A Fully-automated One-pot Synthesis of [18F]Fluoromethylcholine with Reduced Dimethylaminoethanol Contamination via [18F]Fluoromethyl Tosylate

PubMed Central

Rodnick, Melissa E.; Brooks, Allen F.; Hockley, Brian G.; Henderson, Bradford D.; Scott, Peter J. H.

2013-01-01

Introduction A novel one-pot method for preparing [18F]fluoromethylcholine ([18F]FCH) via in situ generation of [18F]fluoromethyl tosylate ([18F]FCH2OTs), and subsequent [18F]fluoromethylation of dimethylaminoethanol (DMAE), has been developed. Methods [18F]FCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-18 synthesis module. Initially ditosylmethane was fluorinated to generate [18F]FCH2OTs. DMAE was then added and the reaction was heated at 120°C for 10 min to generate [18F]FCH. After this time, reaction solvent was evaporated, and the crude reaction mixture was purified by solid-phase extraction using C18-Plus and CM-Light Sep-Pak cartridges to provide [18F]FCH formulated in USP saline. The formulated product was passed through a 0.22 μm filter into a sterile dose vial, and submitted for quality control testing. Total synthesis time was 1.25 hours from end-of-bombardment. Results Typical non-decay-corrected yields of [18F]FCH prepared using this method were 91 mCi (7% non-decay corrected based upon ~1.3 Ci [18F]fluoride), and doses passed all other quality control (QC) tests. Conclusion A one-pot liquid-phase synthesis of [18F]FCH has been developed. Doses contain extremely low levels of residual DMAE (31.6 μg / 10 mL dose or ~3 ppm) and passed all other requisite QC testing, confirming their suitability for use in clinical imaging studies. PMID:23665261

Safety, pharmacokinetics, metabolism and radiation dosimetry of 18F-tetrafluoroborate (18F-TFB) in healthy human subjects.

PubMed

Jiang, Huailei; Schmit, Nicholas R; Koenen, Alex R; Bansal, Aditya; Pandey, Mukesh K; Glynn, Robert B; Kemp, Bradley J; Delaney, Kera L; Dispenzieri, Angela; Bakkum-Gamez, Jamie N; Peng, Kah-Whye; Russell, Stephen J; Gunderson, Tina M; Lowe, Val J; DeGrado, Timothy R

2017-10-27

18 F-Tetrafluoroborate ( 18 F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18 F-TFB in healthy human subjects. 18 F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18 F-TFB (333-407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety. 18 F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18 F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18 F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18 F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18 F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant). This initial study in healthy human subjects showed 18 F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18 F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.

A Transmetalation Reaction Enables the Synthesis of [ 18F]5-Fluorouracil from [ 18F]Fluoride for Human PET Imaging

DOE PAGES

Hoover, Andrew J.; Lazari, Mark; Ren, Hong; ...

2016-02-14

Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [ 18F]fluoride of human doses of [ 18F]5-fluorouracil, a PET tracer for cancer imaging in humans. Here, the firstmore » preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [ 18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [ 18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [ 18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination.« less

A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging

PubMed Central

2016-01-01

Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination. PMID:27087736

A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging.

PubMed

Hoover, Andrew J; Lazari, Mark; Ren, Hong; Narayanam, Maruthi Kumar; Murphy, Jennifer M; van Dam, R Michael; Hooker, Jacob M; Ritter, Tobias

2016-04-11

Translation of new 18 F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18 F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18 F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [ 18 F]fluoride of human doses of [ 18 F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [ 18 F]5-fluorouracil precursor. Routine production of >10 mCi doses of [ 18 F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [ 18 F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18 F-fluorination.

A Transmetalation Reaction Enables the Synthesis of [ 18F]5-Fluorouracil from [ 18F]Fluoride for Human PET Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoover, Andrew J.; Lazari, Mark; Ren, Hong

Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [ 18F]fluoride of human doses of [ 18F]5-fluorouracil, a PET tracer for cancer imaging in humans. Here, the firstmore » preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [ 18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [ 18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [ 18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination.« less

TMSOTf assisted synthesis of 2'-deoxy-2'-[18F]fluoro-β-D-arabinofuranosylcytosine ([18F]FAC).

PubMed

Gangangari, Kishore K; Humm, John L; Larson, Steven M; Pillarsetty, Naga Vara Kishore

2018-01-01

[18F]FAC (2'-deoxy-2'-[18F]fluoro-β-D-arabinofuranosylcytosine, 1) is a versatile probe for imaging deoxycytidine kinase (dCK) expression levels in vivo. dCK is responsible for phosphorylation of deoxycytidine (dC, 2) and other nucleoside analogs, plays a key role in immune activation and has demonstrated to be one of the key enzymes in activating nucleoside based drugs including gemcitabine. Reported synthesis of [18F]FAC is high yielding but is quite challenging requiring bromination using HBr and careful drying of excess HBr which is critical for successful synthesis. Here in we report a simplified trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted synthesis of [18F]FAC eliminating the need of bromination and drying. [18F]FAC (β-anomer) was synthesized with average isolated decay corrected yield of 10.59 + 4.2% (n = 6) with radiochemical purity of >98% and total synthesis time of 158 + 19 min.

Thoracic staging in lung cancer: prospective comparison of 18F-FDG PET/MR imaging and 18F-FDG PET/CT.

PubMed

Heusch, Philipp; Buchbender, Christian; Köhler, Jens; Nensa, Felix; Gauler, Thomas; Gomez, Benedikt; Reis, Henning; Stamatis, Georgios; Kühl, Hilmar; Hartung, Verena; Heusner, Till A

2014-03-01

Therapeutic decisions in non-small cell lung cancer (NSCLC) patients depend on the tumor stage. PET/CT with (18)F-FDG is widely accepted as the diagnostic standard of care. The purpose of this study was to compare a dedicated pulmonary (18)F-FDG PET/MR imaging protocol with (18)F-FDG PET/CT for primary and locoregional lymph node staging in NSCLC patients using histopathology as the reference. Twenty-two patients (12 men, 10 women; mean age ± SD, 65.1 ± 9.1 y) with histopathologically confirmed NSCLC underwent (18)F-FDG PET/CT, followed by (18)F-FDG PET/MR imaging, including a dedicated pulmonary MR imaging protocol. T and N staging according to the seventh edition of the American Joint Committee on Cancer staging manual was performed by 2 readers in separate sessions for (18)F-FDG PET/CT and PET/MR imaging, respectively. Results from histopathology were used as the standard of reference. The mean and maximum standardized uptake value (SUV(mean) and SUV(max), respectively) and maximum diameter of the primary tumor was measured and compared in (18)F-FDG PET/CT and PET/MR imaging. PET/MR imaging and (18)F-FDG PET/CT agreed on T stages in 16 of 16 of patients (100%). All patients were correctly staged by (18)F-FDG PET/CT and PET/MR (100%), compared with histopathology. There was no statistically significant difference between (18)F-FDG PET/CT and (18)F-FDG PET/MR imaging for lymph node metastases detection (P = 0.48). For definition of thoracic N stages, PET/MR imaging and (18)F-FDG PET/CT were concordant in 20 of 22 patients (91%). PET/MR imaging determined the N stage correctly in 20 of 22 patients (91%). (18)F-FDG PET/CT determined the N stage correctly in 18 of 22 patients (82%). The mean differences for SUV(mean) and SUV(max) of NSCLC in (18)F-FDG PET/MR imaging and (18)F-FDG PET/CT were 0.21 and -5.06. These differences were not statistically significant (P > 0.05). The SUV(mean) and SUV(max) measurements derived from (18)F-FDG PET/CT and (18)F-FDG PET

Fully automated synthesis of [(18) F]fluoro-dihydrotestosterone ([(18) F]FDHT) using the FlexLab module.

PubMed

Ackermann, Uwe; Lewis, Jason S; Young, Kenneth; Morris, Michael J; Weickhardt, Andrew; Davis, Ian D; Scott, Andrew M

2016-08-01

Imaging of androgen receptor expression in prostate cancer using F-18 FDHT is becoming increasingly popular. With the radiolabelling precursor now commercially available, developing a fully automated synthesis of [(18) F] FDHT is important. We have fully automated the synthesis of F-18 FDHT using the iPhase FlexLab module using only commercially available components. Total synthesis time was 90 min, radiochemical yields were 25-33% (n = 11). Radiochemical purity of the final formulation was > 99% and specific activity was > 18.5 GBq/µmol for all batches. This method can be up-scaled as desired, thus making it possible to study multiple patients in a day. Furthermore, our procedure uses 4 mg of precursor only and is therefore cost-effective. The synthesis has now been validated at Austin Health and is currently used for [(18) F]FDHT studies in patients. We believe that this method can easily adapted by other modules to further widen the availability of [(18) F]FDHT. Copyright © 2016 John Wiley & Sons, Ltd.

The role of 18F-FDOPA and 18F-FDG-PET in the management of malignant and multifocal phaeochromocytomas.

PubMed

Taïeb, D; Tessonnier, L; Sebag, F; Niccoli-Sire, P; Morange, I; Colavolpe, C; De Micco, C; Barlier, A; Palazzo, F F; Henry, J F; Mundler, O

2008-10-01

(18)F-DOPA has emerged as a promising tool in the localization of chromaffin-tissue-derived tumours. Interestingly, phaeochromocytomas (PHEO) are also FDG avid. The aim of this study was to retrospectively evaluate the results of (18)F-FDOPA and/or (18)F-FDG-PET in patients with PHEO and paragangliomas (PGLs) and to compare the outcome of this approach with the traditional therapeutic work-up. Nine patients with non-MEN2 related PHEO or PGL were evaluated. At the time of the PET studies, the patients were classified into three groups based on their clinical history, conventional and SPECT imaging. The groups were malignant disease (n = 5, 1 VHL), apparently unique tumour site in patients with previous surgery (n = 1, SDHB) and multifocal tumours (n = 3, 1 VHL, 1 SDHD). (18)F-FDOPA and (18)F-FDG-PET PET/CT were then performed in all patients. PET successfully identified additional tumour sites in five out of five patients with metastatic disease that had not been identified with SPECT + CI. Whilst tumour tracer uptake varied between patients it exhibited a consistently favourable residence time for delayed acquisitions. (18)F-FDOPA uptake (SUVmax) was superior to (18)F-FDG uptake in cases of neck PGL (three patients, four tumours). If only metastatic forms and abdominal PGLs were considered, (18)F-FDG provided additional information in three cases (two metastatic forms, one multifocal disease with SDHD mutation) compared to (18)F-FDOPA. Our results suggest that tumour staging can be improved by combining (18)F-FDOPA and (18)F-FDG in the preoperative work-up of patients with abdominal and malignant PHEOs. (18)F-FDOPA is also an effective localization tool for neck PGLs. MIBG however, still has a role in these patients as MIBG and FDOPA images did not completely overlap.

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke

PubMed Central

Jenkins, William S. A.; Irkle, Agnese; Moss, Alastair; Sng, Greg; Forsythe, Rachael O.; Clark, Tim; Roberts, Gemma; Fletcher, Alison; Lucatelli, Christophe; Rudd, James H. F.; Davenport, Anthony P.; Mills, Nicholas L.; Al-Shahi Salman, Rustam; Dennis, Martin; Whiteley, William N.; van Beek, Edwin J. R.; Dweck, Marc R.; Newby, David E.

2017-01-01

Background— Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods and Results— We performed 18F-fluoride and 18F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, 18F-fluoride selectively highlighted microcalcification. Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log10standardized uptake valuemean 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log10standardized uptake valuemean 0.29±0.10 versus 0.12±0.11, P=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid 18F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, 18F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. Conclusions— 18F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque

WE-H-207A-05: Spatial Co-Localization of F-18 NaF Vs. F-18 FDG Defined Disease Volumes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferjancic, P; Harmon, S; Jeraj, R

Purpose: Both [F-18]NaF and [F-18]FDG show promise for quantitative PET/CT assessment in metastatic prostate cancer to bone. Broad agreement between the tracers has been shown but voxel-wise correspondence has not been explored in depth. This study evaluates the spatial co-localization of [F-18]NaF PET and [F-18]FDG PET in bone lesions. Methods: Seventy-three lesion contours were identified in six patients receiving dynamic NaF PET/CT and FDG PET/CT scans two hours apart using identical fields-of-view. Tracer uptake (SUV) reflecting 60 minutes post-injection was modeled from kinetic parameters. Lesions were segmented by a physician separately on NaF PET and FDG PET. PET images weremore » rigidly aligned using skeletal references on CT images. Lesion size, degree of overlap, voxel-wise tracer uptake values (SUV), and CT density distributions were compared using Dice coefficient, Positive Predictive Value (PPV), and Spearman rank correlation tests. Results: Across all patients, 42 lesions were identified on NaF PET (median 1.4 cm{sup 3}, range <1–204 cm{sup 3}) compared to 31 using FDG PET (median 1.8 cm{sup 3}, range <1–244 cm{sup 3}). Spatial cooccurrence was found in 25 lesion pairs. Lesions on NaF PET had PPV of 0.91 and on FDG a PPV of 0.65. Overall, NaF-defined lesions were 47% (±24%) larger by volume with moderate overlap to FDG, resulting in mean Dice coefficient of 34% (±22%). In areas of overlap, voxel-wise correlation of NaF and FDG SUV was moderate (ρ=0.56). Expanding to regions of non-spatial overlap, voxels contained in FDG-only contours were almost exclusively low HU (median 118), compared to dense regions of NaF-only voxels (median 250). In sclerotic sub-volumes (HU > 300) NaF-defined contours encompassed 83% of total FDG volume. Conclusion: Moderate voxel-wise correlation of FDG and NaF PET/CT uptake was observed. Spatial discrepancies in FDG and NaF PET/CT imaging of boney metastases could be influenced by poor sensitivity of FDG PET/CT in

Imaging melphalan therapy response in preclinical extramedullary myeloma with 18F-FDOPA and 18F-FDG PET.

PubMed

Hathi, Deep; DeLassus, Elizabeth; Achilefu, Samuel; McConathy, Jonathan; Shokeen, Monica

2018-04-26

Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B-cells that has resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small molecule DNA alkylating agent, are commonly prescribed to patients with relapsed/refractory MM, which necessitates the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 18 F-FDOPA, a clinically available positron emission tomography (PET) radiotracer with specificity to the L-type amino acid transporter-1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57Bl/KaLwRij mice were implanted subcutaneously with unilateral murine 5TGM1-GFP tumors, and divided into three independent groups: untreated, treated beginning week 2, and treated beginning week 3 post tumor implantation. The untreated and week 2 therapy cohorts were imaged with preclinical magnetic resonance imaging (MRI) and dynamic 18 F-FDG and 18 F-FDOPA-PET/computed tomography (PET/CT) at week 4 on separate, contiguous days, while the week 3 therapy cohort was longitudinally imaged weekly for 2 weeks. Metabolic tumor volume, lesion avidity, maximum standard uptake value, and total uptake metrics were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter-1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake metrics for both 18 F-FDG and 18 F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density was increased in the week 2 therapy cohort. Longitudinal imaging of the week 3 group showed variable changes in 18 F-FDG and 18 F-FDOPA uptake, with increase in 18 F-FDOPA lesion avidity in the 2nd week relative to baseline. LAT1 and GLUT1 surface density in the untreated tumor and week 3

(18)F-alfatide II and (18)F-FDG dual-tracer dynamic PET for parametric, early prediction of tumor response to therapy.

