and future developments that have the potential for further improvements in the TOF imaging performance. We conclude with a discussion of some new research areas that have opened up in PET imaging as a result of having good system timing resolution, ranging from new algorithms for attenuation correction, through efficient system calibration techniques, to potential for new PET system designs. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  19. Path Analysis Identifies Receptor Activator of Nuclear Factor-κB Ligand, Osteoprotegerin, and Sclerostin as Potential Mediators of the Tophus-bone Erosion Relationship in Gout.

    PubMed

    Chhana, Ashika; Aati, Opetaia; Gamble, Gregory D; Callon, Karen E; Doyle, Anthony J; Roger, Mark; McQueen, Fiona M; Horne, Anne; Reid, Ian R; Cornish, Jillian; Dalbeth, Nicola

    2016-02-01

    To determine the relationship between tophus, erosion and bone remodeling factors in gout. Computed tomography bone erosion and circulating bone factors were measured in adults with tophaceous gout. Multiple regression modeling and path analysis were used to determine predictors of erosion. Tophus number, Māori or Pacific ethnicity, creatinine, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), and sclerostin were independently associated with erosion. Path analysis showed a direct effect of tophus number on erosion, partially mediated through OPG, RANKL, and sclerostin. Tophus number is strongly associated with bone erosion in gout. Circulating RANKL, OPG, and sclerostin are potential mediators of tophus-related erosion.

  20. POTENTIAL CROSS-CONTAMINATION OF SIMILAR Giardia duodenalis ASSEMBLAGE IN CHILDREN AND PET DOGS IN SOUTHERN BRAZIL, AS DETERMINED BY PCR-RFLP

    PubMed Central

    de QUADROS, Rosiléia Marinho; WEISS, Paulo Henrique Exterchoter; MARQUES, Sandra Marcia Tietz; MILETTI, Luiz Claudio

    2016-01-01

    SUMMARY Giardia duodenalis is an enteric parasite that has distinct genetic groups. Human infections are mainly caused by assemblages A and B, although sporadic infections by assemblages C and D have also been reported. Animals can be infected by a wide range of assemblages (A to H). The aim of this study is to identify the assemblages and sub-assemblages of G. duodenalis with zoonotic features in fecal samples of school-aged children, and in dogs that coexist in the same households in Lages, Santa Catarina, Brazil. Fecal samples of 91 children and 108 dogs were obtained and G. duodenalis cysts were detected in samples from 11 (12.08%) children and 10 (9.25%) dogs. DNA extracted from the 21 positive samples was analyzed by PCR-RFLP, using the gdh gene. Results showed the presence of sub-assemblages AI (2/11), AII (4/11), BIII (2/11), and BIV(3/11) among children and AI (5/10) and BIV(3/10) in dogs, with zoonotic characteristics, and the carnivore specific assemblage C (2/10). G. duodenalis was found to infect both children and dogs living in the same household, with the same sub-assemblage (BIV) indicating that pet dogs are a potential risk of transmission of G. duodenalis to humans. PMID:27680171

  1. POTENTIAL CROSS-CONTAMINATION OF SIMILAR Giardia duodenalis ASSEMBLAGE IN CHILDREN AND PET DOGS IN SOUTHERN BRAZIL, AS DETERMINED BY PCR-RFLP.

    PubMed

    Quadros, Rosiléia Marinho de; Weiss, Paulo Henrique Exterchoter; Marques, Sandra Marcia Tietz; Miletti, Luiz Claudio

    2016-09-22

    Giardia duodenalis is an enteric parasite that has distinct genetic groups. Human infections are mainly caused by assemblages A and B, although sporadic infections by assemblages C and D have also been reported. Animals can be infected by a wide range of assemblages (A to H). The aim of this study is to identify the assemblages and sub-assemblages of G. duodenalis with zoonotic features in fecal samples of school-aged children, and in dogs that coexist in the same households in Lages, Santa Catarina, Brazil. Fecal samples of 91 children and 108 dogs were obtained and G. duodenalis cysts were detected in samples from 11 (12.08%) children and 10 (9.25%) dogs. DNA extracted from the 21 positive samples was analyzed by PCR-RFLP, using the gdh gene. Results showed the presence of sub-assemblages AI (2/11), AII (4/11), BIII (2/11), and BIV(3/11) among children and AI (5/10) and BIV(3/10) in dogs, with zoonotic characteristics, and the carnivore specific assemblage C (2/10). G. duodenalis was found to infect both children and dogs living in the same household, with the same sub-assemblage (BIV) indicating that pet dogs are a potential risk of transmission of G. duodenalis to humans.

  2. Pet allergy: how important for Turkey where there is a low pet ownership rate.

    PubMed

    Mungan, Dilşad; Celik, Gülfem; Bavbek, Sevim; Misirligil, Zeynep

    2003-01-01

    have the potential to become an important source of indoor allergens in our population. Our findings also suggest that current pet ownership--but not childhood pet keeping--seems to be a risk for the development of sensitization to pets.

  3. Pets for Handicapped Children.

    ERIC Educational Resources Information Center

    Frith, Greg H.

    1982-01-01

    Pets can provide valuable learning for handicapped children, but selection of a type of pet should consider cost, availability and care, parents' attitudes, locality, the animal's susceptibility to training, pet's life expectancy, and the child's handicap and emotional maturity. Suggested pet-related activities are listed. (CL)

  4. A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4.

    PubMed

    Dickson, Bradley M; de Waal, Parker W; Ramjan, Zachary H; Xu, H Eric; Rothbart, Scott B

    2016-10-21

    In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a -3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.

  5. A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4

    NASA Astrophysics Data System (ADS)

    Dickson, Bradley M.; de Waal, Parker W.; Ramjan, Zachary H.; Xu, H. Eric; Rothbart, Scott B.

    2016-10-01

    In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a -3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.

  6. LigandRNA: computational predictor of RNA-ligand interactions.

    PubMed

    Philips, Anna; Milanowska, Kaja; Lach, Grzegorz; Bujnicki, Janusz M

    2013-12-01

    RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA-small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA-ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a "meta-predictor" leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http://ligandrna.genesilico.pl.

  7. Synthesis and biodistribution of lipophilic and monocationic gallium radiopharmaceuticals derived from N,N'-bis(3-aminopropyl)-N,N'-dimethylethylenediamine: potential agents for PET myocardial imaging with 68Ga.

    PubMed

    Hsiao, Yui-May; Mathias, Carla J; Wey, Shiaw-Pyng; Fanwick, Phillip E; Green, Mark A

    2009-01-01

    In locations that lack nearby cyclotron facilities for radionuclide production, generator-based (68)Ga radiopharmaceuticals might have clinical utility for positron emission tomography (PET) studies of myocardial perfusion and other physiological processes. The lipophilic and monocationic (67)Ga-labeled gallium chelates of five novel hexadentate bis(salicylaldimine) ligands the bis(salicylaldimine), bis(3-methoxysalicylaldimine), bis(4-methoxysalicylaldimine), bis(6-meth,oxysalicylaldimine), and bis(4,6-dimethoxysalicylaldimine) of N,N'-bis(3-aminopropyl)-N,N'-dimethylethylenediamine (BAPDMEN), were prepared. The structure of the unlabeled [Ga(4-MeOsal)(2)BAPDMEN](+)PF(6)(-) salt was determined by X-ray crystallography, and the biodistribution of each of the (67)Ga-labeled gallium chelates was determined in rats following intravenous administration and compared with the biodistribution of [(86)Rb]rubidium chloride. The [Ga(4-MeOsal)(2)BAPDMEN](+)PF(6)(-) complex exhibited the expected pseudo-octahedral N(4)O(2)(2-) coordination sphere about the Ga(3+) center with a trans disposition of the phenolate oxygen atoms. All five (67)Ga radiopharmaceuticals were found to afford the desired myocardial retention of the radiogallium. The [(67/68)Ga][Ga(3-MeOsal)(2)BAPDMEN](1+) radiopharmaceutical appears to have the best properties for myocardial imaging, exhibiting 2% of the injected dose in the heart 1 min and 2 h postinjection and very high heart/nontarget ratios (heart/blood ratios of 7.6+/-1.0 and 54+/-10 at 1 and 120 min, respectively; heart/liver ratios of 1.8+/-0.4 and 39+/-3 at 1 and 120 min, respectively). Most of these new agents, particularly [(67/68)Ga][Ga(3-MeOsal)(2)BAPDMEN](1+), would appear superior to previously reported bis(salicylaldimine) ligands of N,N'-bis(3-aminopropyl)ethylenediamine as candidates for PET imaging of the heart with (68)Ga.

  8. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    SciTech Connect

    Sako, Takeo; Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky; Senda, Michio; Watanabe, Yasuyoshi

    2013-12-06

    Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

  9. A potential role for the midbrain in integrating fat-free mass determined energy needs: An H2 (15) O PET study.

    PubMed

    Weise, Christopher M; Thiyyagura, Pradeep; Reiman, Eric M; Chen, Kewei; Krakoff, Jonathan

    2015-06-01

    Little is known on how sensing of energy needs is centrally represented, integrated, and translated into the behavioral aspects of energy homeostasis. Fat free mass (FFM) is the major determinant of energy expenditure. We investigated how interindividual variances in FFM relate to neuronal activity in humans. Healthy adults (n = 64, 21F/43M; age 31.3 ± 9.1y; percentage of body fat [PFAT] 25.6 ± 10.7%; BMI 30.4 ± 9) underwent a 36h fast and subsequent H(2) (15) O positron emission tomographic (PET) measurement of regional cerebral blood flow (rCBF). Multiple variable regression analysis revealed significant associations of FFM with rCBF within the midbrain [including parts of the periaqueductal gray (PAG), ventral tegmental area (VTA), thalamic and hypothalamic regions], the bilateral parahippocampal region, left anterior cingulate, left insular cortex, right cerebellum, and distinct regions within the temporal and occipital cortex. In contrast, no significant associations were found for fat mass (FM). We investigated the potential functional-anatomical link between FFM and central regulation of food intake by performing a conjunction analysis of FFM and the perceived hunger feelings. This showed a significant overlap within the midbrain PAG. Mediation analysis demonstrated a significant indirect effect of FFM on hunger with PAG rCBF as mediator. Most regions we found to be associated with FFM form part in ascending homeostatic pathways and cortical circuitries implicated in the regulation of basic bodily functions indicating a potential role of these central networks in the integration of FFM determined energy needs. © 2015 Wiley Periodicals, Inc.

  10. Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands.

    PubMed

    Elmazar, M M A; Nau, H

    2004-11-01

    Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21-28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2-9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465-487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RARalpha-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all- trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic

  11. 64Cu-DOTATATE PET/MRI for Detection of Activated Macrophages in Carotid Atherosclerotic Plaques

    PubMed Central

    Sandholt, Benjamin Vikjær; Keller, Sune Høgild; Hansen, Adam Espe; Clemmensen, Andreas Ettrup; Sillesen, Henrik; Højgaard, Liselotte; Ripa, Rasmus Sejersten; Kjær, Andreas

    2015-01-01

    Objective— A feature of vulnerable atherosclerotic plaques of the carotid artery is high activity and abundance of lesion macrophages. There is consensus that this is of importance for plaque vulnerability, which may lead to clinical events, such as stroke and transient ischemic attack. We used positron emission tomography (PET) and the novel PET ligand [64Cu] [1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid]-d-Phe1,Tyr3-octreotate (64Cu-DOTATATE) to specifically target macrophages via the somatostatin receptor subtype-2 in vivo. Approach and Results— Ten patients underwent simultaneous PET/MRI to measure 64Cu-DOTATATE uptake in carotid artery plaques before carotid endarterectomy. 64Cu-DOTATATE uptake was significantly higher in symptomatic plaque versus the contralateral carotid artery (P<0.001). Subsequently, a total of 62 plaque segments were assessed for gene expression of selected markers of plaque vulnerability using real-time quantitative polymerase chain reaction. These results were compared with in vivo 64Cu-DOTATATE uptake calculated as the mean standardized uptake value. Univariate analysis of real-time quantitative polymerase chain reaction and PET showed that cluster of differentiation 163 (CD163) and CD68 gene expression correlated significantly but weakly with mean standardized uptake value in scans performed 85 minutes post injection (P<0.001 and P=0.015, respectively). Subsequent multivariate analysis showed that CD163 correlated independently with 64Cu-DOTATATE uptake (P=0.031) whereas CD68 did not contribute significantly to the final model. Conclusions— The novel PET tracer 64Cu-DOTATATE accumulates in atherosclerotic plaques of the carotid artery. CD163 gene expression correlated independently with 64Cu-DOTATATE uptake measured by real-time quantitative polymerase chain reaction in the final multivariate model, indicating that 64Cu-DOTATATE PET is detecting alternatively activated macrophages. This association could

  12. G-quadruplex ligand RHPS4 potentiates the antitumor activity of camptothecins in preclinical models of solid tumors.

    PubMed

    Leonetti, Carlo; Scarsella, Marco; Riggio, Giuseppe; Rizzo, Angela; Salvati, Erica; D'Incalci, Maurizio; Staszewsky, Lidia; Frapolli, Roberta; Stevens, Malcolm F; Stoppacciaro, Antonella; Mottolese, Marcella; Antoniani, Barbara; Gilson, Eric; Zupi, Gabriella; Biroccio, Annamaria

    2008-11-15

    The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors. The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice. RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival. Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.

  13. Analogs of LDL Receptor Ligand Motifs in Dengue Envelope and Capsid Proteins as Potential Codes for Cell Entry.

    PubMed

    Guevara, Juan; Romo, Jamie; McWhorter, Troy; Guevara, Natalia Valentinova

    It is established that cell entry of low density lipoprotein particles (LLPs) containing Apo B100 and Apo E is mediated by receptors and GAGs. Receptor ligand motifs, XBBBXXBX, XBBXBX, and ΨBΨXB, and mono- and bipartite NLS sequences are abundant in Apo E and Apo B100 as well as in envelope and capsid proteins of Dengue viruses 1-4 (DENV1-4). Synthetic, fluorescence-labeled peptides of sequences in DENV2 envelope protein, and DENV3 capsid that include these motifs were used to conduct a qualitative assessment of cell binding and entry capacity using HeLa cells. DENV2 envelope peptide, Dsp2EP, (0564)Gly-Gly(0595), was shown to bind and remain at the cell surface. In contrast, DENV3 capsid protein peptide, Dsp3CP, (0002)Asn-Gln(0028), readily enters HeLa cells and accumulates at discrete loci in the nucleus. FITC-labeled dengue synthetic peptides colocalize with Low Density Lipoprotein-CM-DiI and Apo E-CM-DiI to a degree that suggests that Dengue viruses may utilize cell entry pathways used by LLPs.

  14. Autocrine regulation of stomatal differentiation potential by EPF1 and ERECTA-LIKE1 ligand-receptor signaling

    PubMed Central

    Qi, Xingyun; Han, Soon-Ki; Dang, Jonathan H; Garrick, Jacqueline M; Ito, Masaki; Hofstetter, Alex K; Torii, Keiko U

    2017-01-01

    Development of stomata, valves on the plant epidermis for optimal gas exchange and water control, is fine-tuned by multiple signaling peptides with unique, overlapping, or antagonistic activities. EPIDERMAL PATTERNING FACTOR1 (EPF1) is a founding member of the secreted peptide ligands enforcing stomatal patterning. Yet, its exact role remains unclear. Here, we report that EPF1 and its primary receptor ERECTA-LIKE1 (ERL1) target MUTE, a transcription factor specifying the proliferation-to-differentiation switch within the stomatal cell lineages. In turn, MUTE directly induces ERL1. The absolute co-expression of ERL1 and MUTE, with the co-presence of EPF1, triggers autocrine inhibition of stomatal fate. During normal stomatal development, this autocrine inhibition prevents extra symmetric divisions of stomatal precursors likely owing to excessive MUTE activity. Our study reveals the unexpected role of self-inhibition as a mechanism for ensuring proper stomatal development and suggests an intricate signal buffering mechanism underlying plant tissue patterning. DOI: http://dx.doi.org/10.7554/eLife.24102.001 PMID:28266915

  15. Analogs of LDL Receptor Ligand Motifs in Dengue Envelope and Capsid Proteins as Potential Codes for Cell Entry

    PubMed Central

    Guevara, Juan; Romo, Jamie; McWhorter, Troy; Guevara, Natalia Valentinova

    2016-01-01

    It is established that cell entry of low density lipoprotein particles (LLPs) containing Apo B100 and Apo E is mediated by receptors and GAGs. Receptor ligand motifs, XBBBXXBX, XBBXBX, and ΨBΨXB, and mono- and bipartite NLS sequences are abundant in Apo E and Apo B100 as well as in envelope and capsid proteins of Dengue viruses 1–4 (DENV1–4). Synthetic, fluorescence-labeled peptides of sequences in DENV2 envelope protein, and DENV3 capsid that include these motifs were used to conduct a qualitative assessment of cell binding and entry capacity using HeLa cells. DENV2 envelope peptide, Dsp2EP, 0564Gly-Gly0595, was shown to bind and remain at the cell surface. In contrast, DENV3 capsid protein peptide, Dsp3CP, 0002Asn-Gln0028, readily enters HeLa cells and accumulates at discrete loci in the nucleus. FITC-labeled dengue synthetic peptides colocalize with Low Density Lipoprotein-CM-DiI and Apo E-CM-DiI to a degree that suggests that Dengue viruses may utilize cell entry pathways used by LLPs. PMID:27123468

  16. [Innovation and Future Technologies for PET Scanners].

    PubMed

    Yamaya, Taiga

    2015-01-01

    Positron emission tomography (PET) plays important roles in cancer diagnosis, neuroimaging and molecular imaging research; but potential points remain for which big improvements could be made, including spatial resolution, sensitivity and manufacturing costs. Higher spatial resolution is essential to enable earlier diagnosis, and improved sensitivity results in reduced radiation exposure and shortened measurement time. Therefore, research on next generation PET technologies remains a hot topic worldwide. In this paper, innovation and future technologies for the next generation PET scanners, such as time-of-flight measurement and simultaneous PET/MRI measurement, are described. Among them, depth-of-interaction (DOI) measurement in the radiation sensor will be a key technology to get any significant improvement in sensitivity while maintaining high spatial resolution. DOI measurement also has a potential to expand PET application fields because it allows for more flexible detector arrangement. As an example, the world's first, open-type PET geometry "OpenPET", which is expected to lead to PET imaging during treatment, is under development. The DOI detector itself continues to evolve with the help of recently developed semiconductor photodetectors, often referred to as silicon photomultipliers.

  17. Synthesis, Characterization, and Biological Studies of a Piperidinyl Appended Dipicolylamine Ligand and Its Rhenium Tricarbonyl Complex as Potential Therapeutic Agents for Human Breast Cancer

    PubMed Central

    Subasinghe, Amali; Perera, Inoka C.; Pakhomova, Svetlana

    2016-01-01

    A novel ligand bearing a central piperidinyl sulfonamide group, N(SO2pip)dpa, and its corresponding Re tricarbonyl complex, [Re(CO)3(N(SO2pip)dpa)]+, have been synthesized in good yield. The methylene CH2 signal seen as a singlet (4.54 ppm) in a 1H NMR spectrum of the ligand in DMSO-d6 appears as two doublets (5.39, 5.01 ppm) in a spectrum of the [Re(CO)3(N(SO2pip)dpa)]+ complex and confirms the presence of magnetically nonequivalent protons upon coordination to Re. Structural results revealed that the Re–N bond lengths fall within the normal range establishing coordination of ligand to metal. The presence of intraligand π → π⁎ and n → π⁎ transitions is indicated by the absorption peaks around 200–250 nm in UV-visible spectra. Absorption peaks in UV-visible spectra around 300 nm for metal complexes were identified as MLCT transitions. The S–N stretch observed as a strong peak at 923 cm−1 for N(SO2pip)dpa appeared at a shorter frequency, at 830 cm−1 in an FTIR spectrum of the [Re(CO)3(N(SO2pip)dpa)]+. The intense fluorescence displayed by the N(SO2pip)dpa ligand has quenched upon coordination to Re. Relatively low IC50 values given by human breast cancer cells, MCF-7, (N(SO2pip)dpa = 139 μM, [Re(CO)3(N(SO2pip)dpa)]+ = 360 μM) indicate that N(SO2pip)dpa and [Re(CO)3(N(SO2pip)dpa)]+ are promising novel compounds that can be further investigated on their usage as potential anticancer agents. PMID:27847444

  18. Exposure of cultured fibroblasts to the peptide PR-11 for the identification of induced proteome alterations and discovery of novel potential ligands.

    PubMed

    Breguez, Gustavo Silveira; Neves, Leandro Xavier; Silva, Karina Taciana Santos; de Freitas, Lorran Miranda Andrade; de Oliveira Faria, Gabriela; Isoldi, Mauro César; Castro-Borges, William; de Andrade, Milton Hércules Guerra

    2016-12-01

    The PR-11 peptide corresponds to the N-terminal and active region of the endogenously synthesized PR-39 molecule, of porcine origin. It is known to possess various biological effects including antimicrobial properties, angiogenic and anti-inflammatory activities. Apart from its reported activity as a proteasome inhibitor, a more comprehensive understanding of its function, at the molecular level, is still lacking. In this study, we used a label-free shotgun strategy to evaluate the proteomic alterations caused by exposure of cultured fibroblasts to the peptide PR-11. This approach revealed that more than half of the identified molecules were related to signalling, transcription and translation. Proteins directly associated to regulation of angiogenesis and interaction with the hypoxia-inducible factor 1-α (HIF-1α) were significantly altered. In addition, at least three differentially expressed molecules of the NF-κB pathway were detected, suggesting an anti-inflammatory property of PR-11. At last, we demonstrated novel potential ligands of PR-11, through its immobilization for affinity chromatography. Among the eluted molecules, gC1qR, a known complement receptor, appeared markedly enriched. This provided preliminary evidence of a PR-11 ligand possibly involved in the internalization of this peptide. Altogether, our findings contributed to a better understanding of the cellular pathways affected by PR-39 derived molecules. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. 44Sc-DOTA-BN[2-14]NH2 in comparison to 68Ga-DOTA-BN[2-14]NH2 in pre-clinical investigation. Is 44Sc a potential radionuclide for PET?