PubMed

Guo, Jinxia; Guo, Ning; Lang, Lixin; Kiesewetter, Dale O; Xie, Qingguo; Li, Quanzheng; Eden, Henry S; Niu, Gang; Chen, Xiaoyuan

2014-01-01

A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor's status under quasiconstant conditions. This study aimed to investigate the utility of dual-tracer dynamic PET imaging with (18)F-alfatide II ((18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2) and (18)F-FDG for parametric monitoring of tumor responses to therapy. We administered doxorubicin to one group of athymic nude mice with U87MG tumors and paclitaxel protein-bound particles to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting with injection via the tail vein catheters with (18)F-alfatide II, followed 40 min later by (18)F-FDG. To achieve signal separation of the 2 tracers, we fit a 3-compartment reversible model to the time-activity curve of (18)F-alfatide II for the 40 min before (18)F-FDG injection and then extrapolated to 90 min. The (18)F-FDG tumor time-activity curve was isolated from the 90-min dual-tracer tumor time-activity curve by subtracting the fitted (18)F-alfatide II tumor time-activity curve. With separated tumor time-activity curves, the (18)F-alfatide II binding potential (Bp = k3/k4) and volume of distribution (VD) and (18)F-FDG influx rate ((K1 × k3)/(k2 + k3)) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single-tracer imaging and to monitor therapeutic response. The transport and binding rate parameters K1-k3 of (18)F-alfatide II, calculated from the first 40 min of the dual-tracer dynamic scan, as well as Bp and VD correlated well with the parameters from the 60-min single-tracer scan (R(2) > 0.95). Compared with the results of single-tracer PET imaging, (18)F-FDG tumor uptake and influx were recovered well from dual-tracer imaging. On doxorubicin treatment, whereas no significant changes in static tracer uptake values of (18)F-alfatide II

Comparison of three dimeric 18F-AlF-NOTA-RGD tracers.

PubMed

Guo, Jinxia; Lang, Lixin; Hu, Shuo; Guo, Ning; Zhu, Lei; Sun, Zhongchan; Ma, Ying; Kiesewetter, Dale O; Niu, Gang; Xie, Qingguo; Chen, Xiaoyuan

2014-04-01

RGD peptide-based radiotracers are well established as integrin αvβ3 imaging probes to evaluate tumor angiogenesis or tissue remodeling after ischemia or infarction. In order to optimize the labeling process and pharmacokinetics of the imaging probes, we synthesized three dimeric RGD peptides with or without PEGylation and performed in vivo screening. Radiolabeling was achieved through the reaction of F-18 aluminum-fluoride complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Three imaging probes were synthesized as (18)F-AlF-NOTA-E[c(RGDfK)]2, (18)F-AlF-NOTA-PEG4-E[c(RGDfK)]2, and (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2. The receptor binding affinity was determined by competitive cell binding assay, and the stability was evaluated by mouse serum incubation. Tumor uptake and whole body distribution of the three tracers were compared through direct tissue sampling and PET quantification of U87MG tumor-bearing mice. All three compounds remained intact after 120 min incubation with mouse serum. They all had a rapid and relatively high tracer uptake in U87MG tumors with good target-to-background ratios. Compared with the other two tracers, (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2 had the highest tumor uptake and the lowest accumulation in the liver. The integrin receptor specificity was confirmed by co-injection of unlabeled dimeric RGD peptide. The rapid one-step radiolabeling strategy by the complexation of (18)F-aluminum fluoride with NOTA-peptide conjugates was successfully applied to synthesize three dimeric RGD peptides. Among the three probes developed, (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2 with relatively low liver uptake and high tumor accumulation appears to be a promising candidate for further translational research.

18F-Alfatide II and 18F-FDG Dual Tracer Dynamic PET for Parametric, Early Prediction of Tumor Response to Therapy

PubMed Central

Guo, Jinxia; Guo, Ning; Lang, Lixin; Kiesewetter, Dale O.; Xie, Qingguo; Li, Quanzheng; Eden, Henry S.; Niu, Gang; Chen, Xiaoyuan

2014-01-01

A single dynamic PET acquisition using multiple tracers administered closely in time could provide valuable complementary information about a tumor’s status under quasi-constant conditions. This study aims to investigate the utility of dual-tracer dynamic PET imaging with 18F-Alfatide II (18F-AlF-NOTA-E[PEG4-c(RGDfk)]2) and 18F-FDG for parametric monitoring of tumor responses to therapy. Methods We administered doxorubicin to one group of athymic nude mice with U87MG tumors and Abraxane to another group of mice with MDA-MB-435 tumors. To monitor therapeutic responses, we performed dual-tracer dynamic imaging, in sessions that lasted 90 min, starting by injecting the mice via tail vein catheters with 18F-Alfatide II, followed 40 minutes later by 18F-FDG. To achieve signal separation of the two tracers, we fit a three-compartment reversible model to the time activity curve (TAC) of 18F-Alfatide II for the 40 min prior to 18F-FDG injection, and then extrapolated to 90 min. The 18F-FDG tumor TAC was isolated from the 90 min dual tracer tumor TAC by subtracting the fitted 18F-Alfatide II tumor TAC. With separated tumor TACs, the 18F-Alfatide II binding potential (Bp=k3/k4) and volume of distribution (VD), and 18F-FDG influx rate ((K1×k3)/(k2 + k3)) based on the Patlak method were calculated to validate the signal recovery in a comparison with 60-min single tracer imaging and to monitor therapeutic response. Results The transport and binding rate parameters K1-k3 of 18F-Alfatide II, calculated from the first 40 min of dual tracer dynamic scan, as well as Bp and VD, correlated well with the parameters from the 60 min single tracer scan (R2 > 0.95). Compared with the results of single tracer PET imaging, FDG tumor uptake and influx were recovered well from dual tracer imaging. Upon doxorubicin treatment, while no significant changes in static tracer uptake values of 18F-Alfatide II or 18F-FDG were observed, both 18F-Alfatide II Bp and 18F-FDG influx from kinetic

Magnetic Droplet Microfluidics as a Platform for the Concentration of [18F]Fluoride and Radiosynthesis of Sulfonyl [18F]Fluoride.

PubMed

Fiel, Somewhere A; Yang, Hua; Schaffer, Paul; Weng, Samuel; Inkster, James A H; Wong, Michael C K; Li, Paul C H

2015-06-17

The radioisotope 18F is often considered the best choice for positron emission tomography (PET) owing to its desirable chemical and radiochemical properties. However, nucleophilic 18F-fluorination of large, water-soluble biomolecules, based on C-F bond formation, has traditionally been difficult. Thus, several aqueous fluorination approaches that offer significant versatility in radiopharmaceutical synthesis with sensitive targeting vectors have been developed. Furthermore, because 18F decays rapidly, production of these 18F-labeled compounds requires an automated process to reduce production time, reduce radiation exposure, and minimize losses due to the transfer of reagents during tracer synthesis. Herein, we report the use of magnetic droplet microfluidics (MDM) as a means to concentrate [18F]fluoride from the cyclotron target solution, followed by the synthesis of an 18F-labeled compound on a microfluidic platform. Using this method, we have demonstrated 18F preconcentration in a small-volume droplet through the use of anion exchanging magnetic particles. By using MDM, the preconcentration step took approximately 5 min, and the [18F]fluoride solution was preconcentrated by 15-fold. After the preconcentration step, an 18F-labeling reaction was performed on the MDM platform using the S-F bond formation in aqueous conditions to produce an arylsulfonyl [18F]fluoride compound which can be used as a prosthetic group to label PET targeting ligands. The high radiochemical purity of 95±1% was comparable to the 96% previously reported using a conventional method. In addition, when MDM was used, the total synthesis time was improved to 15 min with lower reagent volumes (50-60 μL) used.

Automated PET Radiotracer Manufacture on the BG75 System and Imaging Validation Studies of [18F]fluoromisonidazole ([18F]FMISO).

PubMed

Yuan, Hong; Frank, Jonathan E; Merrill, Joseph R; Hillesheim, Daniel A; Khachaturian, Mark H; Anzellotti, Atilio I

2016-01-01

The hypoxia PET tracer, 1-[18F]fluoro-3-(2-nitro-1Himidazol- 1-yl)-propan-2-ol ([18F]FMISO) is the first radiotracer developed for hypoxia PET imaging and has shown promising for cancer diagnosis and prognosis. However, access to [18F]FMISO radiotracer is limited due to the needed cyclotron and radiochemistry expertise. The study aimed to develop the automated production method on the [18F]FMISO radiotracer with the novel fully automated platform of the BG75 system and validate its usage on animal tumor models. [18F]FMISO was produced with the dose synthesis cartridge automatically on the BG75 system. Validation of [18F]FMISO hypoxia imaging functionality was conducted on two tumor mouse models (FaDu/U87 tumor). The distribution of [18F]FMISO within tumor was further validated by the standard hypoxia marker EF5. The average radiochemical purity was (99±1) % and the average pH was 5.5±0.2 with other quality attributes passing standard criteria (n=12). Overall biodistribution for [18F]FMISO in both tumor models was consistent with reported studies where bladder and large intestines presented highest activity at 90 min post injection. High spatial correlation was found between [18F]FMISO autoradiography and EF5 hypoxia staining, indicating high hypoxia specificity of [18MF]FMISO. This study shows that qualified [18F]FMISO can be efficiently produced on the BG75 system in an automated "dose-on-demand" mode using single dose disposable cards. The possibilities of having a low-cost, automated system manufacturing ([18F]Fluoride production + synthesis + QC) different radiotracers will greatly enhance the potential for PET technology to reach new geographical areas and underserved patient populations. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Association Between Osteogenesis and Inflammation During the Progression of Calcified Plaque Evaluated by 18F-Fluoride and 18F-FDG.

PubMed

Li, Xiang; Heber, Daniel; Cal-Gonzalez, Jacobo; Karanikas, Georgios; Mayerhoefer, Marius E; Rasul, Sazan; Beitzke, Dietrich; Zhang, Xiaoli; Agis, Hermine; Mitterhauser, Markus; Wadsak, Wolfgang; Beyer, Thomas; Loewe, Christian; Hacker, Marcus

2017-06-01

18 F-FDG is the most widely validated PET tracer for the evaluation of atherosclerotic inflammation. Recently, 18 F-NaF has also been considered a potential novel biomarker of osteogenesis in atherosclerosis. We aimed to analyze the association between inflammation and osteogenesis at different stages of atherosclerosis, as well as the interrelationship between these 2 processes during disease progression. Methods: Thirty-four myeloma patients underwent 18 F-NaF and 18 F-FDG PET/CT examinations. Lesions were divided into 3 groups (noncalcified, mildly calcified, and severely calcified lesions) on the basis of calcium density as measured in Hounsfield units by CT. Tissue-to-background ratios were determined from PET for both tracers. The association between inflammation and osteogenesis during atherosclerosis progression was evaluated in 19 patients who had at least 2 examinations with both tracers. Results: There were significant correlations between the maximum tissue-to-background ratios of the 2 tracers (Spearman r = 0.5 [ P < 0.01]; Pearson r = 0.4 [ P < 0.01]) in the 221 lesions at baseline. The highest uptake of both tracers was observed in noncalcified lesions, but without any correlation between the tracers (Pearson r = 0.06; P = 0.76). Compared with noncalcified plaques, mildly calcified plaques showed concordant significantly lower accumulation, with good correlation between the tracers (Pearson r = 0.7; P < 0.01). In addition, enhanced osteogenesis-derived 18 F-NaF uptake and regressive inflammation-derived 18 F-FDG uptake were observed in severely calcified lesions (Pearson r = 0.4; P < 0.01). During follow-up, increased calcium density and increased mean 18 F-NaF uptake were observed, whereas mean 18 F-FDG uptake decreased. Most noncalcified (86%) and mildly calcified (81%) lesions and 47% of severely calcified lesions had concordant development of both vascular inflammation and osteogenesis. Conclusion: The combination of 18 F-NaF PET imaging and 18 F

Functional imaging of SDHx-related head and neck paragangliomas: comparison of 18F-fluorodihydroxyphenylalanine, 18F-fluorodopamine, 18F-fluoro-2-deoxy-D-glucose PET, 123I-metaiodobenzylguanidine scintigraphy, and 111In-pentetreotide scintigraphy.

PubMed

King, Kathryn S; Chen, Clara C; Alexopoulos, Dimitrios K; Whatley, Millie A; Reynolds, James C; Patronas, Nicholas; Ling, Alexander; Adams, Karen T; Xekouki, Paraskevi; Lando, Howard; Stratakis, Constantine A; Pacak, Karel

2011-09-01

Accurate diagnosis of head and neck paragangliomas is often complicated by biochemical silence and lack of catecholamine-associated symptoms, making accurate anatomical and functional imaging techniques essential to the diagnostic process. Ten patients (seven SDHD, three SDHB), with a total of 26 head and neck paragangliomas, were evaluated with anatomical and functional imaging. This study compares five different functional imaging techniques [(18)F-fluorodihydroxyphenylalanine ((18)F-FDOPA) positron emission tomography (PET), (18)F-fluorodopamine ((18)F-FDA) PET/computed tomography (CT), (18)F-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT, (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy, and (111)In-pentetreotide scintigraphy] in the localization of head and neck paragangliomas. Prospectively (18)F-FDOPA PET localized 26 of 26 lesions in the 10 patients, CT/magnetic resonance imaging localized 21 of 26 lesions, (18)F-FDG PET/CT localized 20 of 26 lesions, (111)In-pentetreotide scintigraphy localized 16 of 25 lesions, (18)F-FDA PET/CT localized 12 of 26 lesions, and (123)I-MIBG scintigraphy localized eight of 26 lesions. Differences in imaging efficacy related to genetic phenotype, even in the present small sample size, included the negativity of (18)F-FDA PET/CT and (123)I-MIBG scintigraphy in patients with SDHB mutations and the accuracy of (18)F-FDG PET/CT in all patients with SDHD mutations, as compared with the accuracy of (18)F-FDG PET/CT in only one patient with an SDHB mutation. Overall, (18)F-FDOPA PET proved to be the most efficacious functional imaging modality in the localization of SDHx-related head and neck paragangliomas and may be a potential first-line functional imaging agent for the localization of these tumors.