    PubMed

    Koumarianou, E; Loktionova, N S; Fellner, M; Roesch, F; Thews, O; Pawlak, D; Archimandritis, S C; Mikolajczak, R

    2012-12-01

    In the present study we demonstrate the in vitro and in vivo comparison of the (44)Sc and (68)Ga labeled DOTA-BN[2-14]NH(2). (44)Sc is a positron emitter with a half life of 3.92 h. Hence it could be used for PET imaging with ligands requiring longer observation time than in the case of (68)Ga. The binding affinity of (nat)Sc-DOTA-BN[2-14]NH(2) and (nat)Ga-DOTA-BN[2-14]NH(2) to GRP receptors was studied in competition to [(125)I-Tyr(4)]-Bombesin in the human prostate cancer cell line PC-3. A preliminary biodistribution in normal rats was performed, while first microPET images were assessed in male Copenhagen rats bearing the androgen-independent Dunning R-3327-AT-1 prostate cancer tumor. The affinity to GRP receptors in the PC-3 cell line was higher for (nat)Ga-DOTA-BN[2-14]NH(2) (IC(50)(nM)=0.85 ± 0.06) than that of (nat)Sc-DOTA-BN[2-14]NH(2) (IC(50) (nM)=6.49 ± 0.13). The internalization rate of (68)Ga labeled DOTA-BN[2-14]NH(2) was slower than that of (44)Sc, but their final internalization percents were comparable. (68)Ga-DOTA-BN[2-14]NH(2) was externalized faster than (44)Sc-DOTA-BN[2-14]NH(2). The biodistribution of (44)Sc-DOTA-BN[2-14]NH(2) and (68)Ga-DOTA-BN[2-14]NH(2) in normal rats revealed a higher uptake in target organs and tissues of the first one while both excreted mainly through urinary tract. In microPET images both tracers were accumulated in the tumor with similar uptake patterns. Despite the differences in the receptor affinity both the (68)Ga- and the (44)Sc-labeled DOTA-BN[2-14]NH(2) tracers showed comparable distribution and similar time constants of uptake and elimination. Moreover no differences in tumor accumulation (neither in the overall uptake nor in the dynamics) were observed from the microPet imaging. From that perspective the use of either (44)Sc or (68)Ga for detecting tumors with GRP receptors is equivalent. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. DNA Detection and Genotypic Identification of Potentially Human-Pathogenic Microsporidia from Asymptomatic Pet Parrots in South Korea as a Risk Factor for Zoonotic Emergence ▿

    PubMed Central

    Lee, So-Young; Lee, Sung-Seok; Lyoo, Young S.; Park, Hee-Myung

    2011-01-01

    We detected and identified genotypes of human-pathogenic microsporidia in fecal samples from 51 asymptomatic captive-bred pet parrots in South Korea. Microsporidia were identified in 8 samples (15.7%); 7 parrots tested positive for Encephalitozoon hellem, and 1 parrot tested positive for both E. hellem and Encephalitozoon cuniculi. In genotypic identifications, E. hellem was present in genotypes 1A and 2B and E. cuniculi was present in genotype II. Pet parrots might be a source of human microsporidian infection. PMID:21965400

  1. Association between the use of surveillance PET/CT and the detection of potentially salvageable occult recurrences among patients with resected high-risk melanoma.

    PubMed

    Leon-Ferre, Roberto A; Kottschade, Lisa A; Block, Matthew S; McWilliams, Robert R; Dronca, Roxana S; Creagan, Edward T; Allred, Jacob B; Lowe, Val J; Markovic, Svetomir N

    2017-03-14

    The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III-IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I-II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68-6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94-93.31%), specificity (90%, 95% CI=88.56-91.56%), and negative predictive value (99%, 95% CI=98.46-99.52%). However, the positive predictive value was only 37% (95% CI=31.32-43.68%). In patients with resected stage III-IV melanoma, surveillance PET/CT detected a large

  2. DNA detection and genotypic identification of potentially human-pathogenic microsporidia from asymptomatic pet parrots in South Korea as a risk factor for zoonotic emergence.

    PubMed

    Lee, So-Young; Lee, Sung-Seok; Lyoo, Young S; Park, Hee-Myung

    2011-12-01

    We detected and identified genotypes of human-pathogenic microsporidia in fecal samples from 51 asymptomatic captive-bred pet parrots in South Korea. Microsporidia were identified in 8 samples (15.7%); 7 parrots tested positive for Encephalitozoon hellem, and 1 parrot tested positive for both E. hellem and Encephalitozoon cuniculi. In genotypic identifications, E. hellem was present in genotypes 1A and 2B and E. cuniculi was present in genotype II. Pet parrots might be a source of human microsporidian infection.

  3. Trends in PET imaging

    SciTech Connect

    Moses, William W.

    2000-11-01

    Positron Emission Tomography (PET) imaging is a well established method for obtaining information on the status of certain organs within the human body or in animals. This paper presents an overview of recent trends PET instrumentation. Significant effort is being expended to develop new PET detector modules, especially those capable of measuring depth of interaction. This is aided by recent advances in scintillator and pixellated photodetector technology. The other significant area of effort is development of special purpose PET cameras (such as for imaging breast cancer or small animals) or cameras that have the ability to image in more than one modality (such as PET / SPECT or PET / X-Ray CT).

  4. Introduction to PET instrumentation.

    PubMed

    Turkington, T G

    2001-03-01

    The purpose of this paper is to introduce technologists to the basic principles of PET imaging and to the instrumentation used to acquire PET data. PET imaging is currently being done on a variety of imaging system types, and the technologist will be introduced to these systems and learn about the basic physical image-degrading factors in PET. After reading this article, the technologist should be able to describe the basics of coincidence imaging, identify at least 3 physical degrading factors in PET, and describe 2 different types of PET scanning systems.

  5. PET Imaging of Inflammation Biomarkers

    PubMed Central

    Wu, Chenxi; Li, Fang; Niu, Gang; Chen, Xiaoyuan

    2013-01-01

    Inflammation plays a significant role in many disease processes. Development in molecular imaging in recent years provides new insight into the diagnosis and treatment evaluation of various inflammatory diseases and diseases involving inflammatory process. Positron emission tomography using 18F-FDG has been successfully applied in clinical oncology and neurology and in the inflammation realm. In addition to glucose metabolism, a variety of targets for inflammation imaging are being discovered and utilized, some of which are considered superior to FDG for imaging inflammation. This review summarizes the potential inflammation imaging targets and corresponding PET tracers, and the applications of PET in major inflammatory diseases and tumor associated inflammation. Also, the current attempt in differentiating inflammation from tumor using PET is also discussed. PMID:23843893

  6. PET/MRI – Technical Review

    PubMed Central

    Muzic, Raymond F.; DiFilippo, Frank P.

    2015-01-01

    PET/MR is a hybrid imaging technology with the potential to combine the molecular and functional information of PET with the soft-tissue contrast of MR. Herein we review the technical features and challenges of putting these different technologies together. We emphasize the conceptual to make the material accessible to a wide audience. We begin by reviewing PET/CT, a more mature multi-modality imaging technology, to provide a basis for comparison to the history of PET/MR development. We discuss the motivation and challenges of PET/MR and different approaches that have been used to meet the challenges. We conclude with a speculation about the future of this exciting imaging method. PMID:25497909

  7. Kinetic modeling in PET imaging of hypoxia

    PubMed Central

    Li, Fan; Joergensen, Jesper T; Hansen, Anders E; Kjaer, Andreas

    2014-01-01

    Tumor hypoxia is associated with increased therapeutic resistance leading to poor treatment outcome. Therefore the ability to detect and quantify intratumoral oxygenation could play an important role in future individual personalized treatment strategies. Positron Emission Tomography (PET) can be used for non-invasive mapping of tissue oxygenation in vivo and several hypoxia specific PET tracers have been developed. Evaluation of PET data in the clinic is commonly based on visual assessment together with semiquantitative measurements e.g. standard uptake value (SUV). However, dynamic PET contains additional valuable information on the temporal changes in tracer distribution. Kinetic modeling can be used to extract relevant pharmacokinetic parameters of tracer behavior in vivo that reflects relevant physiological processes. In this paper, we review the potential contribution of kinetic analysis for PET imaging of hypoxia. PMID:25250200

  8. Pet RX: Implications for Good Health.

    ERIC Educational Resources Information Center

    Wilkes, C. Newton; And Others

    1989-01-01

    Studies reveal that potential health values exist in use of pets in the rehabilitation process. Animal therapy can be a salutary form of rehabilitation if the program is organized, supervised, and implemented in a professional manner. (JD)

  9. Pet RX: Implications for Good Health.

    ERIC Educational Resources Information Center

    Wilkes, C. Newton; And Others

    1989-01-01

    Studies reveal that potential health values exist in use of pets in the rehabilitation process. Animal therapy can be a salutary form of rehabilitation if the program is organized, supervised, and implemented in a professional manner. (JD)

  10. PET/MRI and PET/MRI/SISCOM coregistration in the presurgical evaluation of refractory focal epilepsy.

    PubMed

    Fernández, S; Donaire, A; Serès, E; Setoain, X; Bargalló, N; Falcón, C; Sanmartí, F; Maestro, I; Rumià, J; Pintor, L; Boget, T; Aparicio, J; Carreño, M

    2015-03-01

    We aimed to investigate the usefulness of coregistration of positron emission tomography (PET) and magnetic resonance imaging (MRI) findings (PET/MRI) and of coregistration of PET/MRI with subtraction ictal single-photon emission computed tomography (SPECT) coregistered to MRI (SISCOM) (PET/MRI/SISCOM) in localizing the potential epileptogenic zone in patients with drug-resistant epilepsy. We prospectively included 35 consecutive patients with refractory focal epilepsy whose presurgical evaluation included a PET study. Separately acquired PET and structural MRI images were coregistered for each patient. When possible, ictal SPECT and SISCOM were obtained and coregistered with PET/MRI. The potential location of the epileptogenic zone determined by neuroimaging was compared with the seizure onset zone determined by long-term video-EEG monitoring and with invasive EEG studies in patients who were implanted. Structural MRI showed no lesions in 15 patients. In these patients, PET/MRI coregistration showed a hypometabolic area in 12 (80%) patients that was concordant with seizure onset zone on EEG in 9. In 7 patients without MRI lesions, PET/MRI detected a hypometabolism that was undetected on PET alone. SISCOM, obtained in 25 patients, showed an area of hyperperfusion concordant with the seizure onset zone on EEG in 7 (58%) of the 12 of these patients who had normal MRI findings. SISCOM hyperperfusion was less extensive than PET hypometabolism. A total of 19 patients underwent surgery; 11 of these underwent invasive-EEG monitoring and the seizure onset zone was concordant with PET/MRI in all cases. PET/MRI/SISCOM coregistration, performed in 4 of these patients, was concordant in 3 (75%). After epilepsy surgery, 13 (68%) patients are seizure-free after a mean follow-up of 4.5 years. PET/MRI and PET/MRI/SISCOM coregistration are useful for determining the potential epileptogenic zone and thus for planning invasive EEG studies and surgery more precisely, especially in

  11. Healthy Pets and People

    MedlinePlus

    ... Keep Your Pet Healthy Whether you have a dog, cat, horse, parakeet, gerbil, or bearded dragon, providing ... Good Pet Hygiene Make sure to remove your dog’s feces (poop) from your yard or public places ...

  12. Pet Disaster Preparedness

    MedlinePlus

    ... behavior problems persist. Download the Pet First Aid App Get critical first aid info for your pet at your fingertips. Find it in the Apple App Store , Google Play , or Amazon Marketplace Download your ...

  13. [¹⁸F]-fluorodeoxyglucose PET imaging of atherosclerosis.

    PubMed

    Blomberg, Björn A; Høilund-Carlsen, Poul Flemming

    2015-01-01

    [(18)F]-fluorodeoxyglucose PET ((18)FDG PET) imaging has emerged as a promising tool for assessment of atherosclerosis. By targeting atherosclerotic plaque glycolysis, a marker for plaque inflammation and hypoxia, (18)FDG PET can assess plaque vulnerability and potentially predict risk of atherosclerosis-related disease, such as stroke and myocardial infarction. With excellent reproducibility, (18)FDG PET can be a surrogate end point in clinical drug trials, improving trial efficiency. This article summarizes key findings in the literature, discusses limitations of (18)FDG PET imaging of atherosclerosis, and reports recommendations to optimize imaging protocols. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Novel targets for positron emission tomography (PET) radiopharmaceutical tracers for visualization of neuroinflammation

    NASA Astrophysics Data System (ADS)

    Shchepetkin, I.; Shvedova, M.; Anfinogenova, Y.; Litvak, M.; Atochin, D.

    2017-08-01

    Non-invasive molecular imaging techniques can enhance diagnosis of neurological diseases to achieve their successful treatment. Positron emission tomography (PET) imaging can identify activated microglia and provide detailed functional information based on molecular biology. This imaging modality is based on detection of isotope labeled tracers, which emit positrons. The review summarizes the developments of various radiolabeled ligands for PET imaging of neuroinflammation.

  15. Pets and Parasites

    MedlinePlus

    ... in Children and TeensRead MoreBMI Calculator Cat and Dog BitesApril 2017September 2000Pets and Animalsfamilydoctor.org editorial staffCat- ... and Parasites Share Print Pets and Parasites A dog may be man’s best friend. However, household pets ...

  16. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO.

    PubMed

    Girgis, Ragy R; Slifstein, Mark; D'Souza, Deepak; Lee, Yih; Periclou, Antonia; Ghahramani, Parviz; Laszlovszky, István; Durgam, Suresh; Adham, Nika; Nabulsi, Nabeel; Huang, Yiyun; Carson, Richard E; Kiss, Béla; Kapás, Margit; Abi-Dargham, Anissa; Rakhit, Ashok

    2016-10-01

    Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia. The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia. Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations. A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing. This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

  17. α-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein.

    PubMed

    Davis, Sterenn; Davis, Benjamin M; Richens, Joanna L; Vere, Kelly-Ann; Petrov, Peter G; Winlove, C Peter; O'Shea, Paul

    2015-08-01

    α-Tocopherol (vitamin E) has attracted considerable attention as a potential protective or palliative agent. In vitro, its free radical-scavenging antioxidant action has been widely demonstrated. In vivo, however, vitamin E treatment exhibits negligible benefits against oxidative stress. α-Tocopherol influences lipid ordering within biological membranes and its derivatives have been suggested to inhibit the multi-drug efflux pump, P-glycoprotein (P-gp). This study employs the fluorescent membrane probe, 1-(3-sulfonatopropyl)-4-[β[2-(di-n-octylamino)-6-naphthyl]vinyl] pyridinium betaine, to investigate whether these effects are connected via influences on the membrane dipole potential (MDP), an intrinsic property of biological membranes previously demonstrated to modulate P-gp activity. α-Tocopherol and its non-free radical-scavenging succinate analog induced similar decreases in the MDP of phosphatidylcholine vesicles. α-Tocopherol succinate also reduced the MDP of T-lymphocytes, subsequently decreasing the binding affinity of saquinavir for P-gp. Additionally, α-tocopherol succinate demonstrated a preference for cholesterol-treated (membrane microdomain enriched) cells over membrane cholesterol-depleted cells. Microdomain disruption via cholesterol depletion decreased saquinavir's affinity for P-gp, potentially implicating these structures in the influence of α-tocopherol succinate on P-gp. This study provides evidence of a microdomain dipole potential-dependent mechanism by which α-tocopherol analogs influence P-gp activity. These findings have implications for the use of α-tocopherol derivatives for drug delivery across biological barriers.

  18. Measurements and Modeling To Determine the Reduction Potential of Uncomplexed Bi(III) in Nitrate Solutions for Application in Bi(III)-Ligand Equilibria Studies by Voltammetry.

    PubMed

    Billing, Caren; Cukrowski, Ignacy

    2016-05-12

    The free metal ion potential, E(M), is a critical parameter in the calculation of formation constants when using voltammetry. When studying complex formation of Bi(III), however, E(Bi) cannot be directly measured. In this work a nitrate background electrolyte was employed to obtain reversible reduction waves. To determine E(Bi), measurements have to be made below pH ∼ 2 before the bismuth-oxy-nitrate species precipitates and thus corrections for the diffusion junction potential (monitored using Tl(I) as an internal reference ion) must be made. Additionally shifts in potential due to both Bi(III) hydrolysis and Bi(III) nitrate formation must also be compensated for before E(Bi) can be evaluated. The value of E(Bi) was determined relative to E(Tl) so that in an experiments where ligand is added to determine formation constants, E(Bi) can be determined as accurately as possible (since E(Tl) can generally still be measured). The value of E(Bi) - E(Tl) was found to be 495.6 ± 1.4 mV for the conditions employed.

  19. PET in the management of urologic malignancies.

    PubMed

    Kumar, Rakesh; Zhuang, Hongming; Alavi, Abass

    2004-11-01

    FDG-PET has a limited role in diagnosis of prostate cancer mainly because of the low uptake of FDG in the tumor and normal excretion of FDG through urine. FDG-PET has shown some promise in the assessment of lymph nodes and bone metastases. There is a large degree of variability when FDG-PET is compared with bone scintigraphy. New C11-labeled radiotracers (acetate, choline, and methionine) have shown promising initial results but further studies are required to determine their role in such settings. These radiotracers provide a unique opportunity for dynamic, multitracer, and quantitative studies, which improve the sensitivity and specificity on PET in this population. Short half-lives and of C-11, however with the limits to their use requires an on-site cyclotron. Recent synthesis schemes with [18F]-labeling, however, may overcome this limitation. FDG-PET has a significant potential to assist with the diagnosis and management of testicular cancer. PET has been most useful in defining the presence or absence of disease in patients with residual masses. PET has shown promising results for the initial diagnosis of this cancer, but further for studies ar required to determine its role in the management of this malignancy. PET can be used in conjunction with conventional imaging techniques to diagnose retroperitoneal masses in patients with primary testicular cancer. FDG-PET has shown very encouraging results in a limited number of studies, and has also demonstrated a good sensitivity for initial staging. FDG-PET seems to be superior to conventional imaging modalities for detecting local disease and recurrence, and distant metastases.

  20. PET Tau and Amyloid-β Burden in Mild Alzheimer’s Disease: Divergent Relationship with Age, Cognition, and Cerebrospinal Fluid Biomarkers

    PubMed Central

    Koychev, Ivan; Gunn, Roger N.; Firouzian, Azadeh; Lawson, Jennifer; Zamboni, Giovanna; Ridha, Basil; Sahakian, Barbara J.; Rowe, James B.; Thomas, Alan; Rochester, Lynn; Ffytche, Dominic; Howard, Robert; Zetterberg, Henrik; MacKay, Clare; Lovestone, Simon

    2017-01-01

    Background: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer’s disease (AD). Objective: We sought to characterize the relationship between Aβ and tau ligands as well as with other measures of pathology. Methods: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. Results: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Aβ associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not Aβ. Conclusion: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker— the CSF total tau/Aβ ratio. PMID:28800330

  1. Potential Pathogens in the Environment: Isolation, Enumeration, and Identification of Seven Genera of Intestinal Bacteria Associated with Small Green Pet Turtles1

    PubMed Central

    McCoy, R. H.; Seidler, Ramon J.

    1973-01-01

    Bacteriological analyses were performed on fecal swabs and the aquarium water of 27 individually purchased specimens of the small green pet turtle, Pseudemys scripta elegans. Representatives of Aeromonas, Citrobacter, Enterobacter, Klebsiella, Proteus, Salmonella, and Serratia were isolated. Enterobacter, Klebsiella, and Salmonella were encountered in 20% or more of the specimens, whereas Aeromonas was isolated from 63%. Klebsiella pneumoniae counts ranged from 103 to 104 per milliliter of aquarium water, whereas Aeromonas routinely exceeded 104 per milliliter. Aeromonas cultures from turtles were identical to 7 human isolates in some 29 biochemical tests. On the basis of our findings, we question whether the Salmonella-free certification program alone is sufficient to render these reptiles as safe pets. PMID:4572984

  2. Potential therapeutic application of dendrimer/cyclodextrin conjugates with targeting ligands as advanced carriers for gene and oligonucleotide drugs.

    PubMed

    Arima, Hidetoshi; Motoyama, Keiichi; Higashi, Taishi

    2017-04-01

    Despite the recent approval of some gene medicines and nucleic acid drugs, further improvement of delivery techniques for these drugs is strongly required. Several delivery technologies for these drugs have been developed, in other words, viral and two types of nonviral (lipofection and polyfection) vectors. Among the polyfection system, the potential use of various cyclodextrin (CyD) derivatives and CyD-appended polymers as carriers for gene and nucleic acid drugs has been demonstrated. The polyamidoamine dendrimer (G3) conjugates with α-CyD (α-CDE (G3)) have been reported to possess noteworthy properties as DNA and nucleic acid drugs carriers. This review will focus on the attempts to develop such cell-specific drug carriers by preparing polyethylene glycol, galactose, lactose, mannose, fucose and folic acid-appended α-CDEs as tissue and cell-selective carriers of gene and nucleic acid drugs.

  3. Trans-platinum(II)/(IV) Complexes with Acetylpyridine Ligands as Antivascular Agents in vitro: Cytotoxic and Antiangiogenic Potential.