Comparative evaluation of 18F-FLT and 18F-FDG for detecting cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis.

PubMed

Norikane, Takashi; Yamamoto, Yuka; Maeda, Yukito; Noma, Takahisa; Dobashi, Hiroaki; Nishiyama, Yoshihiro

2017-08-29

18 F-FDG PET has been used in sarcoidosis for diagnosis and determination of the extent of the disease. However, assessing inflammatory lesions in cardiac sarcoidosis using 18 F-FDG can be challenging because it accumulates physiologically in normal myocardium. Another radiotracer, 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT), has been investigated as a promising PET tracer for evaluating tumor proliferative activity. In contrast to 18 F-FDG, 18 F-FLT uptake in the normal myocardium is low. The purpose of this retrospective study was to compare the uptake of 18 F-FLT and 18 F-FDG in the evaluation of cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis. Data for 20 patients with newly diagnosed sarcoidosis were examined. 18 F-FLT and 18 F-FDG PET/CT studies had been performed at 1 h after each radiotracer injection. The patients had fasted for at least 18 h before 18 F-FDG PET/CT but were given no special dietary instructions regarding the period before 18 F-FLT PET/CT. Uptake of 18 F-FLT and 18 F-FDG was examined visually and semiquantitatively using maximal standardized uptake value (SUVmax). Two patients had cardiac sarcoidosis, 7 had extra-cardiac thoracic sarcoidosis, and 11 had both cardiac and extra-cardiac thoracic sarcoidosis. On visual analysis for diagnosis of cardiac sarcoidosis, 4/20 18 F-FDG scans were rated as inconclusive because the 18 F-FDG pattern was diffuse, whereas no FLT scans were rated as inconclusive. The sensitivity of 18 F-FDG PET/CT for detection of cardiac sarcoidosis was 85%; specificity, 100%; and accuracy, 90%. The corresponding values for 18 F-FLT PET/CT were 92, 100, and 95%, respectively. Using semiquantitative analysis of cardiac sarcoidosis, the mean 18 F-FDG SUVmax was significantly higher than the mean 18 F-FLT SUVmax (P < 0.005). Both 18 F-FDG and 18 F-FLT PET/CT studies detected all 24 extra-cardiac lesions. Using semiquantitative analysis of extra-cardiac sarcoidosis, the mean 18

Relationship Between Clinicopathological Characteristics and PET/CT Uptake in Esophageal Squamous Cell Carcinoma: [18F]Alfatide versus [18F]FDG.

PubMed

Dong, Yinjun; Wei, Yuchun; Chen, Guanxuan; Huang, Yong; Song, Pingping; Liu, Shuguang; Zheng, Jinsong; Cheng, Monica; Yuan, Shuanghu

2018-06-04

To assess a novel radiotracer aluminum [ 18 F]fluoride-1,4,7-triazacyclononane-triacetic acid-pegylated dimeric RGD ([ 18 F]ALF-NOTA-PRGD 2 , denoted as [ 18 F]Alfatide) for positron emission tomography (PET)/X-ray computed tomography (CT) and explore the relationships between clinicopathological characteristics and maximum standard uptake values in primary (SUV P ) and metastatic lymph nodes (SUV LN ) of patients with esophageal squamous cell carcinoma (ESCC), as verified by pathologic examination and compared with those obtained with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]DG) PET. We prospectively enrolled patients with newly diagnosed ESCC who agreed to undergo [ 18 F]Alfatide PET/CT or [ 18 F]FDG PET/CT scans before surgery at Shandong Cancer Hospital from May 2011 to July 2017. SUVs and the pathological tumor-node-metastasis (pTNM) stages of primary tumors and metastatic lymph nodes (LNs) were measured and confirmed pathologically. Immunohistochemical (IHC) staining for integrin αvβ3 was performed on tumor samples (both primary tumors and metastatic LNs) collected from nine patients. Of 61 patients who underwent PET/CT scans, 46 then underwent curative surgery and were included in our analysis (n = 21 for [ 18 F]Alfatide PET/CT and n = 25 for [ 18 F]FDG PET/CT). No significant differences in the SUV P on [ 18 F]Alfatide PET/CT or [ 18 F]FDG PET/CT were observed among the cohorts according to gender, pathological stage, T stage, status of LNs, and differentiation (all P > 0.05). The SUV LN differed significantly between the pathological stages and status of LNs both on [ 18 F]Alfatide PET/CT (P = 0.03, 0.003) and [ 18 F]FDG PET/CT (P = 0.001. < 0.001), but not according to gender (P = 0.128, 0.129), T stage (P = 0.791, 0.727), or tumor differentiation (P = 0.049, 0.053). Significant positive correlations were observed between the SUV LN on [ 18 F]Alfatide PET/CT and [ 18 F]FDG PET/CT, and pathological stage (r = 0

Prospective study of serial 18F-FDG PET and 18F-fluoride (18F-NaF) PET to predict time to skeletal related events, time-to-progression, and survival in patients with bone-dominant metastatic breast cancer.

PubMed

Peterson, Lanell M; O'Sullivan, Janet; Wu, Qian Vicky; Novakova-Jiresova, Alena; Jenkins, Isaac; Lee, Jean H; Shields, Andrew; Montgomery, Susan; Linden, Hannah M; Gralow, Julie R; Gadi, Vijayakrishna K; Muzi, Mark; Kinahan, Paul E; Mankoff, David A; Specht, Jennifer M

2018-05-10

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18 F-FDG PET was predictive of time to skeletal related events (tSRE) and time-to-progression (TTP). 18 F-NaF PET improves bone metastasis detection compared to bone scans. We prospectively tested 18 F-FDG PET and 18 F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (BD MBC). Methods: Patients with BD MBC were imaged with 18 F-FDG PET and 18 F-NaF PET prior to starting new therapy (scan1) and again at a range of times centered around approximately 4 months later (scan2). SUV max and SULpeak were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18 F-FDG PET and 18 F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) criteria were also applied. Survival curves for mPERCIST compared response categories of Complete Response+Partial Response+Stable Disease versus Progressive Disease (CR+PR+SD vs PD) for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher FDG SULpeak at scan2 predicted shorter time to tSRE ( P = <0.001) and TTP ( P = 0.044). Higher FDG SUV max at scan2 predicted a shorter time to tSRE ( P = <0.001). A multivariable model using FDG SUV max of the index lesion at scan1 plus the difference in SUV max of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18 F-FDG PET mPERCIST, tSRE and TTP were longer in responders (CR, PR, or stable) compared to non-responders (PD) ( P = 0.007, 0.028 respectively), with a trend toward improved survival ( P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18 F-NaF PET was associated with longer OS ( P = 0.027). Conclusion: Changes in 18 F-FDG PET parameters

A novel radiochemical approach to 1-(2'-deoxy-2'-[(18) F]fluoro-β-d-arabinofuranosyl)cytosine ((18) F-FAC).

PubMed

Meyer, Jan-Philip; Probst, Katrin C; Trist, Iuni M L; McGuigan, Christopher; Westwell, Andrew D

2014-09-01

(18) F-FAC (1-(2'-deoxy-2'-[(18) F]fluoro-β-D-arabinofuranosyl)-cytosine) is an important 2'-fluoro-nucleoside-based positron emission tomography (PET) tracer that has been used for in vivo prediction of response to the widely used cancer chemotherapy drug gemcitabine. Previously reported synthetic routes to (18) F-FAC have relied on early introduction of the (18) F radiolabel prior to attachment to protected cytosine base. Considering the (18) F radiochemical half-life (110 min) and the technical challenges of multi-step syntheses on PET radiochemistry modular systems, late-stage radiofluorination is preferred for reproducible and reliable radiosynthesis with in vivo applications. Herein, we report the first late-stage radiosynthesis of (18) F-FAC. Cytidine derivatives with leaving groups at the 2'-position are particularly prone to undergo anhydro side-product formation upon heating because of their electron density at the 2-carbonyl pyrimidone oxygen. Our rationally developed fluorination precursor showed an improved reactivity-to-stability ratio at elevated temperatures. (18) F-FAC was obtained in radiochemical yields of 4.3-5.5% (n = 8, decay-corrected from end of bombardment), with purities ≥98% and specific activities ≥63 GBq/µmol. The synthesis time was 168 min. Copyright © 2014 John Wiley & Sons, Ltd.

Feasibility of myocardial PET imaging using a benzylguanidine analog: meta-(3-[18F]fluoropropyl)benzylguanidine ([18F]mFPBG).

PubMed

Woo, Sang-Keun; Moon, Byung Seok; Kim, Bom Sahn; Kim, Min Hwan; Lee, Yong Jin; Jung, Jae Ho; Lee, Kyo Chul; Seo, Youngho; Kim, Wook; Lim, Sang Moo; Lee, Byung Chul; Kim, Sang Eun

2018-05-03

Global and regional sympathetic activity in the heart can be evaluated using [ 123 I]meta-iodobenzylguanidine ([ 123 I]mIBG) imaging. However, [ 123 I]mIBG is associated with low image spatial resolution and sensitivity in cardiac imaging. We investigated the capability of an F-18-labeled mIBG derivative, meta-(3-[ 18 F]fluoropropyl)benzylguanidine ([ 18 F]mFPBG), for identifying ischemic and viable myocardium in a rat model of myocardial infarction. The ex vivo biodistribution and in vivo metabolic stability of [ 18 F]mFPBG were investigated in Sprague-Dawley rats. Selective cardiac adrenergic activation was confirmed via a blocking experiment involving pretreatment with desipramine (2 mg kg -1 ), followed by the administration of [ 18 F]mFPBG. Imaging properties of [ 18 F]mFPBG were compared with those of traditional cardiac imaging radiotracers ([ 123 I]mIBG and [ 99m Tc]MIBI) in a rat model of myocardial infarction. Non-invasive image-based measurements of infarct sizes were then compared with histological findings by using Bland-Altman analysis. The differences in infarct sizes determined using histological analysis and [ 18 F]mFPBG PET were -2.55 ± 4.99% (range: -12.33 to 7.22), -2.35 ± 3.32% (range: -8.87 to 4.16), and -3.15 ± 6.16% (range: -15.24 to 8.93) at 5, 20, and 40 min, respectively. Furthermore, [ 18 F]mFPBG PET was superior to traditional imaging methods in assessing the degree of ischemia in areas of myocardial infarction, as well as the actual infarct size. Compared to [ 123 I]mIBG, [ 18 F]mFPBG showed improved spatial resolution and sensitivity in a rat model of myocardial infarction. This result suggested that [ 18 F]mFPBG is a promising cardiac PET imaging agent for potential diagnostic application in PET cardiology. Copyright © 2018 Elsevier Inc. All rights reserved.

Monitoring of anti-cancer treatment with 18F-FDG and 18F-FLT PET: a comprehensive review of pre-clinical studies

PubMed Central

Jensen, Mette Munk; Kjaer, Andreas

2015-01-01

Functional imaging of solid tumors with positron emission tomography (PET) imaging is an evolving field with continuous development of new PET tracers and discovery of new applications for already implemented PET tracers. During treatment of cancer patients, a general challenge is to measure treatment effect early in a treatment course and by that to stratify patients into responders and non-responders. With 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) and 3’-deoxy-3’-[18F]fluorothymidine(18F-FLT) two of the cancer hallmarks, altered energy metabolism and increased cell proliferation, can be visualized and quantified non-invasively by PET. With 18F-FDG and 18F-FLT PET changes in energy metabolism and cell proliferation can thereby be determined after initiation of cancer treatment in both clinical and pre-clinical studies in order to predict, at an early time-point, treatment response. It is hypothesized that decreases in glycolysis and cell proliferation may occur in tumors that are sensitive to the applied cancer therapeutics and that tumors that are resistant to treatment will show unchanged glucose metabolism and cell proliferation. Whether 18F-FDG and/or 18F-FLT PET can be used for prediction of treatment response has been analyzed in many studies both following treatment with conventional chemotherapeutic agents but also following treatment with different targeted therapies, e.g. monoclonal antibodies and small molecules inhibitors. The results from these studies have been most variable; in some studies early changes in 18F-FDG and 18F-FLT uptake predicted later tumor regression whereas in other studies no change in tracer uptake was observed despite the treatment being effective. The present review gives an overview of pre-clinical studies that have used 18F-FDG and/or 18F-FLT PET for response monitoring of cancer therapeutics. PMID:26550536

TMSOTf assisted synthesis of 2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosylcytosine ([18F]FAC)

PubMed Central

Humm, John L.; Larson, Steven M.; Pillarsetty, Naga Vara Kishore

2018-01-01

[18F]FAC (2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosylcytosine, 1) is a versatile probe for imaging deoxycytidine kinase (dCK) expression levels in vivo. dCK is responsible for phosphorylation of deoxycytidine (dC, 2) and other nucleoside analogs, plays a key role in immune activation and has demonstrated to be one of the key enzymes in activating nucleoside based drugs including gemcitabine. Reported synthesis of [18F]FAC is high yielding but is quite challenging requiring bromination using HBr and careful drying of excess HBr which is critical for successful synthesis. Here in we report a simplified trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted synthesis of [18F]FAC eliminating the need of bromination and drying. [18F]FAC (β-anomer) was synthesized with average isolated decay corrected yield of 10.59 + 4.2% (n = 6) with radiochemical purity of >98% and total synthesis time of 158 + 19 min. PMID:29715301

High susceptibility prevalence for F4+ and F18+Escherichia coli in Flemish pigs.

PubMed

Nguyen, Ut V; Coddens, Annelies; Melkebeek, Vesna; Devriendt, Bert; Goetstouwers, Tiphanie; Poucke, Mario Van; Peelman, Luc; Cox, Eric

2017-04-01

F4 and/or F18 enterotoxigenic Escherichia coli (F4 + /F18 + ETEC) are responsible for diarrhea while F18 + verotoxigenic E. coli (F18 + VTEC) cause edema disease in pigs. Both infections can result in severe economic losses, which are mainly the result of the medication, growth retardation and mortality. The susceptibility of piglets to these pathogens is determined by the presence of F4 and F18 receptors (F4R and F18R). Understanding the composition of the susceptibility phenotypes of pigs is useful for animal health and breeding management. This study aimed to determine the prevalence of the F4 ETEC susceptibility phenotypes and F18 + E. coli susceptibility among Flemish pig breeds by using the in vitro villous adhesion assay. In this study, seven F4 ETEC susceptibility phenotypes were found, namely A (F4 ab R + , ac R + , ad R + ; 59.16%), B (F4 ab R + , ac R + , ad R - ; 6.28%), C (F4 ab R + , ac R - , ad R + ; 2.62%), D (F4 ab R - , ac R - , ad R + ; 6.28%), E (F4 ab R - , ac R - , ad R - ; 24.08%), F (F4 ab R + , ac R - , ad R - ; 1.05%) and G (F4 ab R - , ac R + , ad R - ; 0.52%). F4ab and F4ac E. coli showed a stronger degree of adhesion to the intestinal villi (53.40% and 52.88% strong adhesion, respectively), compared to F4ad E. coli (43.46% strong adhesion). Furthermore, the correlation between F4ac and F4ab adhesion was higher (r=0.78) than between F4ac and F4ad adhesion (r=0.41) and between F4ab and F4ad adhesion (r=0.57). For F18 + E. coli susceptibility, seven out of 82 pigs were F18R negative (8.54%), but only two of these seven pigs (2.44%) were also negative for F4R. As such, the chance to identify a pig that is positive for a F4 ETEC variant or F18 + E. coli is 97.56%. Therefore, significant economic losses will arise due to F4 + and/or F18 + E. coli infections in the Flemish pig population due to the high susceptibility prevalence. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis of [ 18F]arenes via the copper-mediated [ 18F]fluorination of boronic acids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mossine, Andrew V.; Brooks, Allen F.; Makaravage, Katarina J.