    PubMed

    Lana, Filipović; Sandra, Aranđelović; Ana, Krivokuća; Radmila, Janković; Biljana, Dojčinović; Siniša, Radulović

    2016-01-01

    In vitro biological studies of four trans-platinum complexes of structural formulas trans-[PtCl2(n-acetylpyridine)2] (n = 3 or 4, complex 1 or 2) and [Pt(n-acetylpyridine)2Cl4] (n = 3 or 4, complex 3 or 4) were performed in human endothelial EA.hy 926 cells, in order to evaluate and compare their cytotoxic and antiangiogenic potential. MTT results revealed that trans-Pt(II) complexes exhibited significantly lower IC50 values: 4.0±0.9 μM (1) and 2.1±0.0 μM (2), than cisplatin (27.7±1.3 μM). Combinational drug treatment with N-Acetyl-L-cysteine and L-buthioninesulfoximine strongly counteracted effect of 1 and 2, while the same treatment rather enhanced cytotoxicity of Pt(IV) analogues. ICP-MS results suggested that differential endothelial toxicity of cisplatin and trans-platinum complexes correlated to the differences in their cellular accumulation, rather than to the different affinity of DNA binding. Intracellular accumulation of complexes (ng Pt/106 cells) for 24 h treatment, decreased in order: 1>2>4>3>CDDP, while ratio of DNA binding (pg Pt/μg DNA) decreased as following: 2>1>CDDP>4>3. FACS/Annexin-V-FITC analysis, and morphological study demonstrated that the enhanced cytotoxic and apoptotic potential (18.1%) of complex 2 was related to its highest affinity to bind nuclear DNA. Pt(IV) complexes exhibited the lowest reactivity to cellular DNA and proteins. Regardless of their antiproliferative action, 1-4 at subtoxic concentrations demonstrated in vitro inhibitory effect on tubulogenesis and matrix metalloproteinases (MMPs) 2 and 9 gelatinolitic activity, while 1 and 2 additionally downregulated MMP-2 gene expression.

  4. PET Radiotracers of the Cardiovascular System.

    PubMed

    Gropler, Robert J

    2009-01-01

    Cardiovascular PET provides exquisite measurements of key aspects of the cardiovascular system and as a consequence it plays central role in cardiovascular investigation. Moreover, PET is now playing an ever increasing role in the management of the cardiac patient. Central to the success of PET is the development and use of novel radiotracers that permit measurements of key aspects of cardiovascular health such as myocardial perfusion, metabolism, and neuronal function. Moreover, the development of molecular imaging radiotracers is now permitting the interrogation of cellular and sub cellular processes. This article highlights these various radiotracers and their role in both cardiovascular research and potential clinical applications.

  5. PET Radiopharmaceuticals for Personalized Medicine.

    PubMed

    Sharma, Sushil

    2016-01-01

    modules and multifunctional nanoparticles, will improve biomarker discovery, internal dosimetry, pharmacokinetics, immunotherapy, and stem cell tracking in regenerative medicine. This review provides recent developments in the synthesis of clinically-significant cyclotron and generator- based PET-RPs with potential applications in cardiovascular diseases, neurodegenerative diseases, and cancer to accomplish the ultimate goal of evidence-based personalized theranostics.

  6. Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells.

    PubMed

    Sonnemann, Jürgen; Gekeler, Volker; Sagrauske, Antje; Müller, Cornelia; Hofmann, Hans-Peter; Beck, James F

    2004-07-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta. Transfection of PC-3 cells with second-generation chimeric antisense oligonucleotides against PKCeta caused a time- and dose-dependent knockdown of PKCeta, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of PKCeta resulted in a marked amplification of TRAIL's cytotoxic activity. Cell killing could be substantially prevented by the pan-caspase inhibitor z-VAD-fmk. In addition, PKCeta knockdown and administration of TRAIL significantly synergized in activation of caspase-3 and internucleosomal DNA fragmentation. Knockdown of PKCeta augmented TRAIL-induced dissipation of the mitochondrial transmembrane potential and release of cytochrome c from mitochondria into the cytosol, indicating that PKCeta acts upstream of mitochondria. We conclude that PKCeta represents a considerable resistance factor with respect to TRAIL and a promising target to exploit the therapeutic potential of TRAIL.

  7. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy

    PubMed Central

    Dai, Xiaoyun; Zhang, Jingwen; Arfuso, Frank; Chinnathambi, Arunachalam; Zayed, ME; Alharbi, Sulaiman Ali; Kumar, Alan Prem

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to selectively induce apoptotic cell death in various tumor cells by engaging its death-inducing receptors (TRAIL-R1 and TRAIL-R2). This property has led to the development of a number of TRAIL–receptor agonists such as the soluble recombinant TRAIL and agonistic antibodies, which have shown promising anticancer activity in preclinical studies. However, besides activating caspase-dependent apoptosis in several cancer cells, TRAIL may also activate nonapoptotic signal transduction pathways such as nuclear factor-kappa B, mitogen-activated protein kinases, AKT, and signal transducers and activators of transcription 3, which may contribute to TRAIL resistance that is being now frequently encountered in various cancers. TRAIL resistance can be overcome by the application of efficient TRAIL-sensitizing pharmacological agents. Natural compounds have shown a great potential in sensitizing cells to TRAIL treatment through suppression of distinct survival pathways. In this review, we have summarized both apoptotic and nonapoptotic pathways activated by TRAIL, as well as recent advances in developing TRAIL–receptor agonists for cancer therapy. We also briefly discuss combination therapies that have shown great potential in overcoming TRAIL resistance in various tumors. PMID:25854879

  8. Cytokeratin 8 is an epithelial cell receptor for Pet, a cytotoxic serine protease autotransporter of Enterobacteriaceae.

    PubMed

    Nava-Acosta, Raul; Navarro-Garcia, Fernando

    2013-12-10

    The group of proteins known as serine protease autotransporters of Enterobacteriaceae (SPATE) is a growing family of serine proteases secreted to the external milieu by the type V secretion system. Pet toxin and some other SPATE belong to the class 1 cytotoxic SPATE, which have comparable protease strength on fodrin. Pet is internalized and is directed to its intracellular substrate by retrograde transport. However, the epithelial cell receptor for Pet has yet to be identified. We show that Pet has affinity for the epithelial cell surface until the saturation of the binding sites at 100 nM Pet. Affinity column assays and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis identified a cytokeratin (CK8) which directly binds to Pet, and both proteins colocalized on the cell surface. Interestingly, CK8 is not present in kidney cell lines, which are not susceptible to Pet. Inhibition experiments by using anti-CK8 and ck8 small interfering RNA (siRNA) blocked the cytotoxic effect induced by Pet, while exogenous CK8 expression in kidney cells made them susceptible to Pet intoxication. Recombinant CK8 showed a Pet-binding pattern similar to that seen by using fixed cells. Remarkably, Pet colocalized with CK8 and clathrin at early times (receptor-mediated endocytosis), and subsequently, Pet colocalized with CK8 and Rab5b in the early endosomes. These data support the idea that CK8 is an important receptor for Pet on epithelial cells for starting its cytotoxic effects. These data suggest that therapeutics that block Pet-CK8 interaction may improve outcome of diseases caused by Pet-secreting Enterobacteriaceae such as enteroaggregative Escherichia coli. Receptor-ligand binding is one mechanism by which cells sense and respond to external cues. Receptors may also be utilized by toxins to mediate their own internalization. Pet toxin is secreted by enteroaggregative Escherichia coli, an organism that causes persistent diarrhea in children, traveler

  9. Synthesis of high affinity fluorine-substituted ligands for the androgen receptor. Potential agents for imaging prostatic cancer by positron emission tomography.

    PubMed

    Liu, A; Carlson, K E; Katzenellenbogen, J A

    1992-05-29

    We have prepared nine androgens substituted with fluorine at C-16 or C-20 to evaluate their potential, as positron emission tomographic (PET) imaging agents for prostatic cancer when labeled with the positron emitting radionuclide fluorine-18 (t1/2 = 110 min). These compounds represent members from the following classes of androgens: testosterone (T), 5 alpha-dihydrotestosterone (DHT), 7 alpha-methyl-19-nortestosterone (MNT), mibolerone (Mib), and metribolone (R1881). All of these compounds were prepared by functionalization of suitable androgen precursors, and the synthetic routes were developed to allow the introduction of fluorine by a fluoride ion displacement reaction late in the synthesis, as is required for the preparation of these compounds in fluorine-18 labeled form. We have also prepared four androgens in which the C-3 carbonyl or 17 beta-hydroxyl groups are replaced by fluorine. Most of the fluorine-substituted androgens show high affinity for the androgen receptor (AR), although fluorine substitution lowers their affinity by a small factor. None of the androgens where fluorine replaces oxygen functions at C-3 or C-17 have substantial affinity for AR. Derivatives of the natural androgens (T and DHT) as well as MNT have little affinity for other steroid hormone receptors (progesterone and mineralocorticoid receptors), whereas the Mib and R1881 derivatives have somewhat greater heterologous binding. With sex steroid binding protein, a human serum binding protein, the pattern of binding affinities is nearly the reverse, with derivatives of Mib, R1881 and MNT having low affinity, and DHT and T, high affinity. From these fluorine-substituted compounds, we can select several whose preparation in fluorine-18 labeled form for further tissue distribution studies is merited.

  10. In vitro and ex vivo evaluation of cyclic aminoalkyl benzilates as potential emission tomography ligands for the muscarinic receptor.

    PubMed

    Otto, C A; Mulholland, G K; Perry, S E; Combs, R; Sherman, P S; Fisher, S J

    1989-01-01

    A series of muscarinic antagonists were screened as potential receptor imaging agents. (+)2 alpha-tropanyl benzilate (TRB), N-methyl-4-piperidyl benzilate (NMPB) and several analogs amenable to labeling with positron emitting isotopes were evaluated for muscarinic binding to mouse brain tissue in vitro and ex vivo using [3H]quinuclidinyl benzilate as the probe. The in vitro assay directly compared the innate binding affinities of the compounds. The rank order of binding (IC50) was TRB (0.7 nm), QNB (0.8 nm), scopolamine (1.3 nm) and NMPB (1.6 nm). The ex vivo assay was used to gain information regarding the pharmacokinetics and brain penetration of the compounds in live animals. Ex vivo results demonstrated that TRB was rapidly taken up into the brain and was equipotent with QNB in occupying muscarinic binding sites at early time points, but TRB binding decreased twice as fast over time as QNB binding. The results suggest TRB would be a good candidate for radiolabeling and further study.

  11. Molecular imaging for prostate cancer: Performance analysis of (68)Ga-PSMA PET/CT versus choline PET/CT.

    PubMed

    Michaud, L; Touijer, K A

    2017-06-01

    There is a need for a precise and reliable imaging to improve the management of prostate cancer. In recent years the PET/CT with choline has changed the handling of prostate cancer in Europe, and it is commonly used for initial stratification or for the diagnosis of a biochemical recurrence, although it does not lack limitations. Other markers are being tested, including the ligand of prostate-specific membrane antigen (PSMA), that seems to offer encouraging prospects. The goal of this piece of work was to critically review the role of choline and PSMA PET/CT in prostate cancer. A systematic literature review of databases PUBMED/MEDLINE and EMBASE was conducted searching for articles fully published in English on the PET marker in prostate cancer and its clinical application. It seems as 68Ga-PSMA PET/CT is better than PET/CT in prostate cancer to detect primary prostate lesions, initial metastases in the lymph nodes and recurrence. However, further research is required to obtain high-level tests. Also, other PET markers are studied. Moreover, the emergence of a new PET/MR camera could change the performance of PET imaging. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  12. MR Guided PET Image Reconstruction

    PubMed Central

    Bai, Bing; Li, Quanzheng; Leahy, Richard M.

    2013-01-01

    The resolution of PET images is limited by the physics of positron-electron annihilation and instrumentation for photon coincidence detection. Model based methods that incorporate accurate physical and statistical models have produced significant improvements in reconstructed image quality when compared to filtered backprojection reconstruction methods. However, it has often been suggested that by incorporating anatomical information, the resolution and noise properties of PET images could be improved, leading to better quantitation or lesion detection. With the recent development of combined MR-PET scanners, it is possible to collect intrinsically co-registered MR images. It is therefore now possible to routinely make use of anatomical information in PET reconstruction, provided appropriate methods are available. In this paper we review research efforts over the past 20 years to develop these methods. We discuss approaches based on the use of both Markov random field priors and joint information or entropy measures. The general framework for these methods is described and their performance and longer term potential and limitations discussed. PMID:23178087

  13. Validity of model approximations for receptor-ligand kinetics in nuclear medicine

    SciTech Connect

    Salinas, Cristian A.; Muzic, Raymond F. Jr.; Saidel, Gerald M.

    2007-05-15

    An appropriate mathematical model is required for quantitative analysis of high affinity radioligands as direct or surrogate probes to measure receptor distribution, affinity, concentration, binding potential, and endogenous or exogenous ligand occupancy levels. For studies with positron emission tomography (PET) or single photon emission computed tomography (SPECT), the receptor-ligand compartment model has been well established and widely used. This pharmacokinetic model is represented mathematically by a set of nonlinear ordinary differential equations. Variations of models for PET and SPECT account for radioactive decay differently. These are not equivalent and entail assumptions or approximations that may be not appreciated. In this study, a general form of the model is presented and compared with others with various approximations, which are valid only under specific conditions. The various approximate formulations were analytically compared to the exact model to identify the terms that were neglected in the approximate formulations. The extent to which the approximations impact the model solutions was assessed by computer simulations based on numerical solutions to each set of equations. Specifically, each model formulation was tested using three simulated injection protocols representing a typical PET experiment, a typical SPECT experiment, and an extreme experiment where both the injected activity and the specific activity were very high. No significant differences were found among the output of the three model formulations when the PET and SPECT injection protocols were tested. The only conditions that produced significant differences occurred when the specific activity and the administered activity were simultaneously very high. These conditions, however, have little practical relevance to experimentally achievable conditions due to radiation dose and specific activity of radiopharmaceuticals.

  14. Pet-Related Infections.

    PubMed

    Day, Michael J

    2016-11-15

    Physicians and veterinarians have many opportunities to partner in promoting the well-being of people and their pets, especially by addressing zoonotic diseases that may be transmitted between a pet and a human family member. Common cutaneous pet-acquired zoonoses are dermatophytosis (ringworm) and sarcoptic mange (scabies), which are both readily treated. Toxoplasmosis can be acquired from exposure to cat feces, but appropriate hygienic measures can minimize the risk to pregnant women. Persons who work with animals are at increased risk of acquiring bartonellosis (e.g., cat-scratch disease); control of cat fleas is essential to minimize the risk of these infections. People and their pets share a range of tick-borne diseases, and exposure risk can be minimized with use of tick repellent, prompt tick removal, and appropriate tick control measures for pets. Pets such as reptiles, amphibians, and backyard poultry pose a risk of transmitting Salmonella species and are becoming more popular. Personal hygiene after interacting with these pets is crucial to prevent Salmonella infections. Leptospirosis is more often acquired from wildlife than infected dogs, but at-risk dogs can be protected with vaccination. The clinical history in the primary care office should routinely include questions about pets and occupational or other exposure to pet animals. Control and prevention of zoonoses are best achieved by enhancing communication between physicians and veterinarians to ensure patients know the risks of and how to prevent zoonoses in themselves, their pets, and other people.

  15. Clinical Utility and Future Applications of PET/CT and PET/CMR in Cardiology

    PubMed Central

    Pan, Jonathan A.; Salerno, Michael

    2016-01-01

    Over the past several years, there have been major advances in cardiovascular positron emission tomography (PET) in combination with either computed tomography (CT) or, more recently, cardiovascular magnetic resonance (CMR). These multi-modality approaches have significant potential to leverage the strengths of each modality to improve the characterization of a variety of cardiovascular diseases and to predict clinical outcomes. This review will discuss current developments and potential future uses of PET/CT and PET/CMR for cardiovascular applications, which promise to add significant incremental benefits to the data provided by each modality alone. PMID:27598207

  16. Personalizing NSCLC therapy by characterizing tumors using TKI-PET and immuno-PET.

    PubMed

    Bahce, I; Yaqub, M; Smit, E F; Lammertsma, A A; van Dongen, G A M S; Hendrikse, N H

    2016-05-31

    Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an ever increasing number of drugs directed against a variety of specific tumor targets. Amongst these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are most frequently used. However, as only a sensitive subgroup of patients benefits from targeting drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker for predicting therapy efficacy. Some of the TKIs and mAbs that are in clinical use can be radioactively labeled and used as tracers. PET can visualize and quantify tumor specific uptake of radiolabeled targeting drugs, allowing for characterization of their pharmacokinetic behavior. In this review, the clinical potential of PET using radiolabeled TKIs (TKI-PET) and mAbs (immuno-PET) in NSCLC is discussed, and an overview is provided of the most relevant preclinical and clinical studies.

  17. Novel weight-based dose threshold for 18F-NaF PET-CT imaging using advanced PET-CT systems: a potential tool for reducing radiation burden.

    PubMed

    Marafi, Fahad; Esmail, Abdulreda; Rasheed, Rashid; Alkandari, Fareeda; Usmani, Sharjeel

    2017-09-01

    Fluorine-18-sodium fluoride (F-NaF) PET/CT is an important tool for detecting and evaluating metastatic bone cancer. Besides traditional dose metrics, recent methods such as real-time dose mapping, dose calculation from DICOM information, and their relevance to entrance skin exposure are currently in use to reduce the radiation burden. In this study, we have analyzed the data of 1062 patients retrospectively to evaluate patterns of absorbed dose for institutional weight-based dose protocol as compared with fixed dose method guidelines of Society of Nuclear Medicine and Molecular Imaging (SNMMI). The effective dose imparted by F-NaF (internal exposure) was calculated by using coefficient 0.089 mrem/mCi (0.024 mSv/MBq) according to ICRP publication 106. To estimate the effective dose from whole-body CT scan (external exposure), volume CT dose index (mGy) and dose length product (mGy cm) were directly obtained from the display screen of CT workstation. Effective dose was calculated by multiplying DLP (mGy cm) with ICRP conversion coefficient 'k' 0.015 (mSv/mGy cm). Of the total 1062 patients, there were metastases in 44% (464), probable malignancy in 9% (96), negative findings in 40.5% (433), equivocal findings in 3% (32), and probable benignancy in 3.5% (37). All patients were injected with an institutional agreed protocol of 2.22 MBq/kg (0.06 mCi/kg). The mean injected activity for entire population came out to be 4.79±0.99 mCi. The mean effective absorbed doses were 3.37±0.70 and 5.5±1.35 mSv for F-NaF alone and CT alone, respectively. The mean cumulative effective dose of combined F-NaF PET and CT scan was calculated to be 8.8±1.8 mSv. The minimum absorbed dose for our method was as follows: 1.37 mSv for Kuwait Cancer Control Center vs. 4.44 mSv for SNMMI. Absorbed dose for maximum injected activity was as follows: 5.7 mSv for Kuwait Cancer Control Center vs. 8.88 mSv for SNMMI. Our weight-based doses were also lower when compared

  18. PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status

    PubMed Central

    Lütje, Susanne; Heskamp, Sandra; Cornelissen, Alexander S.; Poeppel, Thorsten D.; van den Broek, Sebastiaan A. M. W.; Rosenbaum-Krumme, Sandra; Bockisch, Andreas; Gotthardt, Martin; Rijpkema, Mark; Boerman, Otto C.

    2015-01-01

    Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided. PMID:26681984

  19. PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status.

    PubMed

    Lütje, Susanne; Heskamp, Sandra; Cornelissen, Alexander S; Poeppel, Thorsten D; van den Broek, Sebastiaan A M W; Rosenbaum-Krumme, Sandra; Bockisch, Andreas; Gotthardt, Martin; Rijpkema, Mark; Boerman, Otto C

    2015-01-01

    Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided.

  20. Gold Nanorods Conjugated with Doxorubicin and cRGD for Combined Anticancer Drug Delivery and PET Imaging

    PubMed Central

    Xiao, Yuling; Hong, Hao; Matson, Vyara Z.; Javadi, Alireza; Xu, Wenjin; Yang, Yunan; Zhang, Yin; Engle, Jonathan W.; Nickles, Robert J.; Cai, Weibo; Steeber, Douglas A.; Gong, Shaoqin

    2012-01-01

    A multifunctional gold nanorod (GNR)-based nanoplatform for targeted anticancer drug delivery and positron emission tomography (PET) imaging of tumors was developed and characterized. An anti-cancer drug (i.e., doxorubicin (DOX)) was covalently conjugated onto PEGylated (PEG: polyethylene glycol) GNR nanocarriers via a hydrazone bond to achieve pH-sensitive controlled drug release. Tumor-targeting ligands (i.e., the cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides, cRGD) and 64Cu-chelators (i.e., 1,4,7-triazacyclononane-N, N', N''-triacetic acid (NOTA)) were conjugated onto the distal ends of the PEG arms to achieve active tumor-targeting and PET imaging, respectively. Based on flow cytometry analysis, cRGD-conjugated nanocarriers (i.e., GNR-DOX-cRGD) exhibited a higher cellular uptake and cytotoxicity than non-targeted ones (i.e., GNR-DOX) in vitro. However, GNR-DOX-cRGD and GNR-DOX nanocarriers had similar in vivo biodistribution according to in vivo PET imaging and biodistribution studies. Due to the unique optical properties of GNRs, this multifunctional GNR-based nanoplatform can potentially be optimized for combined cancer therapies (chemotherapy and photothermal therapy) and multimodality imaging (PET, optical, X-ray computed tomography (CT), etc.). PMID:22916075

  1. Potential of the Biotic Ligand Model (BLM) to Predict Copper Toxicity in the White-Water of the Solimões-Amazon River.