Here, a copper-mediated radiofluorination of aryl- and vinylboronic acids with K 18F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [ 18F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.

Synthesis of [ 18F]arenes via the copper-mediated [ 18F]fluorination of boronic acids

DOE PAGES

Mossine, Andrew V.; Brooks, Allen F.; Makaravage, Katarina J.; ...

2015-11-14

Here, a copper-mediated radiofluorination of aryl- and vinylboronic acids with K 18F is described. This method exhibits high functional group tolerance and is effective for the radiofluorination of a range of electron-deficient, -neutral, and -rich aryl-, heteroaryl-, and vinylboronic acids. This method has been applied to the synthesis of [ 18F]FPEB, a PET radiotracer for quantifying metabotropic glutamate 5 receptors.

Reusable electrochemical cell for rapid separation of [18F]fluoride from [18O]water for flow-through synthesis of 18F-labeled tracers

PubMed Central

Sadeghi, Saman; Liang, Vincent; Cheung, Shilin; Woo, Suh; Wu, Curtis; Ly, Jimmy; Deng, Yuliang; Eddings, Mark; van Dam, R. Michael

2015-01-01

A brass-platinum electrochemical micro flow cell was developed to extract [18F]fluoride from an aqueous solution and release it into an organic based solution, suitable for subsequent radio-synthesis, in a fast and reliable manner. This cell does not suffer electrode erosion and is thus reusable while operating faster by enabling increased voltages. By optimizing temperature, trapping and release potentials, flow rates, and electrode materials, an overall [18F]fluoride trapping and release efficiency of 84±5% (n=7) was achieved. X-ray photoelectron spectroscopy (XPS) was used to analyze electrode surfaces of various metal-metal systems and the findings were correlated with the performance of the electrochemical cell. To demonstrate the reactivity of the released [18F]fluoride, the cell was coupled to a flow-through reactor and automated synthesis of [18F]FDG with a repeatable decay-corrected yield of 56±4% (n=4) was completed in <15 min. A multi-human dose of 5.92 GBq [18F]FDG was also demonstrated. PMID:23474380

18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance in Lymphoma

PubMed Central

Giraudo, Chiara; Raderer, Markus; Karanikas, Georgios; Weber, Michael; Kiesewetter, Barbara; Dolak, Werner; Simonitsch-Klupp, Ingrid; Mayerhoefer, Marius E.

2016-01-01

Objectives The aim of this study was to compare 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance (MR) (with and without diffusion-weighted imaging [DWI]) to 18F-FDG PET/computed tomography (CT), with regard to the assessment of nodal and extranodal involvement, in patients with Hodgkin lymphoma and non-Hodgkin lymphoma, without restriction to FDG-avid subytpes. Materials and Methods Patients with histologically proven lymphoma were enrolled in this prospective, institutional review board–approved study. After a single 18F-FDG injection, patients consecutively underwent 18F-FDG PET⁄CT and 18F-FDG PET/MR on the same day for staging or restaging. Three sets of images were analyzed separately: 18F-FDG PET/CT, 18F-FDG PET/MR without DWI, and 18F-FDG PET/MR with DWI. Region-based agreement and examination-based sensitivity and specificity were calculated for 18F-FDG PET/CT, 18F-FDG PET/MR without DWI, and 18F-FDG PET/MR DWI. Maximum and mean standardized uptake values (SUVmax, SUVmean) on 18F-FDG PET/CT and 18F-FDG PET/MR were compared and correlated with minimum and mean apparent diffusion coefficients (ADCmin, ADCmean). Results Thirty-four patients with a total of 40 examinations were included. Examination-based sensitivities for 18F-FDG PET/CT, 18F-FDG PET/MR, and 18F-FDG PET/MR DWI were 82.1%, 85.7%, and 100%, respectively; specificities were 100% for all 3 techniques; and accuracies were 87.5%, 90%, and 100%, respectively. 18F-FDG PET/CT was false negative in 5 of 40 examinations (all with mucosa-associated lymphoid tissue lymphoma), and 18F-FDG PET/MR (without DWI) was false negative in 4 of 40 examinations. Region-based percentages of agreement were 99% (κ, 0.95) between 18F-FDG PET/MR DWI and 18F-FDG PET/CT, 99.2% (κ, 0.96) between 18F-FDG PET/MR and 18F-FDG PET/CT, and 99.4% (κ, 0.97) between 18F-FDG PET/MR DWI and 18F-FDG PET/MR. There was a strong correlation between 18F-FDG PET/CT and 18F-FDG PET/MR for SUVmax (r = 0

Combined early dynamic (18)F-FDG PET/CT and conventional whole-body (18)F-FDG PET/CT provide one-stop imaging for detecting hepatocellular carcinoma.

PubMed

Wang, Shao-Bo; Wu, Hu-Bing; Wang, Quan-Shi; Zhou, Wen-Lan; Tian, Ying; Li, Hong-Sheng; Ji, Yun-Hai; Lv, Liang

2015-06-01

It is widely accepted that conventional (18)F-FDG PET/CT (whole-body static (18)F-FDG PET/CT, WB (18)F-FDG PET/CT) has a low detection rate for hepatocellular carcinoma (HCC). We prospectively assessed the role of early dynamic (18)F-FDG PET/CT (ED (18)F-FDG PET/CT) and WB (18)F-FDG PET/CT in detecting HCC, and we quantified the added value of ED (18)F-FDG PET/CT to WB (18)F-FDG PET/CT. Twenty-two patients with 37 HCC tumors (HCCs) who underwent both a liver ED (18)F-FDG PET/CT (performed simultaneously with a 5.5 MBq/kg (18)F-FDG bolus injection and continued for 240 s) and a WB (18)F-FDG PET/CT were enrolled in the study. The WB (18)F-FDG PET/CT and ED (18)F-FDG PET/CT scans were positive in 56.7% (21/37) and 78.4% (29/37) HCCs, respectively (P<0.05). ED (18)F-FDG PET/CT in conjunction with WB (18)F-FDG PET/CT (one-stop (18)F-FDG PET/CT) improved the positive detection rates of WB and ED (18)F-FDG PET/CT alone from 56.7% and 78.4% to 91.9% (34/37) (P<0.001 and P>0.05, respectively). One-stop (18)F-FDG PET/CT appears to be useful to improve WB (18)F-FDG PET/CT for HCC detection. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Accuracy of 18F-FDOPA Positron Emission Tomography and 18F-FET Positron Emission Tomography for Differentiating Radiation Necrosis from Brain Tumor Recurrence.

PubMed

Yu, Jun; Zheng, Jingwei; Xu, Weilin; Weng, Jiaqi; Gao, Liansheng; Tao, Li; Liang, Feng; Zhang, Jianmin

2018-06-01

Distinguishing radiation necrosis from brain tumor recurrence remains challenging. We performed a meta-analysis to assess the diagnostic accuracy of 2 different amino acid tracers used in positron emission tomography/computed tomography scans: 18 F-FDOPA (6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine) and 18 F-FET (O-(2-18F-fluoroethyl)-L-tyrosine). We searched for studies in 3 databases: PubMed, Embase, and Chinese Biomedical databases. The data were extracted from eligible studies and then processed with heterogeneity test, threshold effect test, and calculations of sensitivity, specificity, and area under the summary receiver operating characteristic curve. Meta-regression and subgroup analyses were performed to explore the source of heterogeneity. A total of 48 studies ( 18 F-FDOPA, n = 21; 18 F-FET, n = 27) were included. Quantitative synthesis determined pooled weight values in the 18 F-FDOPA and 18 F-FET groups: sensitivity, 0.85 versus 0.82; specificity, 0.77 versus 0.80; diagnostic odds ratio, 21.7 versus 23.03; area under the curve (AUC) values, 0.8771 versus 0.8976 (P = 0.46). Moreover, the type of tumor was identified as the possible source of the significant heterogeneity (I 2  = 52%; P = 0.003) found in the 18 F-FDOPA group. In meta-regression and subgroup analyses, 18 F-FDOPA showed better diagnostic accuracy in patients with glioma compared with patients with brain metastases (AUC values, 0.9691 vs. 0.837; P < 0.01). 18 F-FDOPA also showed a significant advantage in the diagnosis of glioma recurrence compared with 18 F-FET (AUC values, 0.9691 vs. 0.9124; P = 0.015). Both 18 F-FDOPA and 18 F-FET exhibit moderate overall accuracy in diagnosing brain tumor recurrence from radiation necrosis. However, 18 F-FDOPA is more adept at diagnosing glioma recurrence compared with brain metastases, and it is more effective than 18 F-FET in diagnosing glioma recurrence. Copyright © 2018 Elsevier Inc. All rights reserved.

Prospective Comparison of 99mTc-MDP Scintigraphy, Combined 18F-NaF and 18F-FDG PET/CT, and Whole-Body MRI in Patients with Breast and Prostate Cancer.

PubMed

Minamimoto, Ryogo; Loening, Andreas; Jamali, Mehran; Barkhodari, Amir; Mosci, Camila; Jackson, Tatianie; Obara, Piotr; Taviani, Valentina; Gambhir, Sanjiv Sam; Vasanawala, Shreyas; Iagaru, Andrei

2015-12-01

We prospectively evaluated the use of combined (18)F-NaF/(18)F-FDG PET/CT in patients with breast and prostate cancer and compared the results with those for (99m)Tc-MDP bone scintigraphy and whole-body MRI. Thirty patients (15 women with breast cancer and 15 men with prostate cancer) referred for standard-of-care bone scintigraphy were prospectively enrolled in this study. (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI were performed after bone scintigraphy. The whole-body MRI protocol consisted of both unenhanced and contrast-enhanced sequences. Lesions detected with each test were tabulated, and the results were compared. For extraskeletal lesions, (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI had no statistically significant differences in sensitivity (92.9% vs. 92.9%, P = 1.00), positive predictive value (81.3% vs. 86.7%, P = 0.68), or accuracy (76.5% vs. 82.4%, P = 0.56). However, (18)F-NaF/(18)F-FDG PET/CT showed significantly higher sensitivity and accuracy than whole-body MRI (96.2% vs. 81.4%, P < 0.001, 89.8% vs. 74.7%, P = 0.01) and bone scintigraphy (96.2% vs. 64.6%, P < 0.001, 89.8% vs. 65.9%, P < 0.001) for the detection of skeletal lesions. Overall, (18)F-NaF/(18)F-FDG PET/CT showed higher sensitivity and accuracy than whole-body MRI (95.7% vs. 83.3%, P < 0.002, 87.6% vs. 76.0%, P < 0.02) but not statistically significantly so when compared with a combination of whole-body MRI and bone scintigraphy (95.7% vs. 91.6%, P = 0.17, 87.6% vs. 83.0%, P = 0.53). (18)F-NaF/(18)F-FDG PET/CT showed no significant difference from a combination of (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI. No statistically significant differences in positive predictive value were noted among the 3 examinations. (18)F-NaF/(18)F-FDG PET/CT is superior to whole-body MRI and (99m)Tc-MDP scintigraphy for evaluation of skeletal disease extent. Further, (18)F-NaF/(18)F-FDG PET/CT and whole-body MRI detected extraskeletal disease that may change the management of these patients. (18)F-NaF

Novel radiosynthesis of PET HSV-tk gene reporter probes [18F]FHPG and [18F]FHBG employing dual Sep-Pak SPE techniques.

PubMed

Wang, Ji-Quan; Zheng, Qi-Huang; Fei, Xiangshu; Mock, Bruce H; Hutchins, Gary D

2003-11-17

Positron emission tomography (PET) herpes simplex virus thymidine kinase (HSV-tk) gene reporter probes 9-[(3-[(18)F]fluoro-1-hydroxy-2-propoxy)methyl]guanine ([(18)F]FHPG) and 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG) were prepared by nucleophilic substitution of the appropriate tosylated precursors with [(18)F]KF/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with a simplified dual Silica Sep-Pak solid-phase extraction (SPE) method in 15-30% radiochemical yield.

(18)F-Fluoroglucosylation of peptides, exemplified on cyclo(RGDfK).

PubMed

Hultsch, Christina; Schottelius, Margret; Auernheimer, Jörg; Alke, Andrea; Wester, Hans-Jürgen

2009-09-01

Oxime formation between an aminooxy-functionalized peptide and an (18)F-labelled aldehyde has recently been introduced as a powerful method for the rapid one-step chemoselective synthesis of radiofluorinated peptides. Here, the potential of using routinely produced and thus readily available [(18)F]fluorodeoxyglucose ([(18)F]FDG) as the aldehydic prosthetic group was investigated using an aminooxyacetyl-conjugated cyclic RGD peptide (cyclo(RGDfK(Aoa-(Boc)) as a model peptide. The use of [(18)F]FDG from routine production ([(18)F]FDGTUM) containing an excess of D: -glucose did not allow the radiosynthesis of [(18)F]FDG-RGD in activities >37 MBq in reasonable yield, rendering the direct use of clinical grade [(18)F]FDG for the routine clinical synthesis of (18)F-labelled peptides impossible. Using no-carrier-added (n.c.a.) [(18)F]FDG obtained via HPLC separation of [(18)F]FDGTUM from excess glucose, however, afforded [(18)F]FDG-RGD in yields of 56-93% (decay corrected) and activities up to 37 MBq. Suitable reaction conditions were 20 min at 120 degrees C and pH 2.5, and a peptide concentration of 5 mM. In a preliminary in vivo biodistribution study in M21 melanoma-bearing nude mice, [(18)F]FDG-RGD showed increased tumour accumulation compared to the "gold standard" [(18)F]galacto-RGD (2.18 vs 1.49 %iD/g, respectively, at 120 min after injection), but also slightly increased uptake in non-target organs, leading to comparable tumour/organ ratios for both compounds. These data demonstrate that chemoselective (18)F-labelling of aminooxy-functionalized peptides using n.c.a. [(18)F]FDG represents a radiofluorination/glycosylation strategy that allows preparation of (18)F-labelled peptides in high yield with suitable pharmacokinetics. As soon as the necessary n.c.a. preparation of [(18)F]FDG prior to reaction with the Aoa-peptide can be implemented in a fully automated [(18)F]FDG-synthesis, [(18)F]fluoroglucosylation of peptides may represent a promising alternative to

[18F]CFT [(18F)WIN 35,428], a radioligand to study the dopamine transporter with PET: characterization in human subjects.

PubMed

Laakso, A; Bergman, J; Haaparanta, M; Vilkman, H; Solin, O; Hietala, J

1998-03-01

We have characterized the usage of [18F]CFT (also known as [18F]WIN 35,428) as a radioligand for in vivo studies of human dopamine transporter by PET. CFT was labeled with 18F to a high specific activity, and dynamic PET scans were conducted in healthy volunteers at various time points up to 5 h from [18F]CFT injection. The regional distribution of [18F]CFT uptake correlated well with the known distribution of dopaminergic nerve terminals in the human brain and also with that of other dopamine transporter radioligands. Striatal binding peaked at 225 min after injection and declined thereafter, demonstrating the reversible nature of the binding to the dopamine transporter. Therefore, due to the relatively long half-life of 18F (109.8 min), PET scans with [18F]CFT could easily be conducted during the binding equilibrium, allowing estimation of Bmax/Kd values (i.e., binding potential). Binding potentials for putamen and caudate measured at equilibrium were 4.79+/-0.11 and 4.50+/-0.23, respectively. We were able to also visualize midbrain dopaminergic neurons (substantia nigra) with [18F]CFT in some subjects. In conclusion, the labeling of CFT with 18F allows PET scans to be conducted at binding equilibrium, and therefore a high signal-to-noise ratio and reliable quantification of binding potential can be achieved. With a high resolution 3D PET scanner, the quantification of extrastriatal dopamine transporters should become possible.

Improved synthesis of [(18)F]FLETT via a fully automated vacuum distillation method for [(18)F]2-fluoroethyl azide purification.

PubMed

Ackermann, Uwe; Plougastel, Lucie; Goh, Yit Wooi; Yeoh, Shinn Dee; Scott, Andrew M

2014-12-01

The synthesis of [(18)F]2-fluoroethyl azide and its subsequent click reaction with 5-ethynyl-2'-deoxyuridine (EDU) to form [(18)F]FLETT was performed using an iPhase FlexLab module. The implementation of a vacuum distillation method afforded [(18)F]2-fluoroethyl azide in 87±5.3% radiochemical yield. The use of Cu(CH3CN)4PF6 and TBTA as catalyst enabled us to fully automate the [(18)F]FLETT synthesis without the need for the operator to enter the radiation field. [(18)F]FLETT was produced in higher overall yield (41.3±6.5%) and shorter synthesis time (67min) than with our previously reported manual method (32.5±2.5% in 130min). Copyright © 2014 Elsevier Ltd. All rights reserved.

^2H(^18F,p)^19F Study at 6 MeV/u

NASA Astrophysics Data System (ADS)

Kozub, R. L.; Nesaraja, C. D.; Moazen, B. H.; Scott, J. P.; Bardayan, D. W.; Blackmon, J. C.; Gross, C. J.; Shapira, D.; Smith, M. S.; Batchelder, J. C.; Brune, C. R.; Champagne, A. E.; Sahin, L.; Cizewski, J. A.; Thomas, J. S.; Davinson, T.; Woods, P. J.; Greife, U.; Jewett, C.; Livesay, R. J.; Ma, Z.; Parker, P. D.

2003-04-01

The degree to which the (p,α) and (p,γ) reactions destroy ^18F at temperatures ˜1-4 x 10^8 K is important for understanding the synthesis of nuclei in nova explosions and for using ^18F as a monitor of nova mechanisms in gamma ray astronomy. The reactions are dominated by low-lying proton resonances near the ^18F+p threshold (E_x=6.411 MeV excitation energy in ^19Ne). To gain further information about these resonances, we have used the inverse ^18F(d,p)^19F neutron transfer reaction at the Holifield Radioactive Ion Beam Facility to selectively populate corresponding mirror states in ^19F. Proton angular distributions were measured for states in ^19F in the excitation energy range 0-9 MeV. Results and implications for the ^18F+p reactions and nuclear structure will be presented. ^1Supported by DOE. ^2ORNL is managed by UT-Battelle, LLC, for the USDOE.

Stereotactic Comparison Study of (18)F-Alfatide and (18)F-FDG PET Imaging in an LLC Tumor-Bearing C57BL/6 Mouse Model.

PubMed

Wei, Yu-Chun; Gao, Yongsheng; Zhang, Jianbo; Fu, Zheng; Zheng, Jinsong; Liu, Ning; Hu, Xudong; Hou, Wenhong; Yu, Jinming; Yuan, Shuanghu

2016-06-28

This study aimed to stereotactically compare the PET imaging performance of (18)F-Alfatide ((18)F-ALF-NOTA-PRGD2, denoted as (18)F-Alfatide) and (18)F-fluorodeoxyglucose (FDG) and immunohistochemistry (IHC) staining in Lewis lung carcinoma (LLC) tumor-bearing C57BL/6 mouse model. (18)F-FDG standard uptake values (SUVs) were higher than (18)F-Alfatide SUVs in tumors, most of the normal tissues and organs except for the bladder. Tumor-to-brain, tumor-to-lung, and tumor-to-heart ratios of (18)F-Alfatide PET were significantly higher than those of (18)F-FDG PET (P < 0.001). The spatial heterogeneity of the tumors was detected, and the tracer accumulation enhanced from the outer layer to the inner layer consistently using the two tracers. The parameters of the tumors were significantly correlated with each other between (18)F-FDG SUV and GLUT-1 (R = 0.895, P < 0.001), (18)F-Alfatide SUV and αvβ3 (R = 0.595, P = 0.019), (18)F-FDG SUV and (18)F-Alfatide SUV (R = 0.917, P < 0.001), and GLUT-1 and αvβ3 (R = 0.637, P = 0.011). Therefore, (18)F-Alfatide PET may be an effective tracer for tumor detection, spatial heterogeneity imaging and an alternative supplement to (18)F-FDG PET, particularly for patients with enhanced characteristics in the brain, chest tumors or diabetes, meriting further study.

(18)F-FDG and (18)F-FLT PET/CT imaging in the characterization of mediastinal lymph nodes.

PubMed

Rayamajhi, Sampanna Jung; Mittal, Bhagwant Rai; Maturu, Venkata Nagarjuna; Agarwal, Ritesh; Bal, Amanjit; Dey, Pranab; Shukla, Jaya; Gupta, Dheeraj

2016-04-01

There is currently no single modality for accurate characterization of enlarged mediastinal lymph nodes into benign or malignant. Recently (18)F-fluorothymidine (FLT) has been used as a proliferation marker. In this prospective study, we examined the role of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) and (18)F-FLT PET/CT in categorizing mediastinal lymph nodes as benign or malignant. A total of 70 consecutive patients with mediastinal lymphadenopathy detected on computed tomography (CT) or chest radiograph underwent whole body (18)F-FLT PET/CT and (18)F-FDG PET/CT (within 1 week of each other). Lymph nodal tracer uptake was determined by calculation of standardized uptake value (SUV) with both the tracers. Results of PET/CT were compared with histopathology of the lymph nodes. Histopathology results showed thirty-seven patients with sarcoidosis, seven patients with tuberculosis, nine patients with non-small cell lung cancer, five patients with Hodgkin's lymphoma and twelve patients with non-Hodgkin's lymphoma. The mean FDG SUVmax of sarcoidosis, tuberculosis, Hodgkin's and non-Hodgkin's lymphoma was 12.7, 13.4, 8.2, and 8.8, respectively, and the mean FLT SUVmax was 6.0, 5.4, 4.4, and 3.8, respectively. It was not possible to characterize mediastinal lymphadenopathy as benign or malignant solely based on FDG SUVmax values (p > 0.05) or FLT SUVmax values (p > 0.05). There was no significant difference in FDG uptake (p > 0.9) or FLT uptake (p > 0.9) between sarcoidosis and tuberculosis. In lung cancer patients, the FDG SUVmax and FLT SUVmax of those lymph nodes with tumor infiltration on biopsy was 6.7 and 3.9, respectively, and those without nodal infiltration was 6.4 and 3.7, respectively, and both the tracers were not able to characterize the nodal status as malignant or benign (p > 0.05). Though (18)F-FLT PET/CT and (18)F-FDG PET/CT reflect different aspects of biology, i.e., proliferation and metabolism

This NASA Dryden F/A-18 is participating in the Automated Aerial Refueling (AAR) project. F/A-18 (No

NASA Technical Reports Server (NTRS)

2002-01-01

A NASA Dryden F/A-18 is participating in the Automated Aerial Refueling (AAR) project. F/A-18 (No. 847) is acting as an in-flight refueling tanker in the study to develop analytical models for an automated aerial refueling system for unmanned vehicles. A 300-gallon aerodynamic pod containing air-refueling equipment is seen beneath the fuselage. The hose and refueling basket are extended during an assessment of their dynamics on the F/A-18A.

Assessment of glucose metabolism and cellular proliferation in multiple myeloma: a first report on combined 18F-FDG and 18F-FLT PET/CT imaging.

PubMed

Sachpekidis, C; Goldschmidt, H; Kopka, K; Kopp-Schneider, A; Dimitrakopoulou-Strauss, A

2018-04-10

Despite the significant upgrading in recent years of the role of 18 F-FDG PET/CT in multiple myeloma (MM) diagnostics, there is a still unmet need for myeloma-specific radiotracers. 3'-Deoxy-3'-[ 18 F]fluorothymidine ( 18 F-FLT) is the most studied cellular proliferation PET agent, considered a potentially new myeloma functional imaging tracer. The aim of this pilot study was to evaluate 18 F-FLT PET/CT in imaging of MM patients, in the context of its combined use with 18 F-FDG PET/CT. Eight patients, four suffering from symptomatic MM and four suffering from smoldering MM (SMM), were enrolled in the study. All patients underwent 18 F-FDG PET/CT and 18 F-FLT PET/CT imaging by means of static (whole body) and dynamic PET/CT of the lower abdomen and pelvis (dPET/CT) in two consecutive days. The evaluation of PET/CT studies was based on qualitative evaluation, semi-quantitative (SUV) calculation, and quantitative analysis based on two-tissue compartment modeling. 18 F-FDG PET/CT demonstrated focal, 18 F-FDG avid, MM-indicative bone marrow lesions in five patients. In contrary, 18 F-FLT PET/CT showed focal, 18 F-FLT avid, myeloma-indicative lesions in only two patients. In total, 48 18 F-FDG avid, focal, MM-indicative lesions were detected with 18 F-FDG PET/CT, while 17 18 F-FLT avid, focal, MM-indicative lesions were detected with 18 F-FLT PET/CT. The number of myeloma-indicative lesions was significantly higher for 18 F-FDG PET/CT than for 18 F-FLT PET/CT. A common finding was a mismatch of focally increased 18 F-FDG uptake and reduced 18 F-FLT uptake (lower than the surrounding bone marrow). Moreover, 18 F-FLT PET/CT was characterized by high background activity in the bone marrow compartment, further complicating the evaluation of bone marrow lesions. Semi-quantitative evaluation revealed that both SUV mean and SUV max were significantly higher for 18 F-FLT than for 18 F-FDG in both MM lesions and reference tissue. SUV values were higher in MM lesions than in

One-Proton Breakup of 18F and the 17O(p,γ)18F Reaction in Classical Novae

NASA Astrophysics Data System (ADS)

Isherwood, Bryan; Banu, A.; E491 Collaboration

2013-10-01

Classical nova studies are of considerable interest for understanding the chemical evolution of the Galaxy. They have been proposed as the most significant source for the nucleosynthesis of the isotopes 13C, 15N, and 17O in the Universe. Novae are also likely to synthesize the short-lived radioisotope 18F (T1/2 = 110 min), which is expected to be the most important contributor to the observed emission of 511 keV gamma radiation by space-based γ-ray telescopes. This emission is produced by electron-positron annihilation following the beta + decay of radioactive nuclei. A detection of these gamma rays could significantly constrain the nova simulation models. 18F nucleosynthesis in classical novae strongly depends on the thermonuclear rate of the 17O(p,γ)18F reaction, which is part of the CNO cycle. This work presents preliminary results toward determination of the 17O(p,γ)18F reaction cross section, which was measured by the indirect method of one-proton nuclear breakup at intermediate energies. The experiment was carried out at GANIL using a beam of 18F at 40 MeV/u impinging on a carbon target. Longitudinal momentum distributions of the 17O breakup fragments were measured in coincidence with γ-rays emitted by 17O residues.

Comparison of [(18)F]altanserin and [(18)F]deuteroaltanserin for PET imaging of serotonin(2A) receptors in baboon brain: pharmacological studies.

PubMed

Staley, J K; Van Dyck, C H; Tan, P Z; Al Tikriti, M; Ramsby, Q; Klump, H; Ng, C; Garg, P; Soufer, R; Baldwin, R M; Innis, R B

2001-04-01

The regional distribution in brain, distribution volumes, and pharmacological specificity of the PET 5-HT(2A) receptor radiotracer [(18)F]deuteroaltanserin were evaluated and compared to those of its non-deuterated derivative [(18)F]altanserin. Both radiotracers were administered to baboons by bolus plus constant infusion and PET images were acquired up to 8 h. The time-activity curves for both tracers stabilized between 4 and 6 h. The ratio of total and free parent to metabolites was not significantly different between radiotracers; nevertheless, total cortical R(T) (equilibrium ratio of specific to nondisplaceable brain uptake) was significantly higher (34-78%) for [(18)F]deuteroaltanserin than for [(18)F]altanserin. In contrast, the binding potential (Bmax/K(D)) was similar between radiotracers. [(18)F]Deuteroaltanserin cortical activity was displaced by the 5-HT(2A) receptor antagonist SR 46349B but was not altered by changes in endogenous 5-HT induced by fenfluramine. These findings suggest that [(18)F]deuteroaltanserin is essentially equivalent to [(18)F]altanserin for 5-HT(2A) receptor imaging in the baboon.

Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF

PubMed Central

2016-01-01

A copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [18F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [18F]F-phenylalanine and [18F]F-DOPA. In addition, an automated synthesis of [18F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol. PMID:27718581

Copper-Mediated Radiofluorination of Arylstannanes with [ 18F]KF

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makaravage, Katarina J.; Brooks, Allen F.; Mossine, Andrew V.

In this article, a copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [ 18F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [ 18F]F-phenylalanine and [ 18F]F-DOPA. In addition, an automated synthesis of [ 18F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.