    PubMed

    Pont, Giorgi Dal; Domingos, Fabíola Xochilt Valdez; Fernandes-de-Castilho, Marisa; Val, Adalberto Luis

    2017-01-01

    In this study, we evaluated the capacity of the Biotic Ligand Model (BLM) to predict copper toxicity in white-waters of the Solimões-Amazon River. LC50 tests using the species Otocinclus vittatus (Regan, 1904) were performed with Solimões-Amazon river water (100%) at 20%, 40%, 60%, and 80% dilutions. A sevenfold decrease in both dissolved and total Cu toxicity was observed in the experiment conducted with 100% when compared to 20% white-water, indicating that physicochemical characteristics of white-water attenuate Cu toxicity. There was agreement between the observed LC50 and the LC50 predicted by the BLM after the adjustment of critical accumulation concentration (LA50) for O. vittatus. BLM modeling indicated that dissolved organic carbon (DOC) and pH were the most important water parameters influencing Cu toxicity, followed by Ca(2+). Our results highlight the first evidence that the BLM presents potential to predict Cu toxicity to aquatic organisms in the white-water of the Solimões-Amazon River.

  2. Two-ligand priming mechanism for potentiated phosphoinositide synthesis is an evolutionarily conserved feature of Sec14-like phosphatidylinositol and phosphatidylcholine exchange proteins

    PubMed Central

    Huang, Jin; Ghosh, Ratna; Tripathi, Ashutosh; Lönnfors, Max; Somerharju, Pentti; Bankaitis, Vytas A.

    2016-01-01

    Lipid signaling, particularly phosphoinositide signaling, plays a key role in regulating the extreme polarized membrane growth that drives root hair development in plants. The Arabidopsis AtSFH1 gene encodes a two-domain protein with an amino-terminal Sec14-like phosphatidylinositol transfer protein (PITP) domain linked to a carboxy-terminal nodulin domain. AtSfh1 is critical for promoting the spatially highly organized phosphatidylinositol-4,5-bisphosphate signaling program required for establishment and maintenance of polarized root hair growth. Here we demonstrate that, like the yeast Sec14, the AtSfh1 PITP domain requires both its phosphatidylinositol (PtdIns)- and phosphatidylcholine (PtdCho)-binding properties to stimulate PtdIns-4-phosphate [PtdIns(4)P] synthesis. Moreover, we show that both phospholipid-binding activities are essential for AtSfh1 activity in supporting polarized root hair growth. Finally, we report genetic and biochemical evidence that the two-ligand mechanism for potentiation of PtdIns 4-OH kinase activity is a broadly conserved feature of plant Sec14-nodulin proteins, and that this strategy appeared only late in plant evolution. Taken together, the data indicate that the PtdIns/PtdCho-exchange mechanism for stimulated PtdIns(4)P synthesis either arose independently during evolution in yeast and in higher plants, or a suitable genetic module was introduced to higher plants from a fungal source and subsequently exploited by them. PMID:27193303

  3. Ultraviolet light converts propranolol, a nonselective β-blocker and potential lupus-inducing drug, into a proinflammatory AhR ligand.

    PubMed

    Dorgham, Karim; Amoura, Zahir; Parizot, Christophe; Arnaud, Laurent; Frances, Camille; Pionneau, Cédric; Devilliers, Hervé; Pinto, Sandra; Zoorob, Rima; Miyara, Makoto; Larsen, Martin; Yssel, Hans; Gorochov, Guy; Mathian, Alexis

    2015-11-01

    UV light and some medications are known to trigger lupus erythematosus (LE). A common mechanism underlying the immunopathologic effect, resulting from exposure to these two seemingly unrelated factors, remains unknown. The aryl hydrocarbon receptor (AhR) plays a key role in the regulation of IL-22 production in humans and can be activated by both xenobiotics and naturally occurring photoproducts. A significant expansion of Th17 and Th22 cells was observed in the peripheral blood of active systemic LE (SLE) patients, compared to inactive patients and controls. We also show that propranolol, a potential lupus-inducing drug, induced stronger AhR activation in PBMCs of SLE patients than in those of controls. AhR agonist activity of propranolol was enhanced by UV light exposure. MS analysis of irradiated propranolol revealed the generation of a proinflammatory photoproduct. This compound behaves like the prototypic AhR ligand 6-formylindolo[3,2-b]carbazole, a cutaneous UV light-induced tryptophan metabolite, both promoting IL-22, IL-8, and CCL2 secretion by T-cells and macrophages. Finally, LE patients exhibit signs of cutaneous AhR activation that correlate with lesional expression of the same proinflammatory cytokines, suggesting a role for photometabolites in the induction of skin inflammation. The AhR might therefore represent a target for therapeutic intervention in LE. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Complexes of a Zn-metalloenzyme binding site with hydroxamate-containing ligands. A case for detailed benchmarkings of polarizable molecular mechanics/dynamics potentials when the experimental binding structure is unknown.

    PubMed

    Gresh, Nohad; Perahia, David; de Courcy, Benoit; Foret, Johanna; Roux, Céline; El-Khoury, Lea; Piquemal, Jean-Philip; Salmon, Laurent

    2016-12-15

    Zn-metalloproteins are a major class of targets for drug design. They constitute a demanding testing ground for polarizable molecular mechanics/dynamics aimed at extending the realm of quantum chemistry (QC) to very long-duration molecular dynamics (MD). The reliability of such procedures needs to be demonstrated upon comparing the relative stabilities of competing candidate complexes of inhibitors with the recognition site stabilized in the course of MD. This could be necessary when no information is available regarding the experimental structure of the inhibitor-protein complex. Thus, this study bears on the phosphomannose isomerase (PMI) enzyme, considered as a potential therapeutic target for the treatment of several bacterial and parasitic diseases. We consider its complexes with 5-phospho-d-arabinonohydroxamate and three analog ligands differing by the number and location of their hydroxyl groups. We evaluate the energy accuracy expectable from a polarizable molecular mechanics procedure, SIBFA. This is done by comparisons with ab initio quantum-chemistry (QC) calculations in the following cases: (a) the complexes of the four ligands in three distinct structures extracted from the entire PMI-ligand energy-minimized structures, and totaling up to 264 atoms; (b) the solvation energies of several energy-minimized complexes of each ligand with a shell of 64 water molecules; (c) the conformational energy differences of each ligand in different conformations characterized in the course of energy-minimizations; and (d) the continuum solvation energies of the ligands in different conformations. The agreements with the QC results appear convincing. On these bases, we discuss the prospects of applying the procedure to ligand-macromolecule recognition problems. © 2016 Wiley Periodicals, Inc.

  5. Synthesis, 68Ga-Radiolabeling, and Preliminary In Vivo Assessment of a Depsipeptide-Derived Compound as a Potential PET/CT Infection Imaging Agent

    PubMed Central

    Mokaleng, Botshelo B.; Ebenhan, Thomas; Ramesh, Suhas; Govender, Thavendran; Kruger, Hendrik G.; Hazari, Puja P.; Mishra, Anil K.; Marjanovic-Painter, Biljana; Zeevaart, Jan R.; Sathekge, Mike M.

    2015-01-01

    Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection-selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as 67/68Ga-citrate or 18F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with 68Ga for a subsequent in vitro assessment and in vivo infection imaging using Escherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by 68Gallium-radiolabeling. µPET/CT using 68Ga-DOTA-TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. 68Ga-DOTA-TBIA101-PET detected E. coli-infected muscle tissue (SUV = 1.3–2.4) > noninfected thighs (P = 0.322) > forearm muscles (P = 0.092) > background (P = 0.021) in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101's capacity as targeting vector. PMID:25699267

  6. Development of a combined microPET-MR system.

    PubMed

    Lucas, A J; Hawkes, R C; Ansorge, R E; Williams, G B; Nutt, R E; Clark, J C; Fryer, T D; Carpenter, T A

    2006-08-01

    As evidenced by the success of PET-CT, there are many benefits from combining imaging modalities into a single scanner. The combination of PET and MR offers potential advantages over PET-CT, including improved soft tissue contrast, access to the multiplicity of contrast mechanisms available to MR, simultaneous imaging and fast MR sequences for motion correction. In addition, PET-MR is more suitable than PET-CT for cancer screening due to the elimination of the radiation dose from CT. A key issue associated with combining PET and MR is the fact that the performance of the photomultiplier tubes (PMTs) used in conventional PET detectors is degraded in the magnetic field required for MR. Two approaches have been adopted to circumvent that issue: retention of conventional, magnetic field-sensitive PMT-based PET detectors by modification of other features of the MR or PET system, or the use of new, magnetic field-insensitive devices in the PET detectors including avalanche photo-diodes (APDs) and silicon photomultipliers (SiPMs). Taking the former approach, we are assembling a modified microPET Focus 120 within a gap in a novel, 1T superconducting magnet. The PMTs are located in a low magnetic field (approximately 30mT) through a combination of magnet design and the use of fiber optic 'bundles'. Two main features of the modified PET system have been tested, namely the effect of using long fiber optic bundles in the PET detector, and the impact of magnetic field upon the performance of the position sensitive PMTs. The design of a modified microPET-MR system for small animal imaging is completed, and assembly and testing is underway.

  7. Phenyl 1,2,3-Triazole-Thymidine Ligands Stabilize G-Quadruplex DNA, Inhibit DNA Synthesis and Potentially Reduce Tumor Cell Proliferation over 3′-Azido Deoxythymidine

    PubMed Central

    Mahesh Kumar, Jerald; Idris, Mohammed M.; Srinivas, Gunda; Vinay Kumar, Pallerla; Meghah, Vuppalapaty; Kavitha, Mitta; Reddy, Chada Raji; Mainkar, Prathama S.; Pal, Biswajit; Chandrasekar, Srivari; Nagesh, Narayana

    2013-01-01

    Triazoles are known for their non-toxicity, higher stability and therapeutic activity. Few nucleoside (L1, L2 and L3) and non-nucleoside 1,2,3-triazoles (L4–L14) were synthesised using click chemistry and they were screened for tumor cell cytotoxicity and proliferation. Among these triazole ligands studied, nucleoside ligands exhibited higher potential than non-nucleoside ligands. The nucleoside triazole analogues, 3′-Phenyl-1,2,3- triazole-thymidine (L2) and 3′-4-Chlorophenyl-1,2,3-triazole-thymidine (L3), demonstrated higher cytotoxicity in tumor cells than in normal cells. The IC50 value for L3 was lowest (50 µM) among the ligands studied. L3 terminated cell cycle at S, G2/M phases and enhanced sub-G1 populations, manifesting induction of apoptosis in tumor cells. Confocal studies indicated that nucleoside triazole ligands (L2/L3) cause higher DNA fragmentation than other ligands. Preclinical experiments with tumor-induced mice showed greater reduction in tumor size with L3. In vitro DNA synthesis reaction with L3 exhibited higher DNA synthesis inhibition with quadruplex forming DNA (QF DNA) than non quadruplex forming DNA (NQF DNA). Tm of quadruplex DNA increased in the presence of L3, indicating its ability to enhance stability of quadruplex DNA at elevated temperature and the results indicate that it had higher affinity towards quadruplex DNA than the other forms of DNA (like dsDNA and ssDNA). From western blot experiment, it was noticed that telomerase expression levels in the tissues of tumor-induced mice were found to be reduced on L3 treatment. Microcalorimetry results emphasise that two nucleoside triazole ligands (L2/L3) interact with quadruplex DNA with significantly higher affinity (Kd≈10−7 M). Interestingly the addition of an electronegative moiety to the phenyl group of L2 enhanced its anti-proliferative activity. Though IC50 values are not significantly low with L3, the studies on series of synthetic 1,2,3-triazole ligands are useful for

  8. [(68)Ga]Ga-DO(2)A-(OBu-l-tyr)(2): synthesis, (68)Ga-radiolabeling and in vitro studies of a novel (68)Ga-DO(2)A-tyrosine conjugate as potential tumor tracer for PET.

    PubMed

    Burchardt, Carsten; Riss, Patrick J; Zoller, Frederic; Maschauer, Simone; Prante, Olaf; Kuwert, Torsten; Roesch, Frank

    2009-07-01

    The synthesis, (68)Ga-labeling and in vitro study of the novel tyrosine chelate derivative [(68)Ga]Ga-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid-4,10-di-(O-butyl)-l-tyrosine ([(68)Ga]Ga-DO(2)A-(OBu-l-tyr)(2)) as a potential tracer for imaging tumor metabolism by positron emission tomography (PET) is presented. This approach combines the biological amino acid transporter targeting properties of l-tyrosine with the outstanding availability of (68)Ga(III) via the (68)Ge/(68)Ga generator. In vitro studies utilizing the F98-glioblastoma cell line revealed specific uptake of [(68)Ga]Ga-DO2A-(OBu-l-tyr)(2) that was comparable to that of the reference O-(2-[(18)F]fluoroethyl)-l-tyrosine (FET). These promising results indicate a high potential of [(68)Ga]Ga-DO(2)A-(OBu-l-tyr)(2) for molecular imaging of tumor-driven amino acid uptake by PET.

  9. The Role of Non-Standard PET Radionuclides in the Development of New Radiopharmaceuticals

    SciTech Connect

    Avila-Rodriguez, M. A.; McQuarrie, S. A.

    2008-08-11

    This paper discusses the production methods of the most commonly used non-standard PET radionuclides, their decay characteristics and importance in the development of novel radiopharmaceuticals for PET-based molecular imaging and potential applications in therapy.

  10. Specificity of (68)Ga-PSMA PET/CT for Prostate Cancer - Myths and Reality.

    PubMed

    Sasikumar, Arun

    2017-01-01

    68Ga-PSMA ligand PET/CT for imaging prostate cancer is a novel imaging technique, which is rapidly gaining popularity. Sufficient evidence has been accumulated in literature regarding the usefulness of (68)Ga-PSMA PET/CT in prostate cancer. Recently literature regarding the localization of (68)Ga-PSMA PET/CT imaging in non-prostatic malignancies is also published, thus questioning the specificity of the tracer with regards to prostate cancer. This commentary tries to address the issue of specificity of 68Ga-PSMA PET/CT and its relevance in imaging prostate cancer.

  11. Specificity of 68Ga-PSMA PET/CT for Prostate Cancer - Myths and Reality

    PubMed Central

    Sasikumar, Arun

    2017-01-01

    68Ga-PSMA ligand PET/CT for imaging prostate cancer is a novel imaging technique, which is rapidly gaining popularity. Sufficient evidence has been accumulated in literature regarding the usefulness of 68Ga-PSMA PET/CT in prostate cancer. Recently literature regarding the localization of 68Ga-PSMA PET/CT imaging in non-prostatic malignancies is also published, thus questioning the specificity of the tracer with regards to prostate cancer. This commentary tries to address the issue of specificity of 68Ga-PSMA PET/CT and its relevance in imaging prostate cancer. PMID:28242976

  12. Sensory analysis of pet foods.

    PubMed

    Koppel, Kadri

    2014-08-01

    Pet food palatability depends first and foremost on the pet and is related to the pet food sensory properties such as aroma, texture and flavor. Sensory analysis of pet foods may be conducted by humans via descriptive or hedonic analysis, pets via acceptance or preference tests, and through a number of instrumental analysis methods. Sensory analysis of pet foods provides additional information on reasons behind palatable and unpalatable foods as pets lack linguistic capabilities. Furthermore, sensory analysis may be combined with other types of information such as personality and environment factors to increase understanding of acceptable pet foods. Most pet food flavor research is proprietary and, thus, there are a limited number of publications available. Funding opportunities for pet food studies would increase research and publications and this would help raise public awareness of pet food related issues. This mini-review addresses current pet food sensory analysis literature and discusses future challenges and possibilities.

  13. An open-label, randomized positron emission tomography (PET) study in healthy male volunteers consisiting of Part A and Part B. Part A: Clinical validation of norepinephrine transporter (NET) PET ligand, (S,S)-[11C]O-methylreboxetine ([11C]MRB) using different doses of oral atomoxetine as NET reuptake inhibitor. Part B: Evaluation of NET occupancy, as measured by [11C]MRB, with multiple dosing regimens of orally administered GSK372475.

    SciTech Connect

    Fowler, Joanna

    2007-08-31

    Results from human studies with the PET radiotracer (S,S)-[(11)C]O-methyl reboxetine ([(11)C](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K(i)=2-5 nM). METHODS: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [(11)C](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. RESULTS: [(11)C](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density approximately 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24+/-7%; 100 mg=31+/-11%), these differences were not significant. The different blocking between MBR (average decrease=28+/- 10%) and THL (average decrease=17+/-10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the

  14. Expression of a P-selectin ligand in zona pellucida of porcine oocytes and P-selectin on acrosomal membrane of porcine sperm cells. Potential implications for their involvement in sperm-egg interactions.

    PubMed

    Geng, J G; Raub, T J; Baker, C A; Sawada, G A; Ma, L; Elhammer, A P

    1997-05-05

    The selectin family of cell adhesion molecules mediates initial leukocyte adhesion to vascular endothelial cells at sites of inflammation. O-glycan structural similarities between oligosaccharides from human leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) and from zona pellucida glycoproteins of porcine oocytes indicate the possible existence of a P-selectin ligand in the zona pellucida. Here, using biochemical as well as morphological approaches, we demonstrate that a P-selectin ligand is expressed in the porcine zona pellucida. In addition, a search for a specific receptor for this ligand leads to the identification of P-selectin on the acrosomal membrane of porcine sperm cells. In vitro binding of porcine acrosome-reacted sperm cells to oocytes was found to be Ca2+ dependent and inhibitable with either P-selectin, P-selectin receptor-globulin, or leukocyte adhesion blocking antibodies against P-selectin and PSGL-1. Moreover, porcine sperm cells were found to be capable of binding to human promyeloid cell line HL-60. Taken together, our findings implicate a potential role for the oocyte P-selectin ligand and the sperm P-selectin in porcine sperm-egg interactions.

  15. Adjuvant effects of invariant NKT cell ligand potentiates the innate and adaptive immunity to an inactivated H1N1 swine influenza virus vaccine in pigs.

    PubMed

    Dwivedi, Varun; Manickam, Cordelia; Dhakal, Santosh; Binjawadagi, Basavaraj; Ouyang, Kang; Hiremath, Jagadish; Khatri, Mahesh; Hague, Jacquelyn Gervay; Lee, Chang Won; Renukaradhya, Gourapura J

    2016-04-15

    Pigs are considered as the source of some of the emerging human flu viruses. Inactivated swine influenza virus (SwIV) vaccine has been in use in the US swine herds, but it failed to control the flu outbreaks. The main reason has been attributed to lack of induction of strong local mucosal immunity in the respiratory tract. Invariant natural killer T (iNKT) cell is a unique T cell subset, and activation of iNKT cell using its ligand α-Galactosylceramide (α-GalCer) has been shown to potentiate the cross-protective immunity to inactivated influenza virus vaccine candidates in mice. Recently, we discovered iNKT cell in pig and demonstrated its activation using α-GalCer. In this study, we evaluated the efficacy of an inactivated H1N1 SwIV coadministered with α-GalCer intranasally against a homologous viral challenge. Our results demonstrated the potent adjuvant effects of α-GalCer in potentiating both innate and adaptive immune responses to SwIV Ags in the lungs of pigs, which resulted in reduction in the lung viral load by 3 logs compared to without adjuvant. Immunologically, in the lungs of pigs vaccinated with α-GalCer an increased virus specific IgA response, IFN-α secretion and NK cell-cytotoxicity was observed. In addition, iNKT cell-stimulation enhanced the secretion of Th1 cytokines (IFN-γ and IL-12) and reduced the production of immunosuppressive cytokines (IL-10 and TGF-β) in the lungs of pigs⋅ In conclusion, we demonstrated for the first time iNKT cell adjuvant effects in pigs to SwIV Ags through augmenting the innate and adaptive immune responses in the respiratory tract. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Potential of PEGylated Toll-Like Receptor 7 Ligands for Controlling Inflammation and Functional Changes in Mouse Models of Asthma and Silicosis

    PubMed Central

    Ferreira, Tatiana Paula Teixeira; Mariano, Lívia Lacerda; Ghilosso-Bortolini, Roberta; de Arantes, Ana Carolina Santos; Fernandes, Andrey Junior; Berni, Michelle; Cecchinato, Valentina; Uguccioni, Mariagrazia; Maj, Roberto; Barberis, Alcide; Silva, Patricia Machado Rodrigues e; Martins, Marco Aurélio

    2016-01-01

    Prior investigations show that signaling activation through pattern recognition receptors can directly impact a number of inflammatory lung diseases. While toll-like receptor (TLR) 7 agonists have raised interest for their ability to inhibit allergen-induced pathological changes in experimental asthma conditions, the putative benefit of this treatment is limited by adverse effects. Our aim was to evaluate the therapeutic potential of two PEGylated purine-like compounds, TMX-302 and TMX-306, characterized by TLR7 partial agonistic activity; therefore, the compounds are expected to induce lower local and systemic adverse reactions. In vitro approaches and translation to murine models of obstructive and restrictive lung diseases were explored. In vitro studies with human PBMCs showed that both TMX-302 and TMX-306 marginally affects cytokine production as compared with equivalent concentrations of the TLR7 full agonist, TMX-202. The PEGylated compounds did not induce monocyte-derived DC maturation or B cell proliferation, differently from what observed after stimulation with TMX-202. Impact of PEGylated ligands on lung function and inflammatory changes was studied in animal models of acute lung injury, asthma, and silicosis following Lipopolysaccharide (LPS), allergen (ovalbumin), and silica inhalation, respectively. Subcutaneous injection of TMX-302 prevented LPS- and allergen-induced airway hyper-reactivity (AHR), leukocyte infiltration, and production of pro-inflammatory cytokines in the lung. However, intranasal instillation of TMX-302 led to neutrophil infiltration and failed to prevent allergen-induced AHR, despite inhibiting leukocyte counts in the BAL. Aerosolized TMX-306 given prophylactically, but not therapeutically, inhibited pivotal asthma features. Interventional treatment with intranasal instillation of TMX-306 significantly reduced the pulmonary fibrogranulomatous response and the number of silica particles in lung interstitial space in silicotic mice

  17. Allosteric Modulation of Related Ligand-Gated Ion Channels Synergistically Induces Long-Term Potentiation in the Hippocampus and Enhances Cognition

    PubMed Central

    Gu, Zhenglin; Yoshimura, Ryan F.; Villegier, Anne-Sophie; Hogenkamp, Derk J.; Whittemore, Edward R.; Huang, Jin-Cheng; Tran, Minhtam B.; Belluzzi, James D.; Yakel, Jerrel L.; Gee, Kelvin W.