Copper-Mediated Radiofluorination of Arylstannanes with [ 18F]KF

DOE PAGES

Makaravage, Katarina J.; Brooks, Allen F.; Mossine, Andrew V.; ...

2016-10-10

In this article, a copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [ 18F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [ 18F]F-phenylalanine and [ 18F]F-DOPA. In addition, an automated synthesis of [ 18F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.

Comparison of Positron Emission Tomography Using 2-[18F]-fluoro-2-deoxy-D-glucose and 3-deoxy-3-[18F]-fluorothymidine in Lung Cancer Imaging

PubMed Central

Wang, Fu-Li; Tan, Ye-Ying; Gu, Xiang-Min; Li, Tian-Ran; Lu, Guang-Ming; Liu, Gang; Huo, Tian-Long

2016-01-01

Background: The detection of solitary pulmonary nodules (SPNs) that may potentially develop into a malignant lesion is essential for early clinical interventions. However, grading classification based on computed tomography (CT) imaging results remains a significant challenge. The 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/CT imaging produces both false-positive and false-negative findings for the diagnosis of SPNs. In this study, we compared 18F-FDG and 3-deoxy-3-[18F]-fluorothymidine (18F-FLT) in lung cancer PET/CT imaging. Methods: The binding ratios of the two tracers to A549 lung cancer cells were calculated. The mouse lung cancer model was established (n = 12), and micro-PET/CT analysis using the two tracers was performed. Images using the two tracers were collected from 55 lung cancer patients with SPNs. The correlation among the cell-tracer binding ratios, standardized uptake values (SUVs), and Ki-67 proliferation marker expression were investigated. Results: The cell-tracer binding ratio for the A549 cells using the 18F-FDG was greater than the ratio using 18F-FLT (P < 0.05). The Ki-67 expression showed a significant positive correlation with the 18F-FLT binding ratio (r = 0.824, P < 0.01). The tumor-to-nontumor uptake ratio of 18F-FDG imaging in xenografts was higher than that of 18F-FLT imaging. The diagnostic sensitivity, specificity, and the accuracy of 18F-FDG for lung cancer were 89%, 67%, and 73%, respectively. Moreover, the diagnostic sensitivity, specificity, and the accuracy of 18F-FLT for lung cancer were 71%, 79%, and 76%, respectively. There was an obvious positive correlation between the lung cancer Ki-67 expression and the mean maximum SUV of 18F-FDG and 18F-FLT (r = 0.658, P < 0.05 and r = 0.724, P < 0.01, respectively). Conclusions: The 18F-FDG uptake ratio is higher than that of 18F-FLT in A549 cells at the cellular level. 18F-FLT imaging might be superior for the quantitative diagnosis of lung tumor

18F-FPYBF-2, a new F-18 labelled amyloid imaging PET tracer: biodistribution and radiation dosimetry assessment of first-in-man 18F-FPYBF-2 PET imaging.

PubMed

Nishii, Ryuichi; Higashi, Tatsuya; Kagawa, Shinya; Okuyama, Chio; Kishibe, Yoshihiko; Takahashi, Masaaki; Okina, Tomoko; Suzuki, Norio; Hasegawa, Hiroshi; Nagahama, Yasuhiro; Ishizu, Koichi; Oishi, Naoya; Kimura, Hiroyuki; Watanabe, Hiroyuki; Ono, Masahiro; Saji, Hideo; Yamauchi, Hiroshi

2018-05-01

Recently, a benzofuran derivative for the imaging of β-amyloid plaques, 5-(5-(2-(2-(2- 18 F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)- N-methylpyridin-2-amine ( 18 F-FPYBF-2) has been validated as a tracer for amyloid imaging and it was found that 18 F-FPYBF-2 PET/CT is a useful and reliable diagnostic tool for the evaluation of AD (Higashi et al. Ann Nucl Med, https://doi.org/10.1007/s12149-018-1236-1 , 2018). The aim of this study was to assess the biodistribution and radiation dosimetry of diagnostic dosages of 18 F-FPYBF-2 in normal healthy volunteers as a first-in-man study. Four normal healthy volunteers (male: 3, female: 1; mean age: 40 ± 17; age range 25-56) were included and underwent 18 F-FPYBF-2 PET/CT study for the evaluation of radiation exposure and pharmacokinetics. A 10-min dynamic PET/CT scan of the body (chest and abdomen) was performed at 0-10 min and a 15-min whole-body static scan was performed six times after the injection of 18 F-FPYBF-2. After reconstructing PET and CT image data, individual organ time-activity curves were estimated by fitting volume of interest data from the dynamic scan and whole-body scans. The OLINDA/EXM version 2.0 software was used to determine the whole-body effective doses. Dynamic PET imaging demonstrated that the hepatobiliary and renal systems were the principal pathways of clearance of 18 F-FPYBF-2. High uptake in the liver and the gall bladder, the stomach, and the kidneys were demonstrated, followed by the intestines and the urinary bladder. The ED for the adult dosimetric model was estimated to be 8.48 ± 1.25 µSv/MBq. The higher absorbed doses were estimated for the liver (28.98 ± 12.49 and 36.21 ± 15.64 µGy/MBq), the brain (20.93 ± 4.56 and 23.05 ± 5.03µ Gy/MBq), the osteogenic cells (9.67 ± 1.67 and 10.29 ± 1.70 µGy/MBq), the small intestines (9.12 ± 2.61 and 11.12 ± 3.15 µGy/MBq), and the kidneys (7.81 ± 2.62 and 8.71 ± 2.90 µGy/MBq) for

Radiation absorbed dose estimates for 18F-BPA PET.

PubMed

Kono, Yuzuru; Kurihara, Hiroaki; Kawamoto, Hiroshi; Yasui, Naoko; Honda, Naoki; Igaki, Hiroshi; Itami, Jun

2017-09-01

Background Boron neutron capture therapy (BNCT) is a molecular radiation therapy approach based on the 10 B (n, α) 7 Li nuclear reaction in cancer cells. In BNCT, delivery of 10 B in the form of 4-borono-phenylalanine conjugated with fructose (BPA-fr) to the cancer cells is important. The PET tracer 4-borono-2-18F-fluoro-phenylalanine (FBPA) has been used to predict the accumulation of BPA-fr before BNCT. Purpose To determine the biodistribution and dosimetric parameters in 18F-BPA PET/CT studies. Material and Methods Human biokinetic data were obtained during clinical 18F-BPA PET studies between February and June 2015 at one institution. Nine consecutive patients were studied prospectively. The internal radiation dose was calculated on the basis of radioactivity data from blood, urine, and normal tissue of the heart, liver, spleen, kidney, and other parts of the body at each time point using OLINDA/EXM1.1 program. We compared our calculations with published 18F-FDG data. Results Adult patients (3 men, 3 women; age range, 28-68 years) had significantly smaller absorbed doses than pediatric patients (3 patients; age range, 5-12 years) ( P = 0.003). The mean effective dose was 57% lower in adult patients compared with pediatric patients. Mean effective doses for 18F-BPA were 25% lower than those for 18F-FDG presented in International Commission of Radiation Protection (ICRP) publication 106. Conclusion We found significant differences in organ absorbed doses for 18F-BPA against those for 18F-FDG presented in ICRP publication 106. Mean effective doses for 18F-BPA were smaller than those for 18F-FDG in the publication by 0.5-38% (mean difference, 25%).

17 CFR 270.18f-1 - Exemption from certain requirements of section 18(f)(1) (of the Act) for registered open-end...

Code of Federal Regulations, 2010 CFR

2010-04-01

... requirements of section 18(f)(1) (of the Act) for registered open-end investment companies which have the right... EXCHANGE COMMISSION (CONTINUED) RULES AND REGULATIONS, INVESTMENT COMPANY ACT OF 1940 § 270.18f-1 Exemption from certain requirements of section 18(f)(1) (of the Act) for registered open-end investment companies...

Dual Tracer PET Imaging (68Ga-DOTATATE and 18F-FDG) Features in Pulmonary Carcinoid: Correlation with Tumor Proliferation Index.

PubMed

Bhatkar, Dhiraj; Utpat, Ketaki; Basu, Sandip; Joshi, Jyotsna M

2017-01-01

Pulmonary carcinoid tumors are rare group of lung neoplasms representing 1% of all the lung tumors. The typical bronchial carcinoids showed higher and more selective uptake of 68 Ga-DOTATATE than of 18 F-FDG on PET-CT. The Ki-67(MIB-1), a tumor proliferation index is a prognostic marker in neuroendocrine tumors for estimating tumor progression. Atypical carcinoids have higher Ki-67 index and have an increased propensity to metastasize as compared to typical ones. 68 Ga-DOTATATE PET imaging along with Ki-67 can be correlated for better management of patients with neuroendocrine tumors. We describe the dual tracer imaging features in a patient of pulmonary carcinoid with avid 68 Ga-DOTATATE and minimal 18 FDG ( 18 Flurodeoxyglucose) uptake diagnosed on the basis of imaging and bronchoscopic biopsy and its correlation with tumor proliferation index.

GMP-compliant automated synthesis of [(18)F]AV-45 (Florbetapir F 18) for imaging beta-amyloid plaques in human brain.

PubMed

Yao, Cheng-Hsiang; Lin, Kun-Ju; Weng, Chi-Chang; Hsiao, Ing-Tsung; Ting, Yi-Shu; Yen, Tzu-Chen; Jan, Tong-Rong; Skovronsky, Daniel; Kung, Mei-Ping; Wey, Shiaw-Pyng

2010-12-01

We report herein the Good Manufacturing Practice (GMP)-compliant automated synthesis of (18)F-labeled styrylpyridine, AV-45 (Florbetapir), a novel tracer for positron emission tomography (PET) imaging of beta-amyloid (Abeta) plaques in the brain of Alzheimer's disease patients. [(18)F]AV-45 was prepared in 105 min using a tosylate precursor with Sumitomo modules for radiosynthesis under GMP-compliant conditions. The overall yield was 25.4+/-7.7% with a final radiochemical purity of 95.3+/-2.2% (n=19). The specific activity of [(18)F]AV-45 reached as high as 470+/-135 TBq/mmol (n=19). The present studies show that [(18)F]AV-45 can be manufactured under GMP-compliant conditions and could be widely available for routine clinical use. Copyright 2010 Elsevier Ltd. All rights reserved.

In vivo assessment and dosimetry of 2 novel PDE10A PET radiotracers in humans: 18F-MNI-659 and 18F-MNI-654.

PubMed

Barret, Olivier; Thomae, David; Tavares, Adriana; Alagille, David; Papin, Caroline; Waterhouse, Rikki; McCarthy, Timothy; Jennings, Danna; Marek, Ken; Russell, David; Seibyl, John; Tamagnan, Gilles

2014-08-01

Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ((18)F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Eleven healthy volunteers participated in this study ((18)F-MNI-654 test-retest, 2 men; (18)F-MNI-659 test-retest, 4 men and 1 woman; (18)F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for (18)F-MNI-654 and over 3.5 h for (18)F-MNI-659, and pharmacokinetic modeling with plasma- and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for (18)F-MNI-659 and radiation dosimetry estimated with OLINDA. Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that (18)F-MNI-654 kinetics were much slower than (18)F-MNI-659 kinetics. For (18)F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BPND), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The (18)F-MNI-659 effective dose was

Bacterial infection imaging with [18F]fluoropropyl-trimethoprim

PubMed Central

Lee, Iljung; Hou, Catherine; Weng, Chi-Chang; Li, Shihong; Lieberman, Brian P.; Zeng, Chenbo; Mankoff, David A.; Mach, Robert H.

2017-01-01

There is often overlap in the diagnostic features of common pathologic processes such as infection, sterile inflammation, and cancer both clinically and using conventional imaging techniques. Here, we report the development of a positron emission tomography probe for live bacterial infection based on the small-molecule antibiotic trimethoprim (TMP). [18F]fluoropropyl-trimethoprim, or [18F]FPTMP, shows a greater than 100-fold increased uptake in vitro in live bacteria (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa) relative to controls. In a rodent myositis model, [18F]FPTMP identified live bacterial infection without demonstrating confounding increased signal in the same animal from other etiologies including chemical inflammation (turpentine) and cancer (breast carcinoma). Additionally, the biodistribution of [18F]FPTMP in a nonhuman primate shows low background in many important tissues that may be sites of infection such as the lungs and soft tissues. These results suggest that [18F]FPTMP could be a broadly useful agent for the sensitive and specific imaging of bacterial infection with strong translational potential. PMID:28716936

Recent Developments of 18F-FET PET in Neuro-oncology.

PubMed

Muoio, Barbara; Giovanella, Luca; Treglia, Giorgio

2017-11-23

From the past decade to date several studies about O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography (PET) in brain tumours have been published in the literature. Objective The aim of this narrative review is to summarize the recent developments and the current role of 18F-FET PET in brain tumours according to recent literature data. Methods Main findings from selected recently published and relevant articles on the role of 18F-FET PET in neuro-oncology were described. Results 18F-FET PET may be useful in the differential diagnosis between brain tumours and non-neoplastic lesions and between low-grade and high-grade gliomas. Integration of 18F-FET PET into surgical planning allows better delineation of the extent of resection beyond margins visible with standard MRI. For biopsy planning, 18F-FET PET is particularly useful in identifying malignant foci within non-contrast-enhancing gliomas. 18F-FET PET may improve the radiation therapy planning in patients with gliomas. This metabolic imaging method may be useful to evaluate treatment response in patients with gliomas and it improves the differential diagnosis between brain tumours recurrence and post-treatment changes. 18F-FET PET may provide useful prognostic information in high-grade gliomas. Conclusions Based on recent literature data 18F-FET PET may provide additional diagnostic information compared to standard MRI in neuro-oncology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Combined use of (18)F-FDG and (18)F-FMISO in unresectable non-small cell lung cancer patients planned for radiotherapy: a dynamic PET/CT study.