    2011-01-01

    α5 Subunit-containing GABAA receptors (GABAARs) and α7 neuronal nicotinic-acetylcholine receptors (nAChRs) are members of the Cys-loop family of ligand-gated ion channels (LGICs) that mediate cognitive and attentional processes in the hippocampus. α5 GABAARs alter network activity by tonic inhibition of CA1/CA3 pyramidal cells of the hippocampus. Postsynaptic α7 nAChRs in the hippocampus regulate inhibitory GABAergic interneuron activity required for synchronization of pyramidal neurons in the CA1, whereas presynaptic α7 nAChRs regulate glutamate release. Can simultaneous allosteric modulation of these LGICs produce synergistic effects on cognition? We show that combined transient application of two allosteric modulators that individually 1) inhibit α5 GABAARs and 2) enhance α7 nAChRs causes long-term potentiation (LTP) of mossy fiber stimulation-induced excitatory postsynaptic currents (EPSC) from CA1 pyramidal neurons of rat hippocampal slices. The LTP effect evoked by two compounds is replicated by 3-(2,5-difluorophenyl)-6-(N-ethylindol-5-yl)-1,2,4-triazolo[4,3-b]pyridazine (522-054), a compound we designed to simultaneously inhibit α5 GABAARs and enhance α7 nAChRs. Selective antagonists for either receptor block sustained EPSC potentiation produced by 522-054. In vivo, 522-054 enhances performance in the radial arm maze and facilitates attentional states in the five-choice serial reaction time trial with similar receptor antagonist sensitivity. These observations may translate into therapeutic utility of dual action compounds in diseases of hippocampal-based cognitive impairment. PMID:21159751

  18. Laboratory and cyclotron requirements for PET research

    SciTech Connect

    Schlyer, D.J.

    1993-06-01

    This report describes four types of PET facilities: Clinical PET with no radionuclide production; clinical PET with a small accelerator; clinical PET with research support; and research PET facilities. General facility considerations are also discussed.

  19. Tau Positron Emission Tomography (PET) Imaging: Past, Present, and Future.

    PubMed

    Ariza, Manuela; Kolb, Hartmuth C; Moechars, Dieder; Rombouts, Frederik; Andrés, José Ignacio

    2015-06-11

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation of the density and neocortical spread of neurofibrillary tangles (NFTs) with clinical AD disease progression offers an opportunity for the early diagnosis and staging using a noninvasive imaging technique such as positron emission tomography (PET). Thus, PET imaging of NFTs not only holds promise as a diagnostic tool but also may enable the development of disease modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to the identification of high affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.

  20. A Small-Animal Pharmacokinetic/Pharmacodynamic PET Study of Central Serotonin 1A Receptor Occupancy by a Potential Therapeutic Agent for Overactive Bladder

    PubMed Central

    Nakatani, Yosuke; Suzuki, Michiyuki; Tokunaga, Masaki; Maeda, Jun; Sakai, Miyuki; Ishihara, Hiroki; Yoshinaga, Takashi; Takenaka, Osamu; Zhang, Ming-Rong; Suhara, Tetsuya; Higuchi, Makoto

    2013-01-01

    Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB. PMID:24086433

  1. Endothelial targeting of polymeric nanoparticles stably labeled with the PET imaging radioisotope iodine-124.

    PubMed

    Simone, Eric A; Zern, Blaine J; Chacko, Ann-Marie; Mikitsh, John L; Blankemeyer, Eric R; Muro, Silvia; Stan, Radu V; Muzykantov, Vladimir R

    2012-07-01

    Targeting of therapeutics or imaging agents to the endothelium has the potential to improve specificity and effectiveness of treatment for many diseases. One strategy to achieve this goal is the use of nanoparticles (NPs) targeted to the endothelium by ligands of protein determinants present on this tissue, including cell adhesion molecules, peptidases, and cell receptors. However, detachment of the radiolabel probes from NPs poses a significant problem. In this study, we devised polymeric NPs directly labeled with radioiodine isotopes including the positron emission tomography (PET) isotope (124)I, and characterized their targeting to specific endothelial determinants. This approach provided sizable, targetable probes for specific detection of endothelial surface determinants non-invasively in live animals. Direct conjugation of radiolabel to NPs allowed for stable longitudinal tracking of tissue distribution without label detachment even in an aggressive proteolytic environment. Further, this approach permits tracking of NP pharmacokinetics in real-time and non-invasive imaging of the lung in mice using micro-PET imaging. The use of this strategy will considerably improve investigation of NP interactions with target cells and PET imaging in small animals, which ultimately can aid in the optimization of targeted drug delivery.

  2. Endothelial Targeting of Polymeric Nanoparticles Stably Labeled with the PET Imaging Radiosotope Iodine-124

    PubMed Central

    Simone, Eric; Zern, Blaine J.; Chacko, Ann-Marie; Mikitsh, John L.; Blankemeyer, Eric; Muro, Silvia; Stan, Radu V.; Muzykantov, Vladimir R.

    2012-01-01

    Targeting of therapeutics or imaging agents to the endothelium has the potential to improve specificity and effectiveness of treatment for many diseases. One strategy to achieve this goal is the use of nanoparticles (NPs) targeted to the endothelium by ligands of protein determinants present on this tissue, including cell adhesion molecules, peptidases, and cell receptors. However, detachment of the radiolabel probes from NPs poses a significant problem. In this study, we devised polymeric NPs directly labeled with radioiodine isotopes including the position emission tomography (PET) isotope 124I, and characterized their targeting to specific endothelial determinants. This approach provided sizable, targetable probes for specific detection of endothelial surface determinants non-invasively in live animals. Direct conjugation of radiolabel to NPs allowed for stable longitudinal tracking of tissue distribution without label detachment even in an aggressive proteolytic environment. Further, this approach permits tracking of NP pharmacokinetics in real-time and non-invasive imaging of the lung in mice using micro-PET imaging. The use of this strategy will considerably improve investigation of NP interactions with target cells and PET imaging in small animals, which ultimately can aid in the optimization of targeted drug delivery. PMID:22560201

  3. MRI-assisted PET motion correction for neurologic studies in an integrated MR-PET scanner.

    PubMed

    Catana, Ciprian; Benner, Thomas; van der Kouwe, Andre; Byars, Larry; Hamm, Michael; Chonde, Daniel B; Michel, Christian J; El Fakhri, Georges; Schmand, Matthias; Sorensen, A Gregory

    2011-01-01

    Head motion is difficult to avoid in long PET studies, degrading the image quality and offsetting the benefit of using a high-resolution scanner. As a potential solution in an integrated MR-PET scanner, the simultaneously acquired MRI data can be used for motion tracking. In this work, a novel algorithm for data processing and rigid-body motion correction (MC) for the MRI-compatible BrainPET prototype scanner is described, and proof-of-principle phantom and human studies are presented. To account for motion, the PET prompt and random coincidences and sensitivity data for postnormalization were processed in the line-of-response (LOR) space according to the MRI-derived motion estimates. The processing time on the standard BrainPET workstation is approximately 16 s for each motion estimate. After rebinning in the sinogram space, the motion corrected data were summed, and the PET volume was reconstructed using the attenuation and scatter sinograms in the reference position. The accuracy of the MC algorithm was first tested using a Hoffman phantom. Next, human volunteer studies were performed, and motion estimates were obtained using 2 high-temporal-resolution MRI-based motion-tracking techniques. After accounting for the misalignment between the 2 scanners, perfectly coregistered MRI and PET volumes were reproducibly obtained. The MRI output gates inserted into the PET list-mode allow the temporal correlation of the 2 datasets within 0.2 ms. The Hoffman phantom volume reconstructed by processing the PET data in the LOR space was similar to the one obtained by processing the data using the standard methods and applying the MC in the image space, demonstrating the quantitative accuracy of the procedure. In human volunteer studies, motion estimates were obtained from echo planar imaging and cloverleaf navigator sequences every 3 s and 20 ms, respectively. Motion-deblurred PET images, with excellent delineation of specific brain structures, were obtained using these 2 MRI

  4. Preclinical Evaluation of a Potential GSH Ester Based PET/SPECT Imaging Probe DT(GSHMe)2 to Detect Gamma Glutamyl Transferase Over Expressing Tumors

    PubMed Central

    Khurana, Harleen; Meena, Virendra Kumar; Prakash, Surbhi; Chuttani, Krishna; Chadha, Nidhi; Jaswal, Ambika; Dhawan, Devinder Kumar; Mishra, Anil Kumar; Hazari, Puja Panwar

    2015-01-01

    Gamma Glutamyl Transferase (GGT) is an important biomarker in malignant cancers. The redox processes ensuing from GGT-mediated metabolism of extracellular GSH are implicated in critical aspects of tumor cell biology. Reportedly, Glutathione monoethyl ester (GSHMe) is a substrate of GGT, which has been used for its rapid transport over glutathione. Exploring GGT to be an important target, a homobivalent peptide system, DT(GSHMe)2 was designed to target GGT-over expressing tumors for diagnostic purposes. DT(GSHMe)2 was synthesized, characterized and preclinically evaluated in vitro using toxicity, cell binding assays and time dependent experiments. Stable and defined radiochemistry with 99mTc and 68Ga was optimized for high radiochemical yield. In vivo biodistribution studies were conducted for different time points along with scintigraphic studies of radiolabeled DT(GSHMe)2 on xenografted tumor models. For further validation, in silico docking studies were performed on GGT (hGGT1, P19440). Preclinical in vitro evaluations on cell lines suggested minimal toxicity of DT(GSHMe)2 at 100 μM concentration. Kinetic analysis revealed transport of 99mTc-DT(GSHMe)2 occurs via a saturable high-affinity carrier with Michaelis constant (Km) of 2.25 μM and maximal transport rate velocity (Vmax) of 0.478 μM/min. Quantitative estimation of GGT expression from western blot experiments showed substantial expression with 41.6 ± 7.07 % IDV for tumor. Small animal micro PET (Positron Emission Tomography)/CT(Computed Tomography) coregistered images depicted significantly high uptake of DT(GSHMe)2 at the BMG-1 tumor site. ROI analysis showed high tumor to contra lateral muscle ratio of 9.33 in PET imaging studies. Avid accumulation of radiotracer was observed at tumor versus inflammation site at 2 h post i.v. injection in an Ehrlich Ascites tumor (EAT) mice model, showing evident specificity for tumor. We propose DT(GSHMe)2 to be an excellent candidate for prognostication and tumor

  5. Preclinical Evaluation of a Potential GSH Ester Based PET/SPECT Imaging Probe DT(GSHMe)₂ to Detect Gamma Glutamyl Transferase Over Expressing Tumors.

    PubMed

    Khurana, Harleen; Meena, Virendra Kumar; Prakash, Surbhi; Chuttani, Krishna; Chadha, Nidhi; Jaswal, Ambika; Dhawan, Devinder Kumar; Mishra, Anil Kumar; Hazari, Puja Panwar

    2015-01-01

    Gamma Glutamyl Transferase (GGT) is an important biomarker in malignant cancers. The redox processes ensuing from GGT-mediated metabolism of extracellular GSH are implicated in critical aspects of tumor cell biology. Reportedly, Glutathione monoethyl ester (GSHMe) is a substrate of GGT, which has been used for its rapid transport over glutathione. Exploring GGT to be an important target, a homobivalent peptide system, DT(GSHMe)2 was designed to target GGT-over expressing tumors for diagnostic purposes. DT(GSHMe)2 was synthesized, characterized and preclinically evaluated in vitro using toxicity, cell binding assays and time dependent experiments. Stable and defined radiochemistry with 99mTc and 68Ga was optimized for high radiochemical yield. In vivo biodistribution studies were conducted for different time points along with scintigraphic studies of radiolabeled DT(GSHMe)2 on xenografted tumor models. For further validation, in silico docking studies were performed on GGT (hGGT1, P19440). Preclinical in vitro evaluations on cell lines suggested minimal toxicity of DT(GSHMe)2 at 100 μM concentration. Kinetic analysis revealed transport of 99mTc-DT(GSHMe)2 occurs via a saturable high-affinity carrier with Michaelis constant (Km) of 2.25 μM and maximal transport rate velocity (Vmax) of 0.478 μM/min. Quantitative estimation of GGT expression from western blot experiments showed substantial expression with 41.6 ± 7.07 % IDV for tumor. Small animal micro PET (Positron Emission Tomography)/CT(Computed Tomography) coregistered images depicted significantly high uptake of DT(GSHMe)2 at the BMG-1 tumor site. ROI analysis showed high tumor to contra lateral muscle ratio of 9.33 in PET imaging studies. Avid accumulation of radiotracer was observed at tumor versus inflammation site at 2 h post i.v. injection in an Ehrlich Ascites tumor (EAT) mice model, showing evident specificity for tumor. We propose DT(GSHMe)2 to be an excellent candidate for prognostication and tumor

  6. The potential predictive value of MRI and PET-CT in mucinous and nonmucinous rectal cancer to identify patients at high risk of metastatic disease.

    PubMed

    Barbaro, Brunella; Leccisotti, Lucia; Vecchio, Fabio M; Di Matteo, Marialuisa; Serra, Teresa; Salsano, Marco; Poscia, Andrea; Coco, Claudio; Persiani, Roberto; Alfieri, Sergio; Gambacorta, Maria Antonietta; Valentini, Vincenzo; Giordano, Alessandro; Bonomo, Lorenzo

    2017-01-01

    To correlate imaging parameters from baseline MRI diffusion-weighted imaging (DWI) and fludeoxyglucose (FDG) positron emission tomography (PET)-CT with synchronous and metachronous metastases in mucinous carcinoma (MC) and non-mucinous carcinoma (NMC) rectal cancer. 111 patients with extraperitoneal locally advanced rectal cancer, who underwent pelvic MRI, DWI and FDG PET-CT, were stratified into MC (n = 23) and NMC (n = 88). We correlated adverse morphologic features on MRI [mT4, mesorectal fascia involvement, extramural venous invasion (mEMVI), mN2] and quantitative imaging parameters [minimum apparent diffusion coefficient (ADCmin), maximum standardized uptake value, total lesion glycolysis, metabolic tumour volume, T2 weighted and DWI tumour volumes] with the presence of metastatic disease. All patients underwent pre-operative chemoradiation therapy (CRT); 100/111 patients underwent surgery after CRT and were classified as pathological complete response (PCR) and no PCR [tumour regression grade (TRG)1 vs TRG2-5] and as ypN0 and ypN1-2. Median follow-up time was 48 months. Metastases were confirmed on FDG PET-CT and contrast-enhanced multidetector CT. The percentage of mucin measured by MRI correlates with that quantified by histology. On multivariate analysis, the synchronous metastases were correlated with mEMVI [odds ratio (OR) = 21.48, p < 0.01] and low ADCmin (OR = 0.04, p = 0.038) in NMC. The difference of metachronous recurrence between the MC group (10-90% mucin) and NMC group was significant (p < 0.01) (OR = 21.67, 95% confidence interval 3.8-120.5). Metachronous metastases were correlated with ypN2 (OR = 8.24, p = 0.01) in MC and in NMC. In NMC, mEMVI correlated with no PCR (p = 0.018) and ypN2 (p < 0.01). mEMVI could identify patients with NMC, who are at high risk of synchronous metastases. The MC group is at a high risk of developing metachronous metastases. Advances in knowledge: Patients at high risk of

  7. Simultaneous addition of two ligands: a potential strategy for estimating divalent ion affinities in EF-hand proteins by isothermal titration calorimetry.

    PubMed

    Henzl, Michael T; Markus, Lindsey A; Davis, Meredith E; McMillan, Andrew T

    2013-03-01

    Capable of providing a detailed thermodynamic picture of noncovalent association reactions, isothermal titration calorimetry (ITC) has become a popular method for studying protein-ligand interactions. We routinely employ the technique to study divalent ion-binding by two-site EF-hand proteins from the parvalbumin- and polcalcin lineages. The combination of high Ca(2+) affinity and relatively low Mg(2+) affinity, and the attendant complication of parameter correlation, conspire to make the simultaneous extraction of binding constants and -enthalpies for both ions challenging. Although global analysis of multiple ITC experiments can overcome these hurdles, our current experimental protocol includes upwards of 10 titrations - requiring a substantial investment in labor, machine time, and material. This paper explores the potential for using a smaller suite of experiments that includes simultaneous titrations with Ca(2+) and Mg(2+) at different ratios of the two ions. The results obtained for four proteins, differing substantially in their divalent ion-binding properties, suggest that the approach has merit. The Ca(2+)- and Mg(2+)-binding constants afforded by the streamlined analysis are in reasonable agreement with those obtained from the standard analysis protocol. Likewise, the abbreviated analysis provides comparable values for the Ca(2+)-binding enthalpies. However, the streamlined analysis can yield divergent values for the Mg(2+)-binding enthalpies - particularly those for lower affinity sites. This shortcoming can be remedied, in large measure, by including data from a direct Ca(2+) titration in the presence of a high, fixed Mg(2+) concentration. Copyright © 2013. Published by Elsevier Inc.

  8. Two-ligand priming mechanism for potentiated phosphoinositide synthesis is an evolutionarily conserved feature of Sec14-like phosphatidylinositol and phosphatidylcholine exchange proteins.

    PubMed

    Huang, Jin; Ghosh, Ratna; Tripathi, Ashutosh; Lönnfors, Max; Somerharju, Pentti; Bankaitis, Vytas A

    2016-07-15

    Lipid signaling, particularly phosphoinositide signaling, plays a key role in regulating the extreme polarized membrane growth that drives root hair development in plants. The Arabidopsis AtSFH1 gene encodes a two-domain protein with an amino-terminal Sec14-like phosphatidylinositol transfer protein (PITP) domain linked to a carboxy-terminal nodulin domain. AtSfh1 is critical for promoting the spatially highly organized phosphatidylinositol-4,5-bisphosphate signaling program required for establishment and maintenance of polarized root hair growth. Here we demonstrate that, like the yeast Sec14, the AtSfh1 PITP domain requires both its phosphatidylinositol (PtdIns)- and phosphatidylcholine (PtdCho)-binding properties to stimulate PtdIns-4-phosphate [PtdIns(4)P] synthesis. Moreover, we show that both phospholipid-binding activities are essential for AtSfh1 activity in supporting polarized root hair growth. Finally, we report genetic and biochemical evidence that the two-ligand mechanism for potentiation of PtdIns 4-OH kinase activity is a broadly conserved feature of plant Sec14-nodulin proteins, and that this strategy appeared only late in plant evolution. Taken together, the data indicate that the PtdIns/PtdCho-exchange mechanism for stimulated PtdIns(4)P synthesis either arose independently during evolution in yeast and in higher plants, or a suitable genetic module was introduced to higher plants from a fungal source and subsequently exploited by them. © 2016 Huang, Ghosh, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  9. Preparation and characterization of vanadyl complexes with bidentate maltol-type ligands; in vivo comparisons of anti-diabetic therapeutic potential.

    PubMed

    Thompson, Katherine H; Liboiron, Barry D; Sun, Yan; Bellman, Karycia D D; Setyawati, Ika A; Patrick, Brian O; Karunaratne, Veranja; Rawji, Gulnar; Wheeler, Jeffrey; Sutton, Kymberley; Bhanot, Sanjay; Cassidy, Carrie; McNeill, John H; Yuen, Violet G; Orvig, Chris

    2003-01-01

    A series of 2-alkyl-3-hydroxy-4-pyrone oxovanadium(IV) compounds has been synthesized, characterized, and tested for bioactivity as potential insulin-enhancing agents. The vanadyl complexes, bis(maltolato)oxovanadium(IV), BMOV, bis(ethylmaltolato)oxovanadium(IV), BEOV, and bis(isopropylmaltolato)oxovanadium(IV), BIOV, were compared against vanadyl sulfate for glucose-lowering ability, when administered i.p. to STZ-diabetic rats, at a one-time dose of 0.1 mmol kg(-1)body weight. Blood levels of vanadium were determined at regular intervals, to 72 h, following i.p. injection. All complexes tested exceeded vanadyl sulfate in glucose-lowering ability; this effect was not correlated, however, with blood vanadium levels. Analysis of the pharmacokinetics of the disappearance of [ethyl-1-(14)C]BEOV after an oral gavage dose (50 mg kg(-1), 0.144 mmol kg(-1), in a 10 mL kg(-1) volume of 1% CMC solution) indicated clearly that metal ion-ligand dissociation took place relatively soon after oral ingestion of the complex. Half-lives of fast phase uptake and slow phase disappearance for (14)C and V were calculated from a two-compartment model for whole blood, plasma, liver, kidney, bone, small intestine, and lung, ranging from 17 min ( t(1/2)alpha for (14)C, liver) to 30 days ( t(1/2)beta for V, bone). Curves of disappearance of plasma and whole blood (14)C and V diverged dramatically within the first hour after administration of the vanadium complex.

  10. Performance of the Effective Core Potentials of Ca, Hg and Pb in Complexes with Ligands Containing N and O Donor Atoms.

    SciTech Connect

    Ramirez, Jose Z.; Vargas, Rubicelia; Garza, Jorge; Hay, Benjamin P.