PubMed

Sachpekidis, Christos; Thieke, Christian; Askoxylakis, Vasileios; Nicolay, Nils H; Huber, Peter E; Thomas, Michael; Dimitrakopoulou, Georgia; Debus, Juergen; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2015-01-01

Aim of this study was to evaluate and compare, by means of dynamic and static PET/CT, the distribution patterns and pharmacokinetics of fluorine-18 fluorodeoxyglucose ((18)F-FDG) and of fluorine-18-fluoromisonidazole ((18)F-FMISO) in non-small cell lung cancer (NSCLC) patients scheduled for intensity modulated radiation therapy (IMRT). Thirteen patients suffering from inoperable stage III NSCLC underwent PET/CTs with (18)F-FDG and (18)F-FMISO for tumor metabolism and hypoxia assessment accordingly. Evaluation of PET/CT studies was based on visual analysis, semi-quantitative (SUV) calculations and absolute quantitative estimations, after application of a two-tissue compartment model and a non-compartmental approach. (18)F-FDG PET/CT revealed all thirteen primary lung tumors as sites of increased (18)F-FDG uptake. Six patients demonstrated also in total 43 (18)F-FDG avid metastases; these patients were excluded from radiotherapy. (18)F-MISO PET/CT demonstrated 12/13 primary lung tumors with faint tracer uptake. Only one tumor was clearly (18)F-FMISO avid, (SUVaverage = 3.4, SUVmax = 5.0). Mean values for (18)F-FDG, as derived from dPET/CT data, were SUVaverage = 8.9, SUVmax = 15.1, K1 = 0.23, k2 = 0.53, k3 = 0.17, k4 = 0.02, influx = 0.05 and fractal dimension (FD) = 1.25 for the primary tumors. The respective values for (18)F-FMISO were SUVaverage = 1.4, SUVmax = 2.2, K1 = 0.26, k2 = 0.56, k3 = 0.06, k4 = 0.06, influx = 0.02 and FD = 1.14. No statistically significant correlation was observed between the two tracers. (18)F-FDG PET/CT changed therapy management in six patients, by excluding them from planned IMRT. (18)F-FMISO PET/CT revealed absence of significant tracer uptake in the majority of the (18)F-FDG avid NSCLCs. Lack of correlation between the two tracers' kinetics indicates that they reflect different molecular mechanisms and implies the discordance between increased glycolysis and hypoxia in the malignancy.

Combined use of 18F-FDG and 18F-FMISO in unresectable non-small cell lung cancer patients planned for radiotherapy: a dynamic PET/CT study

PubMed Central

Sachpekidis, Christos; Thieke, Christian; Askoxylakis, Vasileios; Nicolay, Nils H; Huber, Peter E; Thomas, Michael; Dimitrakopoulou, Georgia; Debus, Juergen; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2015-01-01

Aim of this study was to evaluate and compare, by means of dynamic and static PET/CT, the distribution patterns and pharmacokinetics of fluorine-18 fluorodeoxyglucose (18F-FDG) and of fluorine-18-fluoromisonidazole (18F-FMISO) in non-small cell lung cancer (NSCLC) patients scheduled for intensity modulated radiation therapy (IMRT). Thirteen patients suffering from inoperable stage III NSCLC underwent PET/CTs with 18F-FDG and 18F-FMISO for tumor metabolism and hypoxia assessment accordingly. Evaluation of PET/CT studies was based on visual analysis, semi-quantitative (SUV) calculations and absolute quantitative estimations, after application of a two-tissue compartment model and a non-compartmental approach. 18F-FDG PET/CT revealed all thirteen primary lung tumors as sites of increased 18F-FDG uptake. Six patients demonstrated also in total 43 18F-FDG avid metastases; these patients were excluded from radiotherapy. 18F-MISO PET/CT demonstrated 12/13 primary lung tumors with faint tracer uptake. Only one tumor was clearly 18F-FMISO avid, (SUVaverage = 3.4, SUVmax = 5.0). Mean values for 18F-FDG, as derived from dPET/CT data, were SUVaverage = 8.9, SUVmax = 15.1, K1 = 0.23, k2 = 0.53, k3 = 0.17, k4 = 0.02, influx = 0.05 and fractal dimension (FD) = 1.25 for the primary tumors. The respective values for 18F-FMISO were SUVaverage = 1.4, SUVmax = 2.2, K1 = 0.26, k2 = 0.56, k3 = 0.06, k4 = 0.06, influx = 0.02 and FD = 1.14. No statistically significant correlation was observed between the two tracers. 18F-FDG PET/CT changed therapy management in six patients, by excluding them from planned IMRT. 18F-FMISO PET/CT revealed absence of significant tracer uptake in the majority of the 18F-FDG avid NSCLCs. Lack of correlation between the two tracers’ kinetics indicates that they reflect different molecular mechanisms and implies the discordance between increased glycolysis and hypoxia in the malignancy. PMID:25973334

First experience with early dynamic (18)F-NaF-PET/CT in patients with chronic osteomyelitis.

PubMed

Freesmeyer, Martin; Stecker, Franz F; Schierz, Jan-Henning; Hofmann, Gunther O; Winkens, Thomas

2014-05-01

This study investigates whether early dynamic positron emission tomography/computed tomography (edPET/CT) using (18)F-sodium fluoride-((18)F-NaF) is feasible in depicting early phases of radiotracer distribution in patients with chronic osteomyelitis (COM). A total of 12 ed(18)F-NaF-PET/CT examinations were performed on 11 consecutive patients (2 female, 9 male; age 53 ± 12 years) in list mode over 5 min starting with radiopharmaceutical injection before standard late (18)F-NaF-PET/CT. Eight consecutive time intervals (frames) were reconstructed for each patient: four 15 s, then four 60 s. Several volumes of interest (VOI) were selected, representing the affected area as well as different reference areas within the bone and soft tissue. Maximum and mean ed standardized uptake values (edSUVmax, edSUVmean, respectively) were calculated in each VOI during each frame to measure early fluoride influx and accumulation. Results were compared between affected and non-affected (contralateral) bones. Starting in the 31-45 s frame, the affected bone area showed significantly higher edSUVmax and edSUVmean compared to the healthy contralateral region. The affected bone areas also significantly differed from non-affected contralateral regions in conventional late (18)F-NaF-PET/CT. This pilot study suggests that, in patients with COM, ed(18)F-NaF -PET offers additional information about early radiotracer distribution to standard (18)F-NaF -PET/CT, similar to a three-phase bone scan. The results should be validated in larger trials which directly compare ed(18)F-NaF-PET to a three-phase bone scan.

Automated Synthesis of 18F-Fluoropropoxytryptophan for Amino Acid Transporter System Imaging

PubMed Central

Shih, I-Hong; Duan, Xu-Dong; Kong, Fan-Lin; Williams, Michael D.; Zhang, Yin-Han; Yang, David J.

2014-01-01

Objective. This study was to develop a cGMP grade of [18F]fluoropropoxytryptophan (18F-FTP) to assess tryptophan transporters using an automated synthesizer. Methods. Tosylpropoxytryptophan (Ts-TP) was reacted with K18F/kryptofix complex. After column purification, solvent evaporation, and hydrolysis, the identity and purity of the product were validated by radio-TLC (1M-ammonium acetate : methanol = 4 : 1) and HPLC (C-18 column, methanol : water = 7 : 3) analyses. In vitro cellular uptake of 18F-FTP and 18F-FDG was performed in human prostate cancer cells. PET imaging studies were performed with 18F-FTP and 18F-FDG in prostate and small cell lung tumor-bearing mice (3.7 MBq/mouse, iv). Results. Radio-TLC and HPLC analyses of 18F-FTP showed that the Rf and Rt values were 0.9 and 9 min, respectively. Radiochemical purity was >99%. The radiochemical yield was 37.7% (EOS 90 min, decay corrected). Cellular uptake of 18F-FTP and 18F-FDG showed enhanced uptake as a function of incubation time. PET imaging studies showed that 18F-FTP had less tumor uptake than 18F-FDG in prostate cancer model. However, 18F-FTP had more uptake than 18F-FDG in small cell lung cancer model. Conclusion. 18F-FTP could be synthesized with high radiochemical yield. Assessment of upregulated transporters activity by 18F-FTP may provide potential applications in differential diagnosis and prediction of early treatment response. PMID:25136592

Automated synthesis of 18F-fluoropropoxytryptophan for amino acid transporter system imaging.

PubMed

Shih, I-Hong; Duan, Xu-Dong; Kong, Fan-Lin; Williams, Michael D; Yang, Kevin; Zhang, Yin-Han; Yang, David J

2014-01-01

This study was to develop a cGMP grade of [(18)F]fluoropropoxytryptophan ((18)F-FTP) to assess tryptophan transporters using an automated synthesizer. Tosylpropoxytryptophan (Ts-TP) was reacted with K(18)F/kryptofix complex. After column purification, solvent evaporation, and hydrolysis, the identity and purity of the product were validated by radio-TLC (1M-ammonium acetate : methanol = 4 : 1) and HPLC (C-18 column, methanol : water = 7 : 3) analyses. In vitro cellular uptake of (18)F-FTP and (18)F-FDG was performed in human prostate cancer cells. PET imaging studies were performed with (18)F-FTP and (18)F-FDG in prostate and small cell lung tumor-bearing mice (3.7 MBq/mouse, iv). Radio-TLC and HPLC analyses of (18)F-FTP showed that the Rf and Rt values were 0.9 and 9 min, respectively. Radiochemical purity was >99%. The radiochemical yield was 37.7% (EOS 90 min, decay corrected). Cellular uptake of (18)F-FTP and (18)F-FDG showed enhanced uptake as a function of incubation time. PET imaging studies showed that (18)F-FTP had less tumor uptake than (18)F-FDG in prostate cancer model. However, (18)F-FTP had more uptake than (18)F-FDG in small cell lung cancer model. (18)F-FTP could be synthesized with high radiochemical yield. Assessment of upregulated transporters activity by (18)F-FTP may provide potential applications in differential diagnosis and prediction of early treatment response.

Fluorine-18 NaF PET imaging of child abuse.

PubMed

Drubach, Laura A; Sapp, Mark V; Laffin, Stephen; Kleinman, Paul K

2008-07-01

We describe the use of 18F-NaF positron emission tomography (PET) whole-body imaging for the evaluation of skeletal trauma in a case of suspected child abuse. To our knowledge, 18F NaF PET has not been used in the past for the evaluation of child abuse. In our patient, this technique detected all sites of trauma shown by initial and follow-up skeletal surveys, including bilateral metaphyseal fractures of the proximal humeri. Fluorine-18 NaF PET has potential advantage over Tc-99m-labeled methylene diphosphonate (MDP) based upon superior image contrast and spatial resolution.

Prognostic Value of 18F-FLT PET in Patients with Neuroendocrine Neoplasms: A Prospective Head-to-Head Comparison with 18F-FDG PET and Ki-67 in 100 Patients.

PubMed

Johnbeck, Camilla B; Knigge, Ulrich; Langer, Seppo W; Loft, Annika; Berthelsen, Anne Kiil; Federspiel, Birgitte; Binderup, Tina; Kjaer, Andreas

2016-12-01

Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumors arising in various organs and with a large span of aggressiveness and survival rates. The Ki-67 proliferation index is presently used as the key marker of prognosis, and treatment guidelines are largely based on this index. 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) is a proliferation tracer for PET imaging valuable in the monitoring of disease progression and treatment response in various types of cancer. However, until now only data from 10 patients with NEN were available in the literature. The aim of the present study was to investigate 18 F-FLT PET as a prognostic marker for NENs in comparison with 18 F-FDG PET and Ki-67 index. One hundred patients were PET-scanned with both 18 F-FLT and 18 F-FDG within the same week, and the prognostic value of a positive scan was examined in terms of progression-free survival (PFS) and overall survival (OS). The correlation between the Ki-67 index and 18 F-FLT uptake was also investigated. Thirty-seven percent of patients had a positive 18 F-FLT PET scan, and 49% had 18 F-FDG PET-positive foci. Patients with a high 18 F-FLT uptake had a significantly shorter OS and PFS than patients with low or no 18 F-FLT uptake. No correlation was found between Ki-67 index and 18 F-FLT uptake. In a multivariate analysis 18 F-FLT, 18 F-FDG, and Ki-67 all were significant prognostic markers of PFS. For OS, only 18 F-FDG and Ki-67 remained significant. 18 F-FLT PET has prognostic value in NEN patients but when 18 F-FDG PET and Ki-67 index are also available, a multivariate model revealed that 18 F-FLT PET only adds information regarding PFS but not OS, whereas 18 F-FDG PET remains predictive of both PFS and OS. However, a clinically robust algorithm including 18 F-FLT in addition to 18 F-FDG and Ki-67 could not be found. Accordingly, the exact role, if any, of 18 F-FLT PET in NENs remains to be established. © 2016 by the Society of Nuclear Medicine and Molecular

Evaluation of 6-([18F] fluoroacetamido)-1-hexanoic-anilide (18F-FAHA) as imaging probe in tumor xenograft mice model

NASA Astrophysics Data System (ADS)

Li, Fiona; Cho, Sung Ju; Yu, Lihai; Hudson, Robert H. E.; Luyt, Leonard G.; Pin, Christopher L.; Kovacs, Michael S.; Koropatnick, James; Lee, Ting-Yim

2016-03-01

Alteration in genetic expression is as important as gene mutation in cancer development and proliferation. Epigenetic changes affect gene expression without altering the DNA sequence. Histone deacetylase (HDAC), an enzyme facilitating histone remodelling, can lead to silencing of tumor suppressor genes making HDAC inhibitors viable anticancer drugs against tumors with increased activity of the enzyme. In this study we evaluated 18F-fluroacetamido-1-hexanoicanilide (18F-FAHA), an artificial HDAC substrate, as imaging probe of HDAC activity of human tumor xenografts in immunocompromised host mice. Human breast and melanoma cell lines, MDA-MB-468 and MDA-MB-435 respectively, known to overexpress HDAC activity were xenografted into immunocompromised mice and HDAC activity was imaged using 18F-FAHA. The melanoma group was treated with saline, SAHA (suberoylanilide hydroxamic acid, an approved anticancer HDAC inhibitor) in DMSO, or DMSO as positive control. Tracer kinetic modelling and SUV were used to estimate HDAC activity from dynamic PET data. Both breast tumor and melanoma group showed great variability in binding rate constant (BRC) of 18F-FAHA suggesting highly variable inter- and intra-tumoral HDAC activity. For the SAHA treated melanoma group, HDAC activity, as monitored by BRC of 18F-FAHA, decreased more than the two (positive and negative) control groups but not tumor growth. Our preliminary study showed that noninvasive PET imaging with 18F-FAHA has the potential to identify patients for whom treatment with HDAC inhibitors are appropriate, to assess the effectiveness of that treatment as an early marker of target reduction, and also eliminate the need for invasive tissue biopsy to individualize treatment.

Synthesis and preliminary evaluation of 18-(18)F-fluoro-4-thia-oleate as a PET probe of fatty acid oxidation.