    2006-11-01

    This paper presents a systematic study of the performance of the relativistic effective core potentials (RECPs) proposed by Stoll-Preuss, Christiansen-Ermler and Hay-Wadt for Ca2+, Hg2+ and Pb2+. The RECPs performance is studied when these cations are combined with ethylene glycol, 2-aminoethanol and ethylenediamine to form bidentate complexes. First, the description of the bidentate ligands is analyzed with the Kohn-Sham method by using SVWN, BLYP and B3LYP exchange-correlation functionals and they are compared with the Moeller-Plesset perturbation theory (MP2), for all these methods the TZVP basis set was used. We found that the BLYP exchange-correlation functional gives similar results that those obtained by the B3LYP and MP2 methods. Thus, the bidentate metal complexes were studied with the BLYP method combined with the RECPs. In order to compare RECPs performance, all the systems considered in this work were studied with the relativistic all-electron Douglas-Kroll (DK3) method. We observed that the Christiansen-Ermler RECPs give the best energetic and geometrical description for Ca and Hg complexes when compared with the all-electron method. For Pb complexes the spin-orbit interaction and Basis Set Superposition error must be taken into account in the RECP. In general, the trend showed in the complexation energies with the all-electron method is followed by the complexation energies computed with all the pseudopotential tested in this work. Battelle operates PNNL for the USDOE.

  11. Does pet arrival trigger prosocial behaviors in individuals with autism?

    PubMed

    Grandgeorge, Marine; Tordjman, Sylvie; Lazartigues, Alain; Lemonnier, Eric; Deleau, Michel; Hausberger, Martine

    2012-01-01

    Alteration of social interactions especially prosocial behaviors--an important aspect of development--is one of the characteristics of autistic disorders. Numerous strategies or therapies are used to improve communication skills or at least to reduce social impairments. Animal-assisted therapies are used widely but their relevant benefits have never been scientifically evaluated. In the present study, we evaluated the association between the presence or the arrival of pets in families with an individual with autism and the changes in his or her prosocial behaviors. Of 260 individuals with autism--on the basis of presence or absence of pets--two groups of 12 individuals and two groups of 8 individuals were assigned to: study 1 (pet arrival after age of 5 versus no pet) and study 2 (pet versus no pet), respectively. Evaluation of social impairment was assessed at two time periods using the 36-items ADI-R algorithm and a parental questionnaire about their child-pet relationships. The results showed that 2 of the 36 items changed positively between the age of 4 to 5 (t(0)) and time of assessment (t(1)) in the pet arrival group (study 1): "offering to share" and "offering comfort". Interestingly, these two items reflect prosocial behaviors. There seemed to be no significant changes in any item for the three other groups. The interactions between individuals with autism and their pets were more--qualitatively and quantitatively--reported in the situation of pet arrival than pet presence since birth. These findings open further lines of research on the impact of pet's presence or arrival in families with an individual with autism. Given the potential ability of individuals with autism to develop prosocial behaviors, related studies are needed to better understand the mechanisms involved in the development of such child-pet relationship.

  12. PET/CT: underlying physics, instrumentation, and advances.

    PubMed

    Torres Espallardo, I

    2017-01-12

    Since it was first introduced, the main goal of PET/CT has been to provide both PET and CT images with high clinical quality and to present them to radiologists and specialists in nuclear medicine as a fused, perfectly aligned image. The use of fused PET and CT images quickly became routine in clinical practice, showing the great potential of these hybrid scanners. Thanks to this success, manufacturers have gone beyond considering CT as a mere attenuation corrector for PET, concentrating instead on design high performance PET and CT scanners with more interesting features. Since the first commercial PET/CT scanner became available in 2001, both the PET component and the CT component have improved immensely. In the case of PET, faster scintillation crystals with high stopping power such as LYSO crystals have enabled more sensitive devices to be built, making it possible to reduce the number of undesired coincidence events and to use time of flight (TOF) techniques. All these advances have improved lesion detection, especially in situations with very noisy backgrounds. Iterative reconstruction methods, together with the corrections carried out during the reconstruction and the use of the point-spread function, have improved image quality. In parallel, CT instrumentation has also improved significantly, and 64- and 128-row detectors have been incorporated into the most modern PET/CT scanners. This makes it possible to obtain high quality diagnostic anatomic images in a few seconds that both enable the correction of PET attenuation and provide information for diagnosis. Furthermore, nowadays nearly all PET/CT scanners have a system that modulates the dose of radiation that the patient is exposed to in the CT study in function of the region scanned. This article reviews the underlying physics of PET and CT imaging separately, describes the changes in the instrumentation and standard protocols in a combined PET/CT system, and finally points out the most important

  13. Protonation Studies of a Tungsten Dinitrogen Complex Supported by a Diphosphine Ligand Containing a Pendant Amine

    SciTech Connect

    Weiss, Charles J.; Egbert, Jonathan D.; Chen, Shentan; Helm, Monte L.; Bullock, R. Morris; Mock, Michael T.

    2014-04-28

    Treatment of trans-[W(N2)2(dppe)(PEtNMePEt)] (dppe = Ph2PCH2CH2PPh2; PEtNMePEt = Et2PCH2N(Me)CH2PEt2) with three equivalents of tetrafluoroboric acid (HBF4∙Et2O) at -78 °C generated the seven-coordinate tungsten hydride trans-[W(N2)2(H)(dppe)(PEtNMePEt)][BF4]. Depending on the temperature of the reaction, protonation of a pendant amine is also observed, affording trans-[W(N2)2(H)(dppe)(PEtNMe(H)PEt)][BF4]2, with formation of the hydrazido complex, [W(NNH2)(dppe)(PEtNMe(H)PEt)][BF4]2, as a minor product. Similar product mixtures were obtained using triflic acid (HOTf). Upon acid addition to the carbonyl analogue, cis-[W(CO)2(dppe)(PEtNMePEt)], the seven-coordinate carbonyl-hydride complex, trans-[W(CO)2(H)(dppe)(PEtN(H)MePEt)][OTf]2 was generated. The mixed diphosphine complex without the pendant amine in the ligand backbone, trans-[W(N2)2(dppe)(depp)] (depp = Et2P(CH2)3PEt2), was synthesized and treated with HBF4∙Et2O, selectively generating a hydrazido complex, [W(NNH2)(F)(dppe)(depp)][BF4]. Computational analysis was used to probe proton affinity of three sites of protonation, the metal, pendant amine, and N2 ligand in these complexes. Room temperature reactions with 100 equivalents of HOTf produced NH4+ from reduction of the N2 ligand (electrons come from W). The addition of 100 equivalents HOTf to trans-[W(N2)2(dppe)(PEtNMePEt)] afforded 0.88 ± 0.02 equivalents NH4+, while 0.36 ± 0.02 equivalents of NH4+was formed upon treatment of trans-[W(N2)2(dppe)(depp)], the complex without the pendant amine. This work was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy Office of Science, Office of Basic Energy Sciences. Computational resources were provided by the National Energy Research Scientific Computing Center (NERSC) at Lawrence Berkeley National Laboratory. Pacific Northwest National Laboratory is operated by Battelle for DOE.

  14. My Pet Rock

    ERIC Educational Resources Information Center

    Lark, Adam; Kramp, Robyne; Nurnberger-Haag, Julie

    2008-01-01

    Many teachers and students have experienced the classic pet rock experiment in conjunction with a geology unit. A teacher has students bring in a "pet" rock found outside of school, and the students run geologic tests on the rock. The tests include determining relative hardness using Mohs scale, checking for magnetization, and assessing luster.…

  15. Mobile PET Center Project

    NASA Astrophysics Data System (ADS)

    Ryzhikova, O.; Naumov, N.; Sergienko, V.; Kostylev, V.

    2017-01-01

    Positron emission tomography is the most promising technology to monitor cancer and heart disease treatment. Stationary PET center requires substantial financial resources and time for construction and equipping. The developed mobile solution will allow introducing PET technology quickly without major investments.

  16. Improving Instruction through PET.

    ERIC Educational Resources Information Center

    Evans, Pamela Roland

    1982-01-01

    Outlines the content and training methods used in the Program for Effective Teaching (PET), the successful staff development program of Newport News (Virginia). PET promotes application of five instructional skills: selecting learning objectives, teaching to the objectives, establishing learner focus, monitoring learner progress, and enhancing…

  17. My Pet Rock

    ERIC Educational Resources Information Center

    Lark, Adam; Kramp, Robyne; Nurnberger-Haag, Julie

    2008-01-01

    Many teachers and students have experienced the classic pet rock experiment in conjunction with a geology unit. A teacher has students bring in a "pet" rock found outside of school, and the students run geologic tests on the rock. The tests include determining relative hardness using Mohs scale, checking for magnetization, and assessing luster.…

  18. Birds Kept as Pets

    MedlinePlus

    ... lighting and is close to activity in the household. Be aware that pet birds can shed germs in their droppings. Plan to wear gloves when cleaning bird cages, and wash your hands thoroughly after any contact with the birds or their environment. Top of Page Importing pet birds into the ...

  19. Profits from precious pets.

    PubMed

    Pennisi, E

    2000-06-09

    In 1998, an anonymous millionaire, hoping to clone his pet dog Missy, awarded a Texas A&M University animal scientist $2.3 million to develop the necessary techniques. Now several companies are cashing in on the boom in frozen-tissue storage of pets for future cloning.

  20. Integrated Whole Body MR/PET: Where Are We?

    PubMed Central

    Yoo, Hye Jin; Lee, Jae Sung

    2015-01-01

    Whole body integrated magnetic resonance imaging (MR)/positron emission tomography (PET) imaging systems have recently become available for clinical use and are currently being used to explore whether the combined anatomic and functional capabilities of MR imaging and the metabolic information of PET provide new insight into disease phenotypes and biology, and provide a better assessment of oncologic diseases at a lower radiation dose than a CT. This review provides an overview of the technical background of combined MR/PET systems, a discussion of the potential advantages and technical challenges of hybrid MR/PET instrumentation, as well as collection of possible solutions. Various early clinical applications of integrated MR/PET are also addressed. Finally, the workflow issues of integrated MR/PET, including maximizing diagnostic information while minimizing acquisition time are discussed. PMID:25598673

  1. Synthesis and Biodistribution of Lipophilic Monocationic Gallium Radiopharmaceuticals Derived from N,N′-bis(3-aminopropyl)-N,N′-dimethylethylenediamine: Potential Agents for PET Myocardial Imaging with 68Ga

    PubMed Central

    Hsiao, Yui-May; Mathias, Carla J.; Wey, Shiaw-Pyng; Fanwick, Phillip E.; Green, Mark A.

    2009-01-01

    Introduction In locations that lack nearby cyclotron facilities for radionuclide production, generator-based 68Ga-radiopharmaceuticals might have clinical utility for positron emission tomography (PET) studies of myocardial perfusion and other physiologic processes. Methods The lipophilic, monocationic 67Ga-labeled gallium chelates of five novel hexadentate bis(salicylaldimine) ligands, the bis(salicylaldimine), bis(3-methoxysalicylaldimine), bis(4-methoxysalicylaldimine), bis(6-methoxysalicylaldimine), and bis(4,6-dimethoxysalicylaldimine) of N,N′-bis(3-aminopropyl)-N,N′-dimethylethylenediamine (BAPDMEN), were prepared. The structure of the unlabeled [Ga(4-MeOsal)2BAPDMEN]+PF6− salt was determined by X-ray crystallography, and the biodistribution of each of the 67Ga-labeled gallium chelates determined in rats following i.v. administration and compared to the biodistribution of [86Rb]rubidium chloride. Results The [Ga(4-MeOsal)2BAPDMEN]+PF6− complex exhibits the expected pseudo-octahedral N4O22− coordination sphere about the Ga3+ center with a trans-disposition of the phenolate oxygen atoms. All five of the 67Ga-radiopharmaceuticals were found to afford the desired myocardial retention of the radiogallium. The [67/68Ga][Ga(3-MeOsal)2BAPDMEN]1+ radiopharmaceutical appears to have the best properties for myocardial imaging, exhibiting 2% of the injected dose in the heart at both 1-minute and 2-hours post-injection and very high heart/non-target ratios (heart/blood ratios of 7.6 ± 1.0 and 54 ± 10 at 1-min and 120-min, respectively; heart/liver ratios of 1.8 ± 0.4 and 39 ± 3 at 1-min and 120-min, respectively). Conclusions Most of these new agents, particularly [67/68Ga][Ga(3-MeOsal)2BAPDMEN]1+, would appear superior to previously reported bis(salicyaldimines) of N,N′-bis(3-aminopropyl)ethylenediamine as candidates for PET imaging of the heart with 68Ga. PMID:19181267

  2. PET as a tool in the clinical evaluation of pituitary adenomas

    SciTech Connect

    Bergstroem, M.M.; Muhr, C.; Lundberg, P.O.; Langstroem B4 )

    1991-04-01

    Positron emission tomography (PET) was used in over 400 examinations in patients with pituitary adenoma. It was demonstrated that PET with carbon-11-methionine can give valuable complementary information in the diagnosis of this tumor due to PET's ability to adequately depict viable tumor tissue in contrast to fibrosis, cysts and necrosis. Furthermore, PET with dopamine D2 receptor ligands can characterize the degree of receptor binding and thus give information as to the prerequisites for dopamine agonist treatment. Most important is the very high sensitivity given by PET with carbon-11-methionine in the evaluation of treatment effects. It is concluded that when properly used PET can be fully justified in the clinical handling of patients with pituitary adenomas and other intracranial tumors.

  3. Biodistribution and radiation dosimetry of 18F-CP-18, a potential apoptosis imaging agent, as determined from PET/CT scans in healthy volunteers.

    PubMed

    Doss, Mohan; Kolb, Hartmuth C; Walsh, Joseph C; Mocharla, Vani; Fan, Hong; Chaudhary, Ashok; Zhu, Zhihong; Alpaugh, R Katherine; Lango, Miriam N; Yu, Jian Q

    2013-12-01

    (18)F-CP-18, or (18S,21S,24S,27S,30S)-27-(2-carboxyethyl)-21-(carboxymethyl)-30-((2S,3R,4R,5R,6S)-6-((2-(4-(3-F18-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)-24-isopropyl-18-methyl-17,20,23,26,29-pentaoxo-4,7,10,13-tetraoxa-16,19,22,25,28-pentaazadotriacontane-1,32-dioic acid, is being evaluated as a tissue apoptosis marker for PET imaging. The purpose of this study was to determine the biodistribution and estimate the normal-organ radiation-absorbed doses and effective dose from (18)F-CP-18. Successive whole-body PET/CT scans were obtained at approximately 7, 45, 90, 130, and 170 min after intravenous injection of (18)F-CP-18 in 7 healthy human volunteers. Blood samples and urine were collected between the PET/CT scans, and the biostability of (18)F-CP-18 was assessed using high-performance liquid chromatography. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on the biodistribution of the tracer. (18)F-CP-18 was 54% intact in human blood at 135 min after injection. The tracer cleared rapidly from the blood pool with a half-life of approximately 30 min. Relatively high (18)F-CP-18 uptake was observed in the kidneys and bladder, with diffuse uptake in the liver and heart. The mean standardized uptake values (SUVs) in the bladder, kidneys, heart, and liver at around 50 min after injection were approximately 65, 6, 1.5, and 1.5, respectively. The calculated effective dose was 38 ± 4 μSv/MBq, with the urinary bladder wall having the highest absorbed dose at 536 ± 61 μGy/MBq using a 4.8-h bladder-voiding interval for the male phantom. For a 1-h voiding interval, these doses were reduced to 15 ± 2 μSv/MBq and 142 ± 15 μGy/MBq, respectively. For a typical injected activity of 555 MBq, the effective dose would be 21.1 ± 2.2 mSv for the 4.8-h interval, reduced to 8.3 ± 1.1 mSv for the 1-h interval

  4. Exploring New Multimodal Quantitative Imaging Indices for the Assessment of Osseous Tumor Burden in Prostate Cancer Using (68)Ga-PSMA PET/CT.

    PubMed

    Bieth, Marie; Krönke, Markus; Tauber, Robert; Dahlbender, Marielena; Retz, Margitta; Nekolla, Stephan G; Menze, Bjoern; Maurer, Tobias; Eiber, Matthias; Schwaiger, Markus

    2017-10-01

    PET combined with CT and prostate-specific membrane antigen (PSMA) ligands has gained significant interest for staging prostate cancer (PC). In this study, we propose 2 multimodal quantitative indices as imaging biomarkers for the assessment of osseous tumor burden using (68)Ga-PSMA PET/CT and present preliminary clinical data. Methods: We defined 2 bone PET indices (BPIs) that incorporate anatomic information from CT and functional information from (68)Ga-PSMA PET: BPIVOL is the percentage of bone volume affected by tumor and BPISUV additionally considers the level of PSMA expression. We describe a semiautomatic computation method based on segmentation of bones in CT and of lesions in PET. Data from 45 patients with castration-resistant PC and bone metastases during (223)Ra-dichloride were retrospectively analyzed. We evaluated the computational stability and reproducibility of the proposed indices and explored their relation to the prostate-specific antigen blood value, the bone scan index (BSI), and disease classification using PERCIST. Results: On the technical side, BPIVOL and BPISUV showed an interobserver maximum difference of 3.5%, and their computation took only a few minutes. On the clinical side, BPIVOL and BPISUV showed significant correlations with BSI (r = 0.76 and 0.74, respectively, P < 0.001) and prostate-specific antigen values (r = 0.57 and 0.54, respectively, P < 0.01). When the proposed indices were compared against expert rating using PERCIST, BPIVOL and BPISUV showed better agreement than BSI, indicating their potential for objective response evaluation. Conclusion: We propose the evaluation of BPIVOL and BPISUV as imaging biomarkers for (68)Ga-PSMA PET/CT in a prospective study exploring their potential for outcome prediction in patients with bone metastases from PC. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

  5. [Research and development for next generation PET instrumentations].

    PubMed

    Yamaya, Taiga

    2012-01-01

    Positron emission tomography (PET) plays important roles in cancer diagnosis and molecular imaging research; but potential points remain for which big improvements could be made, including resolution, sensitivity and costs. For example, the sensitivity of present PET scanners does not exceed 10%. This means that more than 90% of the gamma-rays emitted from a subject are not utilized for imaging. Therefore, research on next generation PET technologies remains a hot topic worldwide. In this paper, we introduce some research trends by describing PET physics research in the National Institute of Radiological Sciences (NIRS). A depth-of-interaction (DOI) detector, for which various methods have been studied, will be a key device to get any significant improvement in sensitivity while maintaining high spatial resolution. DOI measurement also has a potential to expand PET application fields because it allows for more flexible detector arrangement. As an example, we are developing the world's first, open-type PET geometry "OpenPET", which is expected to lead to PET imaging during treatment. The DOI detector itself continues to evolve with the help of recently developed semiconductor photodetectors, often referred to as silicon photomultipliers (SiPMs). We are developing a SiPM-based DOI detector to achieve sub-mm spatial resolution, which is reaching the theoretical limitation of PET imaging.

  6. Clinical oncologic applications of PET/MRI: a new horizon

    PubMed Central

    Partovi, Sasan; Kohan, Andres; Rubbert, Christian; Vercher-Conejero, Jose Luis; Gaeta, Chiara; Yuh, Roger; Zipp, Lisa; Herrmann, Karin A; Robbin, Mark R; Lee, Zhenghong; Muzic, Raymond F; Faulhaber, Peter; Ros, Pablo R

    2014-01-01

    Positron emission tomography/magnetic resonance imaging (PET/MRI) leverages the high soft-tissue contrast and the functional sequences of MR with the molecular information of PET in one single, hybrid imaging technology. This technology, which was recently introduced into the clinical arena in a few medical centers worldwide, provides information about tumor biology and microenvironment. Studies on indirect PET/MRI (use of positron emission tomography/computed tomography (PET/CT) images software fused with MRI images) have already generated interesting preliminary data to pave the ground for potential applications of PET/MRI. These initial data convey that PET/MRI is promising in neuro-oncology and head & neck cancer applications as well as neoplasms in the abdomen and pelvis. The pediatric and young adult oncology population requiring frequent follow-up studies as well as pregnant woman might benefit from PET/MRI due to its lower ionizing radiation dose. The indication and planning of therapeutic interventions and specifically radiation therapy in individual patients could be and to a certain extent are already facilitated by performing PET/MRI. The objective of this article is to discuss potential clinical oncology indications of PET/MRI. PMID:24753986

  7. PET and SPECT imaging in veterinary medicine.

    PubMed

    LeBlanc, Amy K; Peremans, Kathelijne

    2014-01-01

    Veterinarians have gained increasing access to positron emission tomography (PET and PET/CT) imaging facilities, allowing them to use this powerful molecular imaging technique for clinical and research applications. SPECT is currently being used more in Europe than in the United States and has been shown to be useful in veterinary oncology and in the evaluation of orthopedic diseases. SPECT brain perfusion and receptor imaging is used to investigate behavioral disorders in animals that have interesting similarities to human psychiatric disorders. This article provides an overview of the potential applications of PET and SPECT. The use of commercially available and investigational PET radiopharmaceuticals in the management of veterinary disease has been discussed. To date, most of the work in this field has utilized the commercially available PET tracer, (18)F-fluorodeoxyglucose for oncologic imaging. Normal biodistribution studies in several companion animal species (cats, dogs, and birds) have been published to assist in lesion detection and interpretation for veterinary radiologists and clinicians. Studies evaluating other (18)F-labeled tracers for research applications are underway at several institutions and companion animal models of human diseases are being increasingly recognized for their value in biomarker and therapy development. Although PET and SPECT technologies are in their infancy for clinical veterinary medicine, increasing access to and interest in these applications and other molecular imaging techniques has led to a greater knowledge and collective body of expertise for veterinarians worldwide. Initiation and fostering of physician-veterinarian collaborations are key components to the forward movement of this field.

  8. Digital PET compliance to EARL accreditation specifications.

    PubMed

    Koopman, Daniëlle; Groot Koerkamp, Maureen; Jager, Pieter L; Arkies, Hester; Knollema, Siert; Slump, Cornelis H; Sanches, Pedro G; van Dalen, Jorn A

    2017-12-01

    Our aim was to evaluate if a recently introduced TOF PET system with digital photon counting technology (Philips Healthcare), potentially providing an improved image quality over analogue systems, can fulfil EANM research Ltd (EARL) accreditation specifications for tumour imaging with FDG-PET/CT. We have performed a phantom study on a digital TOF PET system using a NEMA NU2-2001 image quality phantom with six fillable spheres. Phantom preparation and PET/CT acquisition were performed according to the European Association of Nuclear Medicine (EANM) guidelines. We made list-mode ordered-subsets expectation maximization (OSEM) TOF PET reconstructions, with default settings, three voxel sizes (4 × 4 × 4 mm(3), 2 × 2 × 2 mm(3) and 1 × 1 × 1 mm(3)) and with/without point spread function (PSF) modelling. On each PET dataset, mean and maximum activity concentration recovery coefficients (RCmean and RCmax) were calculated for all phantom spheres and compared to EARL accreditation specifications. The RCs of the 4 × 4 × 4 mm(3) voxel dataset without PSF modelling proved closest to EARL specifications. Next, we added a Gaussian post-smoothing filter with varying kernel widths of 1-7 mm. EARL specifications were fulfilled when using kernel widths of 2 to 4 mm. TOF PET using digital photon counting technology fulfils EARL accreditation specifications for FDG-PET/CT tumour imaging when using an OSEM reconstruction with 4 × 4 × 4 mm(3) voxels, no PSF modelling and including a Gaussian post-smoothing filter of 2 to 4 mm.

  9. The pet as an anxiolytic intervention.

    PubMed

    Wilson, C C

    1991-08-01

    The effect of a pet on psychological consequences of stress (i.e., state and trait anxiety levels) of college students was examined under three test conditions (i.e., reading aloud, reading quietly, and interacting with a friendly but unknown dog). A repeated-measures analysis of variance with three covariates was used to examine the effect of the treatment on each dependent variable (state and trait anxiety). Reading aloud differed from baseline measure under all treatment conditions (p less than .001). Reading quietly and interacting with the dog were slightly below baseline for variables, with more effect seen by reading quietly than by interacting with the dog. Examination of interactions among variables showed no significant differences. Effects upon state anxiety were significant, while trait anxiety levels remained fairly constant throughout the treatments. Baseline differences in trait anxiety scores indicate a potentially greater benefit for pet owners than nonowners. Selected social network and relationship data related to the role of the pet during anxiety-producing times were also analyzed. While interaction with the pet produced a decrease in anxiety level, pet owners did not report the use of their own pet as a social support (i.e., as confidant) significantly more than did previous owners. Results indicated that interacting with a pet for some individuals does affect both physiological and psychological responses by lowering response levels. However, a parallel effect was also seen by reading quietly. Given the effect of pet interaction upon selected social support indicators of health in well college students, these data suggest the importance of examining this treatment with an "at-risk" group in which it is possible to control for ownership characteristics.

  10. Early-Dynamic Positron Emission Tomography (PET)/Computed Tomography and PET Angiography for Endoleak Detection After Endovascular Aneurysm Repair.

    PubMed

    Drescher, Robert; Gühne, Falk; Freesmeyer, Martin

    2017-06-01

    To propose a positron emission tomography (PET)/computed tomography (CT) protocol including early-dynamic and late-phase acquisitions to evaluate graft patency and aneurysm diameter, detect endoleaks, and rule out graft or vessel wall inflammation after endovascular aneurysm repair (EVAR) in one examination without intravenous contrast medium. Early-dynamic PET/CT of the endovascular prosthesis is performed for 180 seconds immediately after intravenous injection of F-18-fluorodeoxyglucose. Data are reconstructed in variable time frames (time periods after tracer injection) to visualize the arterial anatomy and are displayed as PET angiography or fused with CT images. Images are evaluated in view of vascular abnormalities, graft configuration, and tracer accumulation in the aneurysm sac. Whole-body PET/CT is performed 90 to 120 minutes after tracer injection. This protocol for early-dynamic PET/CT and PET angiography has the potential to evaluate vascular diseases, including the diagnosis of complications after endovascular procedures.

  11. Human Kinetic Modeling of the 5HT6 PET Radioligand 11C-GSK215083 and Its Utility for Determining Occupancy at Both 5HT6 and 5HT2A Receptors by SB742457 as a Potential Therapeutic Mechanism of Action in Alzheimer Disease.

    PubMed

    Parker, Christine A; Rabiner, Eugenii A; Gunn, Roger N; Searle, Graham; Martarello, Laurent; Comley, Robert A; Davy, Maria; Wilson, Alan A; Houle, Sylvain; Mizrahi, Romina; Laruelle, Marc; Cunningham, Vincent J

    2015-12-01

    Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d). In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457. Kinetic analysis of (11)C-GSK215083 uptake in the human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacologic dissection of the in vivo (11)C-GSK215083-specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457 but not by the selective 5-hydroxytryptamine-2A (5HT2A) antagonist ketanserin) and the 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15, and 35 mg/d) saturated the 5HT6 receptors at all doses. In the cortex, 5HT2A receptor occupancy was 24% ± 6% (3 mg/d), 35% ± 4% (15 mg/d), and 58% ± 19% (35 mg/d; mean ± SD), suggesting a progressive engagement of 5HT2A as the dose increased. Collectively, these data support the use of (11)C-GSK215083 as a 5HT6 clinical imaging tool and suggest that blocking both the 5HT6 and the 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  12. The pyrokinin/ pheromone biosynthesis-activating neuropeptide (PBAN) family of peptides and their receptors in Insecta: evolutionary trace indicates potential receptor ligand-binding domains.

    PubMed

    Jurenka, R; Nusawardani, T

    2011-06-01

    The pyrokinin/pheromone biosynthesis-activating neuropeptide (PBAN) family of G-protein-coupled receptors and their ligands have been identified in various insects. Physiological functions of pyrokinin peptides include muscle contraction, whereas PBAN regulates, among other functions, pheromone production in moths which indicates the pleiotropic nature of these peptides. Based on the alignment of annotated genomic sequences, the pyrokinin/PBAN family of receptors have similarity with the corresponding structures of the capa or periviscerokinin receptors of insects and the neuromedin U receptors of vertebrates. In our study, evolutionary trace (ET) analysis on the insect receptor sequences was conducted to predict the putative ligand recognition and binding sites. The ET analysis of four class-specific receptors indicated several amino acid residues that are conserved in the transmembrane domains. The receptor extracellular domains exhibit several class-specific amino acid residues, which could indicate putative domains for activation of these receptors by ligand recognition and binding.

  13. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals.

    PubMed

    Hashimoto, Kenji; Ishiwata, Kiichi

    2006-01-01

    Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

  14. Flutriciclamide (18F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein.

    PubMed

    Fan, Zhen; Calsolaro, Valeria; Atkinson, Rebecca A; Femminella, Grazia D; Waldman, Adam; Buckley, Christopher; Trigg, William; Brooks, David J; Hinz, Rainer; Edison, Paul

    2016-11-01

    Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide ((18)F-GE180) is a recently developed third-generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for (18)F-GE180 PET in (older) healthy controls.

  15. Pigmented villonodular synovitis: dedicated PET imaging findings

    PubMed Central

    Amber, Ian Blake; Clark, Brian J; Greene, Gary Stuart

    2013-01-01

    Pigmented villonodular synovitis (PVNS) is an uncommon entity, which has the potential to cause severe pain. The gold standard for evaluation is MRI, and previous PET findings associated with PVNS have only been documented in the setting of concurrent malignancy. In the setting of recurrent disease, PET is being used to evaluate prebiological and postbiological treatment responses. Recurrent PVNS demonstrates greater hypermetabolic activity than previously documented, supporting the case as a potential mimic of malignant/metastatic disease. Post-treatment evaluations demonstrate decreased metabolic activity, which suggests response to treatment. This behaviour further supports the contention that there is a neoplastic origin to PVNS. PMID:23598941

  16. PET imaging in endocrine tumours.

    PubMed

    Khan, S; Lloyd, C; Szyszko, T; Win, Z; Rubello, D; Al-Nahhas, A

    2008-06-01

    The role of PET in the assessment of endocrine tumours has been, until recently, restricted to the use of (18)F-fluoro-deoxy-D-glucose ((18)F-FDG). Being a marker of metabolically active lesions that show high grading and low differentiation, FDG is not ideal for this purpose since the majority of endocrine tumours are slow growing and highly differentiated. It is however useful when dedifferentiation takes place and provides excellent prognostic information. A number of hormone precursors and amino acids are labelled with (11)C and used successfully in the management of parathyroid, adrenal and pituitary tumours. However, the short half-life of (11)C radiopharmaceuticals restricts their use to centres with access to an on-site cyclotron, while the high cost of production may limit their use to research purposes. A promising new positron-emission tomography (PET) tracer is Gallium-68 obtained by elution from a long shelf-life generator that makes it economic and cyclotron-independent. Its short half-life and flexible labelling ability to a wide range of peptides and antibodies makes it ideal for PET imaging. In addition to imaging GEP-NETs and phaeochromocytoma, it has the potential to be used in a wider range of endocrine tumours.

  17. Glyconanomaterials: Synthesis, Characterization, and Ligand Presentation

    PubMed Central

    Wang, Xin

    2010-01-01

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins. PMID:20301131

  18. Glyconanomaterials: synthesis, characterization, and ligand presentation.

    PubMed

    Wang, Xin; Ramström, Olof; Yan, Mingdi

    2010-05-04

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins.

  19. Synthesis and Characterization of New Binuclear Co(0) Complexes with Diphosphinoamine Ligands. A Potential Approach for Asymmetric Pauson-Khand Reactions.

    PubMed

    Gimbert, Yves; Robert, Frédéric; Durif, André; Averbuch, Marie-Thérèse; Kann, Nina; Greene, Andrew E.

    1999-05-14

    The synthesis of P-N-P bidentate ligands and the evaluation, based on IR and X-ray data, of their pi-acceptor properties in the complexes derived from phenylacetylene-dicobalt hexacarbonyl have been carried out. In addition, the reactivity of these complexes in the Pauson-Khand reaction has been examined.

  20. On the Electronic and Magnetic Properties of the ionic superatomic solid Ni9Te6(PEt3)8 C60

    NASA Astrophysics Data System (ADS)

    Chauhan, Vikas; Sahoo, Sanjubala; Khanna, Shiv; Physics Department VCU Collaboration

    We have carried out first principles electronic structure studies to examine the atomic structure, stability, and electronic and magnetic properties of the recently synthesized Ni9Te6(PEt3)8 C60 ionic material consisting of Ni9Te6(PEt3)8 superatoms and C60. It is shown that the PEt3 ligands result in an internal coulomb well that lifts the quantum states of the Ni9Te6 cluster lowering its ionization potential to 3.39 eV thus creating a superatomic alkali motif. The metallic core has a spin magnetic moment of 5.3 µb in agreement with experiment. The clusters are marked by low magnetic anisotropy energy (MAE) of 2.72 meV and a larger intra-exchange coupling exceeding 0.2 eV indicating that the observed paramagnetic behavior around 10K is due to superparamagnetic relaxations. The magnetic motifs separated by C60 experience a weak superexchange that stabilizes a ferromagnetic ground state as observed around 2K. The calculated MAE is sensitive to the charged state that could account for the observed change in magnetic transition temperature with size of the ligands or anion. We gratefully acknowledge funding support from the Department of Energy under Award Number DE-SC0006420.

  1. Virtual-Pinhole PET

    PubMed Central

    Tai, Yuan-Chuan; Wu, Heyu; Pal, Debashish; O’Sullivan, Joseph A.

    2011-01-01

    We proposed and tested a novel geometry for PET system design analogous to pinhole SPECT called the virtual-pinhole PET (VP-PET) geometry to determine whether it could provide high-resolution images. Methods We analyzed the effects of photon acolinearity and detector sizes on system resolution and extended the empiric formula for reconstructed image resolution of conventional PET proposed earlier to predict the resolutions of VP-PET. To measure the system resolution of VP-PET, we recorded coincidence events as a 22Na point source was stepped across the coincidence line of response between 2 detectors made from identical arrays of 12 × 12 lutetium oxyorthosilicate crystals (each measuring 1.51 × 1.51 × 10 mm3) separated by 565 mm. To measure reconstructed image resolution, we built 4 VP-PET systems using 4 types of detectors (width, 1.51–6.4mm) and imaged 4 point sources of 64Cu (half-life = 12.7 h to allow a long acquisition time). Tangential and radial resolutions were measured and averaged for each source and each system. We then imaged a polystyrene plastic phantom representing a 2.5-cm-thick cross-section of isolated breast volume. The phantom was filled with an aqueous solution of 64Cu (713 kBq/mL) in which the following were imbedded: 4 spheric tumors ranging from 1.8 to 12.6 mm in inner diameter (ID), 6 micropipettes (0.7- or 1.1-mm ID filled with 64Cu at 5×, 20×, or 50× background), and a 10.0-mm outer-diameter cold lesion. Results The shape and measured full width at half maximum of the line spread functions agree well with the predicted values. Measured reconstructed image resolution (2.40–3.24 mm) was ±6% of the predicted value for 3 of the 4 systems. In one case, the difference was 12.6%, possibly due to underestimation of the block effect from the low-resolution detector. In phantom experiments, all spheric tumors were detected. Small line sources were detected if the activity concentration is at least 20× background. Conclusion We have

  2. Synthesis, F-18 Radiolabeling, and MicroPET Evaluation of 3-(2,4-Dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as Ligands of the Corticotropin-Releasing Factor Type-1 (CRF1) Receptor

    PubMed Central

    Stehouwer, Jeffrey S.; Birnbaum, Matthew S.; Voll, Ronald J.; Owens, Michael J.; Plott, Susan J.; Bourke, Chase H.; Wassef, Michael A.; Kilts, Clinton D.; Goodman, Mark M.

    2015-01-01

    A series of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines were synthesized and evaluated as potential positron emission tomography (PET) tracers for the corticotropin-releasing factor type-1 (CRF1) receptor. Compounds 27,28,29, and 30 all displayed high binding affinity (≤ 1.2 nM) to the CRF1 receptor when assessed by in vitro competition binding assays at 23 °C, whereas a decrease in affinity (≥ 10-fold) was observed with compound 26. The logP7.4 values of [18F]26 – [18F]29 were in the range of ~2.2 – 2.8 and microPET evaluation of [18F]26 – [18F]29 in an anesthetized male cynomolgus monkey demonstrated brain penetrance, but specific binding was not sufficient enough to differentiate regions of high CRF1 receptor density from regions of low CRF1 receptor density. Radioactivity uptake in the skull, and sphenoid bone and/or sphenoid sinus during studies with [18F]28, [18F]28-d8, and [18F]29 was attributed to a combination of [18F]fluoride generated by metabolic defluorination of the radiotracer and binding of intact radiotracer to CRF1 receptors expressed on mast cells in the bone marrow. Uptake of [18F]26 and [18F]27 in the skull and sphenoid region was rapid but then steadily washed out which suggests that this behavior was the result of binding to CRF1 receptors expressed on mast cells in the bone marrow with no contribution from [18F]fluoride. PMID:26145817

  3. Does Pet Arrival Trigger Prosocial Behaviors in Individuals with Autism?

    PubMed Central

    Grandgeorge, Marine; Tordjman, Sylvie; Lazartigues, Alain; Lemonnier, Eric; Deleau, Michel; Hausberger, Martine

    2012-01-01

    Alteration of social interactions especially prosocial behaviors – an important aspect of development – is one of the characteristics of autistic disorders. Numerous strategies or therapies are used to improve communication skills or at least to reduce social impairments. Animal-assisted therapies are used widely but their relevant benefits have never been scientifically evaluated. In the present study, we evaluated the association between the presence or the arrival of pets in families with an individual with autism and the changes in his or her prosocial behaviors. Of 260 individuals with autism - on the basis of presence or absence of pets - two groups of 12 individuals and two groups of 8 individuals were assigned to: study 1 (pet arrival after age of 5 versus no pet) and study 2 (pet versus no pet), respectively. Evaluation of social impairment was assessed at two time periods using the 36-items ADI-R algorithm and a parental questionnaire about their child-pet relationships. The results showed that 2 of the 36 items changed positively between the age of 4 to 5 (t0) and time of assessment (t1) in the pet arrival group (study 1): “offering to share” and “offering comfort”. Interestingly, these two items reflect prosocial behaviors. There seemed to be no significant changes in any item for the three other groups. The interactions between individuals with autism and their pets were more – qualitatively and quantitatively - reported in the situation of pet arrival than pet presence since birth. These findings open further lines of research on the impact of pet’s presence or arrival in families with an individual with autism. Given the potential ability of individuals with autism to develop prosocial behaviors, related studies are needed to better understand the mechanisms involved in the development of such child-pet relationship. PMID:22870246

  4. Reproducibility of Quantitative Brain Imaging Using a PET-Only and a Combined PET/MR System

    PubMed Central

    Lassen, Martin L.; Muzik, Otto; Beyer, Thomas; Hacker, Marcus; Ladefoged, Claes Nøhr; Cal-González, Jacobo; Wadsak, Wolfgang; Rausch, Ivo; Langer, Oliver; Bauer, Martin

    2017-01-01

    The purpose of this study was to test the feasibility of migrating a quantitative brain imaging protocol from a positron emission tomography (PET)-only system to an integrated PET/MR system. Potential differences in both absolute radiotracer concentration as well as in the derived kinetic parameters as a function of PET system choice have been investigated. Five healthy volunteers underwent dynamic (R)-[11C]verapamil imaging on the same day using a GE-Advance (PET-only) and a Siemens Biograph mMR system (PET/MR). PET-emission data were reconstructed using a transmission-based attenuation correction (AC) map (PET-only), whereas a standard MR-DIXON as well as a low-dose CT AC map was applied to PET/MR emission data. Kinetic modeling based on arterial blood sampling was performed using a 1-tissue-2-rate constant compartment model, yielding kinetic parameters (K1 and k2) and distribution volume (VT). Differences for parametric values obtained in the PET-only and the PET/MR systems were analyzed using a 2-way Analysis of Variance (ANOVA). Comparison of DIXON-based AC (PET/MR) with emission data derived from the PET-only system revealed average inter-system differences of −33 ± 14% (p < 0.05) for the K1 parameter and −19 ± 9% (p < 0.05) for k2. Using a CT-based AC for PET/MR resulted in slightly lower systematic differences of −16 ± 18% for K1 and −9 ± 10% for k2. The average differences in VT were −18 ± 10% (p < 0.05) for DIXON- and −8 ± 13% for CT-based AC. Significant systematic differences were observed for kinetic parameters derived from emission data obtained from PET/MR and PET-only imaging due to different standard AC methods employed. Therefore, a transfer of imaging protocols from PET-only to PET/MR systems is not straightforward without application of proper correction methods. Clinical Trial Registration: www.clinicaltrialsregister.eu, identifier 2013-001724-19 PMID:28769742

  5. Understanding the complexation of Eu(3+) with potential ligands used for preferential separation of lanthanides and actinides in various stages of nuclear fuel cycle: A luminescence investigation.

    PubMed

    Sengupta, Arijit; Kadam, R M

    2017-02-15

    A systematic photoluminescence based investigation was carried out to understand the complexation of Eu(3+) with different ligands (TBP: tri-n-butyl phosphate, DHOA: di-n-hexyl octanamide, Cyanex 923: tri-n-alkyl phosphine oxide and Cyanex 272: Bis (2,4,4 trimethyl) pentyl phosphinic acid) used for preferential separation of lanthanides and actinides in various stages of nuclear fuel cycle. In case of TBP and DHOA complexes, 3 ligand molecules coordinated in monodentate fashion and 3 nitrate ion in bidentate fashion to Eu(3+) to satisfy the 9 coordination of Eu. In case of Cyanex 923 and Cyanex 272 complexes, 3 ligand molecules, 3 nitrate ion and 3 water molecules coordinated to Eu(3+) in monodentate fashion. The Eu complexes of TBP and DHOA were found to have D3h local symmetry while that for Cyanex 923 and Cyanex 272 were C3h. Judd-Ofelt analysis of these systems revealed that the covalency of EuO bond followed the trend DHOA>TBP>Cyanex 272>Cyanex 923. Different photophysical properties like radiative and non-radiative life time, branching ratio for different transitions, magnetic and electric dipole moment transition probabilities and quantum efficiency were also evaluated and compared for these systems. The magnetic dipole transition probability was found to be almost independent of ligand field perturbation while electric dipole transition probability for (5)D0-(7)F2 transition was found to be hypersensitive with ligand field with a trend DHOA>TBP>Cyanex 272>Cyanex 923. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Understanding the complexation of Eu3 + with potential ligands used for preferential separation of lanthanides and actinides in various stages of nuclear fuel cycle: A luminescence investigation

    NASA Astrophysics Data System (ADS)

    Sengupta, Arijit; Kadam, R. M.

    2017-02-01

    A systematic photoluminescence based investigation was carried out to understand the complexation of Eu3 + with different ligands (TBP: tri-n-butyl phosphate, DHOA: di-n-hexyl octanamide, Cyanex 923: tri-n-alkyl phosphine oxide and Cyanex 272: Bis (2,4,4 trimethyl) pentyl phosphinic acid) used for preferential separation of lanthanides and actinides in various stages of nuclear fuel cycle. In case of TBP and DHOA complexes, 3 ligand molecules coordinated in monodentate fashion and 3 nitrate ion in bidentate fashion to Eu3 + to satisfy the 9 coordination of Eu. In case of Cyanex 923 and Cyanex 272 complexes, 3 ligand molecules, 3 nitrate ion and 3 water molecules coordinated to Eu3 + in monodentate fashion. The Eu complexes of TBP and DHOA were found to have D3h local symmetry while that for Cyanex 923 and Cyanex 272 were C3h. Judd-Ofelt analysis of these systems revealed that the covalency of Eusbnd O bond followed the trend DHOA > TBP > Cyanex 272 > Cyanex 923. Different photophysical properties like radiative and non-radiative life time, branching ratio for different transitions, magnetic and electric dipole moment transition probabilities and quantum efficiency were also evaluated and compared for these systems. The magnetic dipole transition probability was found to be almost independent of ligand field perturbation while electric dipole transition probability for 5D0-7F2 transition was found to be hypersensitive with ligand field with a trend DHOA > TBP > Cyanex 272 > Cyanex 923. Supplementary Table 2: Determination of inner sphere water molecules from the different empirical formulae reported in the literature.

  7. Fluroine-18 labeled 28-carbomethoxy-3{beta}-(4-chlorophenyl)-8-[-3-fluoropropyl] nortropane(FPT): Synthesis and tissue distribution of a potential, radioligand for mapping cocaine receptor sites by PET

    SciTech Connect

    Keil, R.; Goodman, M.M.; Shoup, T.

    1995-05-01

    Highly potent and selective radioligands for the dopamine transporter labeled with fluorine-18 (t {1/2}=110 min) are attractive probes for longitudinal in vivo mapping of cocaine receptor sites in the caudate by PET. Recently, we reported an iodine-123 labeled 3{beta}-aryl analog of cocaine, 2{beta}-carbomethoxy-3{beta}-(4-chlorophenyl)-8-((E)-3-iodopropen-1-yl)nortropane, which was 125 times more potent than cocaine in inhibiting [I-125] RTI-55 binding to rat striatal homogenates and which showed high striatal (S) uptake (0.61% dose/g) and high S to cerebellum (C) ratio S/C=16.5 at 120 min in rats. These results demonstrated bulk tolerance at the 8-position of this I-123 analog. These findings prompted us to synthesize a new radioligand fluorine-18 labeled 2{beta}-carbomethoxy-3{beta}-(4-chlorophenyl)-8-3-fluoropropylnortropane (FPT) as a potential cocaine receptor PET imaging agent. Treatment of 2{beta}-carbomethoxy-3{beta}-(chlorophenyl) nortropane (1) with 1-bromo-3-fluoropropane (2) in CH3CN at 80{degrees}C afforded FPT (3). In Vitro binding studies in rat striatal homogenates using [I-125] RTI-55 resulted in a Ki (nM) of 8.2 for FPT. [F-18]FPT (3) was prepared by treating 1,3-diiodopropane (4) with NCA K[F-18]/K222 for 5 min in CH3CN at 85{degrees}C to give [F-18] 1-fluoro-3-iodopropane (5) in 50% E.O.B. yield. Coupling of [F-18] 5 with 1 in CH3CN at 60{degrees}C afforded [F-18]FPT in 5% yield (not optimized) E.O.B. following HPLC purification in a total synthesis time of 100 min.. [F-18]5 was >99% radiochemically pure with a specific activity of 8 Ci/{mu}mole. Following intravenous administration to rats [F-18]FPT showed high uptake in the striatum (S) with rapid washout from the cerebellum to afford a high S/C ratios=6.2 at 120 min. Primate imaging will also be presented. These results suggest that FPT is an excellent candidate for mapping cocaine receptor sites by PET.

  8. Additive value of amyloid-PET in routine cases of clinical dementia work-up after FDG-PET.

    PubMed

    Brendel, Matthias; Schnabel, Jonas; Schönecker, Sonja; Wagner, Leonie; Brendel, Eva; Meyer-Wilmes, Johanna; Unterrainer, Marcus; Schildan, Andreas; Patt, Marianne; Prix, Catharina; Ackl, Nibal; Catak, Cihan; Pogarell, Oliver; Levin, Johannes; Danek, Adrian; Buerger, Katharina; Bartenstein, Peter; Barthel, Henryk; Sabri, Osama; Rominger, Axel

    2017-09-20

    In recent years, several [(18)F]-labeled amyloid-PET tracers have been developed and have obtained clinical approval. Despite their widespread scientific use, studies in routine clinical settings are limited. We therefore investigated the impact of [(18)F]-florbetaben (FBB)-PET on the diagnostic management of patients with suspected dementia that was still unclarified after [(18)F]-fluordeoxyglucose (FDG)-PET. All subjects were referred in-house with a suspected dementia syndrome due to neurodegenerative disease. After undergoing an FDG-PET exam, the cases were discussed by the interdisciplinary dementia board, where the most likely diagnosis as well as potential differential diagnoses were documented. Because of persistent diagnostic uncertainty, the patients received an additional FBB-PET exam. Results were interpreted visually and classified as amyloid-positive or amyloid-negative, and we then compared the individual clinical diagnoses before and after additional FBB-PET. A total of 107 patients (mean age 69.4 ± 9.7y) were included in the study. The FBB-PET was rated as amyloid-positive in 65/107. In 83% of the formerly unclear cases, a final diagnosis was reached through FBB-PET, and the most likely prior diagnosis was changed in 28% of cases. The highest impact was observed for distinguishing Alzheimer's dementia (AD) from fronto-temporal dementia (FTLD), where FBB-PET altered the most likely diagnosis in 41% of cases. FBB-PET has a high additive value in establishing a final diagnosis in suspected dementia cases when prior investigations such as FDG-PET are inconclusive. The differentiation between AD and FTLD was particularly facilitated by amyloid-PET, predicting a considerable impact on patient management, especially in the light of upcoming disease-modifying therapies.

  9. Quantitative assessment of atherosclerotic plaques on (18)F-FDG PET/MRI: comparison with a PET/CT hybrid system.

    PubMed

    Li, Xiang; Heber, Daniel; Rausch, Ivo; Beitzke, Dietrich; Mayerhoefer, Marius E; Rasul, Sazan; Kreissl, Michael; Mitthauser, Markus; Wadsak, Wolfgang; Hartenbach, Markus; Haug, Alexander; Zhang, Xiaoli; Loewe, Christian; Beyer, Thomas; Hacker, Marcus

    2016-07-01

    PET with (18)F-FDG has the potential to assess vascular macrophage metabolism. (18)F-FDG is most often used in combination with contrast-enhanced CT to localize increased metabolism to specific arterial lesions. Novel (18)F-FDG PET/MRI hybrid imaging shows high potential for the combined evaluation of atherosclerotic plaques, due to the superior morphological conspicuity of plaque lesions. The purpose of this study was to evaluate the reliability and accuracy of (18)F-FDG PET/MRI uptake quantification compared to PET/CT as a reference standard in patients with carotid atherosclerotic plaques. The study group comprised 34 consecutive oncological patients with carotid plaques who underwent both PET/CT and PET/MRI with (18)F-FDG on the same day. The presence of atherosclerotic plaques was confirmed by 3 T MRI scans. Maximum standardized uptake values (SUVmax) for carotid plaque lesions and the average SUV of the blood pool within the adjacent internal jugular vein were determined and target-to-blood ratios (TBRs, plaque to blood pool) were calculated. Atherosclerotic lesions with maximum colocalized focal FDG uptake were assessed in each patient. SUVmax values of carotid plaque lesions were significantly lower on PET/MRI than on PET/CT (2.3 ± 0.6 vs. 3.1 ± 0.6; P < 0.01), but were significantly correlated between PET/CT and PET/MRI (Spearman's r = 0.67, P < 0.01). In contrast, TBRmax values of plaque lesions were similar on PET/MRI and on PET/CT (2.2 ± 0.3 vs. 2.2 ± 0.3; P = 0.4), and again were significantly correlated between PET/MRI and PET/CT (Spearman's r = 0.73, P < 0.01). Considering the increasing trend in SUVmax and TBRmax values from early to delayed imaging time-points on PET/CT and PET/MRI, respectively, with continuous clearance of radioactivity from the blood, a slight underestimation of TBRmax values may also be expected with PET/MRI compared with PET/CT. SUVmax and TBRmax values are widely accepted reference

  10. Heart PET scan

    MedlinePlus

    Heart nuclear medicine scan; Heart positron emission tomography; Myocardial PET scan ... Udelson JE, Dilsizian V, Bonow RO. Nuclear cardiology. In: Mann DL, ... A Textbook of Cardiovascular Medicine . 10th ed. Philadelphia, ...

  11. Appropriate and Inappropriate Pets.

    ERIC Educational Resources Information Center

    Soltow, Willow

    1985-01-01

    Presents an 11-lesson mini unit overview on wild and domestic pets. Lessons contain teacher preparation information and student activities. Skills, discipline orientation, and the humane concept associated with each lesson are also outlined. (ML)

  12. PET studies in epilepsy.

    PubMed

    Sarikaya, Ismet

    2015-01-01

    Various PET studies, such as measurements of glucose, serotonin and oxygen metabolism, cerebral blood flow and receptor bindings are availabe for epilepsy. (18)Fluoro-2-deoxyglucose ((18)F-FDG) PET imaging of brain glucose metabolism is a well established and widely available technique. Studies have demonstrated that the sensitivity of interictal FDG-PET is higher than interictal SPECT and similar to ictal SPECT for the lateralization and localization of epileptogenic foci in presurgical patients refractory to medical treatments who have noncontributory EEG and MRI. In addition to localizing epileptogenic focus, FDG-PET provide additional important information on the functional status of the rest of the brain. The main limitation of interictal FDG-PET is that it cannot precisely define the surgical margin as the area of hypometabolism usually extends beyond the epileptogenic zone. Various neurotransmitters (GABA, glutamate, opiates, serotonin, dopamine, acethylcholine, and adenosine) and receptor subtypes are involved in epilepsy. PET receptor imaging studies performed in limited centers help to understand the role of neurotransmitters in epileptogenesis, identify epileptic foci and investigate new treatment approaches. PET receptor imaging studies have demonstrated reduced (11)C-flumazenil (GABAA-cBDZ) and (18)F-MPPF (5-HT1A serotonin) and increased (11)C-cerfentanil (mu opiate) and (11)C-MeNTI (delta opiate) bindings in the area of seizure. (11)C-flumazenil has been reported to be more sensitive than FDG-PET for identifying epileptic foci. The area of abnormality on GABAAcBDZ and opiate receptor images is usually smaller and more circumscribed than the area of hypometabolism on FDG images. Studies have demonstrated that (11)C-alpha-methyl-L-tryptophan PET (to study synthesis of serotonin) can detect the epileptic focus within malformations of cortical development and helps in differentiating epileptogenic from non-epileptogenic tubers in patients with tuberous

  13. PET studies in epilepsy

    PubMed Central

    Sarikaya, Ismet

    2015-01-01

    Various PET studies, such as measurements of glucose, serotonin and oxygen metabolism, cerebral blood flow and receptor bindings are availabe for epilepsy. 18Fluoro-2-deoxyglucose (18F-FDG) PET imaging of brain glucose metabolism is a well established and widely available technique. Studies have demonstrated that the sensitivity of interictal FDG-PET is higher than interictal SPECT and similar to ictal SPECT for the lateralization and localization of epileptogenic foci in presurgical patients refractory to medical treatments who have noncontributory EEG and MRI. In addition to localizing epileptogenic focus, FDG-PET provide additional important information on the functional status of the rest of the brain. The main limitation of interictal FDG-PET is that it cannot precisely define the surgical margin as the area of hypometabolism usually extends beyond the epileptogenic zone. Various neurotransmitters (GABA, glutamate, opiates, serotonin, dopamine, acethylcholine, and adenosine) and receptor subtypes are involved in epilepsy. PET receptor imaging studies performed in limited centers help to understand the role of neurotransmitters in epileptogenesis, identify epileptic foci and investigate new treatment approaches. PET receptor imaging studies have demonstrated reduced 11C-flumazenil (GABAA-cBDZ) and 18F-MPPF (5-HT1A serotonin) and increased 11C-cerfentanil (mu opiate) and 11C-MeNTI (delta opiate) bindings in the area of seizure. 11C-flumazenil has been reported to be more sensitive than FDG-PET for identifying epileptic foci. The area of abnormality on GABAAcBDZ and opiate receptor images is usually smaller and more circumscribed than the area of hypometabolism on FDG images. Studies have demonstrated that 11C-alpha-methyl-L-tryptophan PET (to study synthesis of serotonin) can detect the epileptic focus within malformations of cortical development and helps in differentiating epileptogenic from non-epileptogenic tubers in patients with tuberous sclerosis complex

  14. Parasites, pets, and people.

    PubMed

    Marx, M B

    1991-03-01

    It is important for the family physician to understand that patients' relationships with their pets play an important role in helping maintain mental and physical health yet provide the potential for causing illness in the patient. Toxocara canis (dog roundworm) and Toxocara cati (cat roundworm) are the ascarids most commonly responsible for VLM and ocular larva migrans in humans. These roundworms live in their adult stage in the small intestine of the dog and cat where their eggs are passed in the feces. The eggs containing the infective larva are very sticky, thus an infant crawling around on the floor can easily pick these up on fingers that almost invariably end up in the mouth. Infections are usually mild and asymptomatic but with a persistent eosinophilia. Ocular larva migrans is the form usually occurring in older children and adults. Some public health veterinarians recommend that a puppy or kitten should not be obtained as a companion for a child who is not old enough to read, thus bypassing the crawling and toddler stages. Hookworm eggs, shed in the feces of infected dogs or cats, develop into the infective second stage within a week. Humans are usually infected when bare areas of skin such as bare feet or the torso come in contact with soil contaminated with the larvae. The second-stage larvae are able to penetrate the intact skin of humans and the foot pads of dogs and cats. In the United States, the common dog hookworm, A. caninum, is a widespread parasite. Human intestinal ancylostomiasis caused by this species is rare, with only six cases recorded in the literature. Infection in humans or animals by the common tapeworm of dogs and cats (Dipylidium caninum) requires ingestion of the intermediate host, the dog or cat flea containing the larva (cysticercoids) of the agent. Many cases in humans are asymptomatic. Dipylidiasis affects mainly infants and young children who may swallow a flea that hops up while the infant is crawling on the floor or fondling

  15. Non-small-cell lung cancer resectability: diagnostic value of PET/MR.

    PubMed

    Fraioli, Francesco; Screaton, Nicholas J; Janes, Samuel M; Win, Thida; Menezes, Leon; Kayani, Irfan; Syed, Rizwan; Zaccagna, Fulvio; O'Meara, Celia; Barnes, Anna; Bomanji, Jamshed B; Punwani, Shonit; Groves, Ashley M

    2015-01-01

    To assess the diagnostic performance of PET/MR in patients with non-small-cell lung cancer. Fifty consecutive consenting patients who underwent routine (18)F-FDG PET/CT for potentially radically treatable lung cancer following a staging CT scan were recruited for PET/MR imaging on the same day. Two experienced readers, unaware of the results with the other modalities, interpreted the PET/MR images independently. Discordances were resolved in consensus. PET/MR TNM staging was compared to surgical staging from thoracotomy as the reference standard in 33 patients. In the remaining 17 nonsurgical patients, TNM was determined based on histology from biopsy, imaging results (CT and PET/CT) and follow-up. ROC curve analysis was used to assess accuracy, sensitivity and specificity of the PET/MR in assessing the surgical resectability of primary tumour. The kappa statistic was used to assess interobserver agreement in the PET/MR TNM staging. Two different readers, without knowledge of the PET/MR findings, subsequently separately reviewed the PET/CT images for TNM staging. The generalized kappa statistic was used to determine intermodality agreement between PET/CT and PET/MR for TNM staging. ROC curve analysis showed that PET/MR had a specificity of 92.3 % and a sensitivity of 97.3 % in the determination of resectability with an AUC of 0.95. Interobserver agreement in PET/MR reading ranged from substantial to perfect between the two readers (Cohen's kappa 0.646 - 1) for T stage, N stage and M stage. Intermodality agreement between PET/CT and PET/MR ranged from substantial to almost perfect for T stage, N stage and M stage (Cohen's kappa 0.627 - 0.823). In lung cancer patients PET/MR appears to be a robust technique for preoperative staging.

  16. 18F-FDG PET and PET/CT in fever of unknown origin.

    PubMed

    Meller, Johannes; Sahlmann, Carsten-Oliver; Scheel, Alexander Konrad

    2007-01-01

    Fever of unknown origin (FUO) was originally defined as recurrent fever of 38.3 degrees C or higher, lasting 2-3 wk or longer, and undiagnosed after 1 wk of hospital evaluation. The last criterion has undergone modification and is now generally interpreted as no diagnosis after appropriate inpatient or outpatient evaluation. The 3 major categories that account for most FUOs are infections, malignancies, and noninfectious inflammatory diseases. The diagnostic approach in FUO includes repeated physical investigations and thorough history-taking combined with standardized laboratory tests and simple imaging procedures. Nevertheless, there is a need for more complex or invasive techniques if this strategy fails. This review describes the impact of (18)F-FDG PET in the diagnostic work-up of FUO. (18)F-FDG accumulates in malignant tissues but also at the sites of infection and inflammation and in autoimmune and granulomatous diseases by the overexpression of distinct facultative glucose transporter (GLUT) isotypes (mainly GLUT-1 and GLUT-3) and by an overproduction of glycolytic enzymes in cancer cells and inflammatory cells. The limited data of prospective studies indicate that (18)F-FDG PET has the potential to play a central role as a second-line procedure in the management of patients with FUO. In these studies, the PET scan contributed to the final diagnosis in 25%-69% of the patients. In the category of infectious diseases, a diagnosis of focal abdominal, thoracic, or soft-tissue infection, as well as chronic osteomyelitis, can be made with a high degree of certainty. Negative findings on (18)F-FDG PET essentially rule out orthopedic prosthetic infections. In patients with noninfectious inflammatory diseases, (18)F-FDG PET is of importance in the diagnosis of large-vessel vasculitis and seems to be useful in the visualization of other diseases, such as inflammatory bowel disease, sarcoidosis, and painless subacute thyroiditis. In patients with tumor fever, diseases

  17. Valproic Acid Upregulates NKG2D Ligand Expression through an ERK-dependent Mechanism and Potentially Enhances NK Cell-mediated Lysis of Myeloma1

    PubMed Central

    Wu, Xiaosong; Tao, Yi; Hou, Jun; Meng, Xiuqin; Shi, Jumei

    2012-01-01

    Modulation of the antitumor immune response through the engagement of NKG2D receptors with their ligands (L) on targets represents a promising therapeutic approach against cancer. In this study, we tested the effect of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, on the expression of NKG2D ligands in myeloma cells. We demonstrated that VPA was able to upregulate both protein and mRNA expression of major histocompatibility complex class I-related chain (MIC) A/B and UL16-binding protein (ULBP) 2 without any significant effect on the expression of ULBP1, ULBP3, and ULBP4 or induction of other natural killer (NK) cell ligands, such as NKp30-L, NKp44-L, and NKp46-L in myeloma cells. A 51Cr release assay and degranulation assay indicated that the induction of MICA/B and ULBP2 augmented NK cell-mediated lysis of myeloma cells, which was abolished by the addition of a blocking NKG2D antibody. Activation of constitutively phosphorylated extracellular signal-regulated kinase (ERK) by VPA is essential for the up-regulation of MICA/B and ULBP2 expressions. Inhibition of ERK using ERK inhibitor PD98059 decreased both MICA/B and ULBP2 expressions and NK cell cytotoxicity. Furthermore, overexpression of constitutively active ERK in ARK resulted in increased MICA/B and ULBP2 expressions and enhanced NK cell lysis. These data indicate that increased sensitivity of VPA-treated myeloma cells to NK cell lysis is caused by higher NKG2D ligand expression, resulting from more active ERK signaling pathway. Our results provide evidence that targeting ERK signaling pathway may be an additional mechanism supporting the antimyeloma activity of HDAC inhibitors and suggest its possible immunotherapeutic value for myeloma treatment. PMID:23308050

  18. Software-based PET-MR image coregistration: combined PET-MRI for the rest of us!

    PubMed

    Robertson, Matthew S; Liu, Xinyang; Plishker, William; Zaki, George F; Vyas, Pranav K; Safdar, Nabile M; Shekhar, Raj

    2016-10-01

    presented a software-based solution that achieves the many benefits of hybrid PET/MRI scanners without actually needing one. The method proved to be accurate and potentially clinically useful.

  19. Simultaneous Multiparametric PET/MRI with Silicon Photomultiplier PET and Ultra-High-Field MRI for Small-Animal Imaging.

    PubMed

    Ko, Guen Bae; Yoon, Hyun Suk; Kim, Kyeong Yun; Lee, Min Sun; Yang, Bo Yeun; Jeong, Jae Min; Lee, Dong Soo; Song, In Chan; Kim, Seok-Ki; Kim, Daehong; Lee, Jae Sung

    2016-08-01

    Visualization of biologic processes at molecular and cellular levels has revolutionized the understanding and treatment of human diseases. However, no single biomedical imaging modality provides complete information, resulting in the emergence of multimodal approaches. Combining state-of-the-art PET and MRI technologies without loss of system performance and overall image quality can provide opportunities for new scientific and clinical innovations. Here, we present a multiparametric PET/MR imager based on a small-animal dedicated, high-performance, silicon photomultiplier (SiPM) PET system and a 7-T MR scanner. A SiPM-based PET insert that has the peak sensitivity of 3.4% and center volumetric resolution of 1.92/0.53 mm(3) (filtered backprojection/ordered-subset expectation maximization) was developed. The SiPM PET insert was placed between the mouse body transceiver coil and gradient coil of a 7-T small-animal MRI scanner for simultaneous PET/MRI. Mutual interference between the MRI and SiPM PET systems was evaluated using various MR pulse sequences. A cylindric corn oil phantom was scanned to assess the effects of the SiPM PET on the MR image acquisition. To assess the influence of MRI on the PET imaging functions, several PET performance indicators including scintillation pulse shape, flood image quality, energy spectrum, counting rate, and phantom image quality were evaluated with and without the application of MR pulse sequences. Simultaneous mouse PET/MRI studies were also performed to demonstrate the potential and usefulness of the multiparametric PET/MRI in preclinical applications. Excellent performance and stability of the PET system were demonstrated, and the PET/MRI combination did not result in significant image quality degradation of either modality. Finally, simultaneous PET/MRI studies in mice d