PubMed

DeGrado, Timothy R; Bhattacharyya, Falguni; Pandey, Mukesh K; Belanger, Anthony P; Wang, Shuyan

2010-08-01

Fatty acid oxidation (FAO) is a major energy-providing process with important implications in cardiovascular, oncologic, neurologic, and metabolic diseases. A novel 4-thia oleate analog, 18-(18)F-fluoro-4-thia-oleate ((18)F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-(18)F-fluoro-4-thia-palmitate ((18)F-FTP) as an FAO probe. (18)F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with (18)F-FTO and (18)F-FTP in rats. A practical synthesis of (18)F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of (18)F-FTO (0.70 +/- 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of (18)F-FTP at 30 min after injection. At 2 h, myocardial uptake of (18)F-FTO was maintained, whereas (18)F-FTP uptake in the heart was 82% reduced. Similar to (18)F-FTP, (18)F-FTO uptake by the heart was approximately 80% reduced at 30 min by pretreatment of rats with the CPT-I inhibitor etomoxir. Folch-type extraction analyses showed 70-90% protein-bound fractions in the heart, liver, and skeletal muscle, consistent with efficient trafficking of (18)F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of (18)F-FTO and of (18)F-FTP into the heart and liver. Images of (18)F-FTO accumulation in the rat myocardium were clearly superior to those of (18)F-FTP. (18)F-FTO is shown to be a promising metabolically trapped FAO probe that warrants further evaluation.

One-pot production of 18F-biotin by conjugation with 18F-FDG for pre-targeted imaging: synthesis and radio-labelling of a PEGylated precursor.

PubMed

Simpson, Michael; Trembleau, Laurent; Cheyne, Richard W; Smith, Tim A D

2011-02-01

The biotin-avidin affinity system is exploited in pre-targeted imaging using avidin-conjugated antibodies. (18)F-FDG is available at all PET centres. (18)F-FDG forms oximes by reaction with oxyamine. Herein we describe the synthesis of oxyamine-funtionalised biotin, its (18)F-labelling by conjugation with (18)F-FDG and confirm its ability to interact with avidin. Copyright © 2010 Elsevier Ltd. All rights reserved.

Heterogeneity in Intratumor Correlations of 18F-FDG, 18F-FLT, and 61Cu-ATSM PET in Canine Sinonasal Tumors

PubMed Central

Bradshaw, Tyler J.; Bowen, Stephen R.; Jallow, Ngoneh; Forrest, Lisa J.; Jeraj, Robert

2014-01-01

Intratumor heterogeneity in biologic properties and in relationships between various phenotypes may present a challenge for biologically targeted therapies. Understanding the relationships between different phenotypes in individual tumor types could help inform treatment selection. The goal of this study was to characterize spatial correlations of glucose metabolism, proliferation, and hypoxia in 2 histologic types of tumors. Methods Twenty canine veterinary patients with spontaneously occurring sinonasal tumors (13 carcinomas and 7 sarcomas) were imaged with 18F-FDG, 18F-labeled 39-deoxy-39-fluorothymidine (18F-FLT), and 61Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone) (61Cu-ATSM) PET/CT on 3 consecutive days. Precise positioning and immobilization techniques coupled with anesthesia enabled motionless scans with repeatable positioning. Standardized uptake values (SUVs) of gross sarcoma and carcinoma volumes were compared by use of Mann– Whitney U tests. Patient images were rigidly registered together, and intratumor tracer uptake distributions were compared. Voxel-based Spearman correlation coefficients were used to quantify intertracer correlations, and the correlation coefficients of sarcomas and carcinomas were compared. The relative overlap of the highest uptake volumes of the 3 tracers was quantified, and the values were compared for sarcomas and carcinomas. Results Large degrees of heterogeneity in SUV measures and phenotype correlations were observed. Carcinoma and sarcoma tumors differed significantly in SUV measures, with carcinoma tumors having significantly higher 18F-FDG maximum SUVs than sarcoma tumors (11.1 vs. 5.0; P = 0.01) as well as higher 61Cu-ATSM mean SUVs (2.6 vs. 1.2; P = 0.02). Carcinomas had significantly higher population-averaged Spearman correlation coefficients than sarcomas in comparisons of 18F-FDG and 18F-FLT (0.80 vs. 0.61; P = 0.02), 18F-FLT and 61Cu-ATSM (0.83 vs. 0.38; P < 0.0001), and 18F-FDG and 61Cu-ATSM (0.82 vs. 0

Brain energy metabolism and neuroinflammation in ageing APP/PS1-21 mice using longitudinal 18F-FDG and 18F-DPA-714 PET imaging.

PubMed

Takkinen, Jatta S; López-Picón, Francisco R; Al Majidi, Rana; Eskola, Olli; Krzyczmonik, Anna; Keller, Thomas; Löyttyniemi, Eliisa; Solin, Olof; Rinne, Juha O; Haaparanta-Solin, Merja

2017-08-01

Preclinical animal model studies of brain energy metabolism and neuroinflammation in Alzheimer's disease have produced conflicting results, hampering both the elucidation of the underlying disease mechanism and the development of effective Alzheimer's disease therapies. Here, we aimed to quantify the relationship between brain energy metabolism and neuroinflammation in the APP/PS1-21 transgenic mouse model of Alzheimer's disease using longitudinal in vivo 18 F-FDG and 18 F-DPA-714) PET imaging and ex vivo brain autoradiography. APP/PS1-21 (TG, n = 9) and wild type control mice (WT, n = 9) were studied longitudinally every third month from age 6 to 15 months with 18 F-FDG and 18 F-DPA-714 with a one-week interval between the scans. Additional TG (n = 52) and WT (n = 29) mice were used for ex vivo studies. In vivo, the 18 F-FDG SUVs were lower and the 18 F-DPA-714 binding ratios relative to the cerebellum were higher in the TG mouse cortex and hippocampus than in WT mice at age 12 to 15 months ( p < 0.05). The ex vivo cerebellum binding ratios supported the results of the in vivo 18 F-DPA-714 studies but not the 18 F-FDG studies. This longitudinal PET study demonstrated decreased energy metabolism and increased inflammation in the brains of APP/PS1-21 mice compared to WT mice.

The feasibility of 18F-AlF-NOTA-PRGD2 PET/CT for monitoring early response of Endostar antiangiogenic therapy in human nasopharyngeal carcinoma xenograft model compared with 18F-FDG

PubMed Central

Liang, Sheng; Zhang, Caiyuan; Cheng, Weiwei; Hai, Wangxi; Yin, Bing; Wang, Dengbin

2016-01-01

Purpose Radiolabeled arginine-glycine-aspartic acid (RGD) peptides have been developed for PET imaging of integrin avβ3 in the tumor vasculature, leading to great potential for noninvasively evaluating tumor angiogenesis and monitoring antiangiogenic treatment. The aim of this study was to investigate a novel one-step labeled integrin-targeted tracer, 18F-AlF-NOTA-PRGD2, for PET/CT for detecting tumor angiogenesis and monitoring the early therapeutic efficacy of antiangiogenic agent Endostar in human nasopharyngeal carcinoma (NPC) xenograft model. Experimental design and results Mice bearing NPC underwent 18F-AlF-NOTA-PRGD2 PET/CT at baseline and after 2, 4, 7, and 14 days of consecutive treatment with Endostar or PBS, compared with 18F-FDG PET/CT. Tumors were harvested at all imaging time points for histopathological analysis with H & E and microvessel density (MVD) and integrin avβ3 immunostaining. The maximum percent injected dose per gram of body weight (%ID/gmax) tumor uptake of 18F-AlF-NOTA-PRGD2 PET/CT was significantly lower than that in the control group starting from day 2 (p < 0.01), much earlier and more accurately than that of 18F-FDG PET/CT. Moreover, a moderate linear correlation was observed between tumor MVD and the corresponding tumor uptake of 18F-AlF-NOTA-PRGD2 PET/CT (r = 0.853, p < 0.01). Conclusions 18F-AlF-NOTA-PRGD2 PET/CT can be used for in vivo angiogenesis imaging and monitoring early response to Endostar antiangiogenic treatment in NPC xenograft model, favoring its potential clinical translation. PMID:27029065

Influence of P-Glycoprotein Inhibition or Deficiency at the Blood-Brain Barrier on (18)F-2-Fluoro-2-Deoxy-D-glucose ( (18)F-FDG) Brain Kinetics.

PubMed

Tournier, Nicolas; Saba, Wadad; Goutal, Sébastien; Gervais, Philippe; Valette, Héric; Scherrmann, Jean-Michel; Bottlaender, Michel; Cisternino, Salvatore

2015-05-01

The fluorinated D-glucose analog (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) is the most prevalent radiopharmaceutical for positron emission tomography (PET) imaging. P-Glycoprotein's (P-gp, MDR1, and ABCB1) function in various cancer cell lines and tumors was shown to impact (18)F-FDG incorporation, suggesting that P-gp function at the blood-brain barrier may also modulate (18)F-FDG brain kinetics. We tested the influence of P-gp inhibition using the cyclosporine analog valspodar (PSC833; 5 μM) on the uptake of (18)F-FDG in standardized human P-gp-overexpressing cells (MDCKII-MDR1). Consequences for (18)F-FDG brain kinetics were then assessed using (i) (18)F-FDG PET imaging and suitable kinetic modelling in baboons without or with P-gp inhibition by intravenous cyclosporine infusion (15 mg kg(-1) h(-1)) and (ii) in situ brain perfusion in wild-type and P-gp/Bcrp (breast cancer resistance protein) knockout mice and controlled D-glucose exposure to the brain. In vitro, the time course of (18)F-FDG uptake in MDR1 cells was influenced by the presence of valspodar in the absence of D-glucose but not in the presence of high D-glucose concentration. PET analysis revealed that P-gp inhibition had no significant impact on estimated brain kinetics parameters K 1, k 2, k 3, V T , and CMRGlc. The lack of P-gp effect on in vivo (18)F-FDG brain distribution was confirmed in P-gp/Bcrp-deficient mice. P-gp inhibition indirectly modulates (18)F-FDG uptake into P-gp-overexpressing cells, possibly through differences in the energetic cell level state. (18)F-FDG is not a P-gp substrate at the BBB and (18)F-FDG brain kinetics as well as estimated brain glucose metabolism are influenced by neither P-gp inhibition nor P-gp/Bcrp deficiencies in baboon and mice, respectively.

Depicting changes in tumor biology in response to cetuximab mono- or combination therapy by apoptosis and proliferation imaging using 18F-ICMT-11 and 3'-Deoxy-3'-[18F]Fluorothymidine (18F-FLT) PET.

PubMed

Heinzmann, Kathrin; Nguyen, Quang-De; Honess, Davina Jean; Smith, Donna-Michelle; Stribbling, Stephen; Brickute, Diana; Barnes, Christopher; Griffiths, John Richard; Aboagye, Eric Ofori

2018-05-24

Imaging biomarkers must demonstrate their value in monitoring treatment. Two PET tracers, the caspase-3/7-specific isatin-5-sulfonamide 18 F-ICMT-11 and 3'-Deoxy-3'-[ 18 F]Fluorothymidine ( 18 F-FLT), were employed to detect early treatment-induced changes in tumor biology and whether any changes indicate response to cetuximab, administered as mono- or combination therapy with gemcitabine. Methods: Effects of single or repeated doses of the anti-Epidermal Growth Factor Receptor (EGFR) antibody cetuximab (10mg/kg on day 1 only or day 1 and 2) and/or a single dose of gemcitabine (125mg/kg; day 2) were investigated in mice bearing cetuximab-sensitive H1975 tumors (non-small cell lung cancer) by 18 F-ICMT-11 or 18 F-FLT-PET (day 3). Imaging was also performed in mice bearing cetuximab-insensitive HCT116 tumors (colorectal cancer) after two doses of cetuximab (day 1 and 2). For imaging/histology comparison, tumors were evaluated for proliferation (Ki67; thymidine kinase 1, TK1), cell death (cleaved caspase-3, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL)) and target engagement (EGFR expression) by immunohistochemistry, immunofluorescence and immunoblot, respectively. Tumor and plasma were analysed for thymidine and gemcitabine metabolites by liquid chromatography-mass spectrometry. Results: Retention of both tracers was sensitive to cetuximab in H1975 tumors. 18 F-ICMT-11 uptake and ex vivo cleaved caspase-3 staining notably increased in tumors treated with repeated doses of cetuximab- (75%) and combination-treatment (46%). While one dose of cetuximab was insufficient to induce apoptosis it did affect proliferation. Significant reduction in tumor 18 F-FLT uptake (44 to 50%; P < 0.001) induced by cetuximab mono- and combination-therapy were paralleled with a clear decrease in proliferation (%Ki67 decrease: 72 to 95%; P < 0.0001) and followed by marked tumor growth delay. TK1 expression and tumor thymidine concentrations were profoundly

Imaging of prostate cancer with PET/CT using 18F-Fluorocholine

PubMed Central

Vali, Reza; Loidl, Wolfgang; Pirich, Christian; Langesteger, Werner; Beheshti, Mohsen

2015-01-01

While 18F-Fluorodeoxyglucose (18F-FDG) Positron-Emission Tomography (PET) has limited value in prostate cancer (PCa), it may be useful for specific subgroups of PCa patients with hormone-resistant poorly differentiated cell types. 18F-Fluorocholine (18F-FCH) PET/CT has been increasingly used in primary and recurrent PCa and has been shown to add valuable information. Although there is a correlation between the foci of activity and the areas of malignancy in the prostate gland, the clinical value of 18F-FCH is still controversial for detection of the malignant focus in the prostate. For the T-staging of PCa at diagnosis the value of 18F-FCH is limited. This is probably due to limited resolution of PET system and positive findings in benign prostate diseases. Conversely, 18F-FCH PET/CT is a promising imaging modality for the delineation of local and distant nodal recurrence and bone metastases and is poised to have an impact on therapy management. In this review, recent studies of 18F-FCH PET/CT in PCa are summarized. PMID:25973332

N,N-dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)-benzylamine (4-(18)F-ADAM): an improved PET radioligand for serotonin transporters.

PubMed

Shiue, Grace G; Choi, Seok-Rye; Fang, Ping; Hou, Catherine; Acton, Paul D; Cardi, Chris; Saffer, Janet R; Greenberg, Joel H; Karp, Joel S; Kung, Hank F; Shiue, Chyng-Yann

2003-12-01

There has been considerable interest in the development of PET radioligands that are useful for imaging serotonin transporter (SERT) in the living human brain. For the last decade, (11)C-(+)McN5652 has been the most promising PET agent for studying SERT in humans. However, this agent has some limitations. Recently, a new promising SERT PET radioligand, 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile, has been reported. We recently reported the synthesis of a new (18)F-labeled SERT PET radioligand, N,N-dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)benzylamine (4-(18)F-ADAM), which may have advantages over (11)C-labeled radioligands. The purpose of this study was to evaluate this newly developed (18)F-labeled PET radioligand as a promising agent for studying SERT in the living human brain. This agent was evaluated by studying its in vitro binding to different monoamine transporters, its in vivo biodistributions in rats, its integrity and pharmacologic profiles in rat brain, and its distribution in a female baboon brain. In vitro binding assays showed that 4-F-ADAM displayed high affinity to SERT sites (inhibition constant = 0.081 nmol/L, using membrane preparations of LLC-PK1 cells expressing the specific transporter) and showed more than 1,000- and 28,000-fold selectivity for SERT over norepinephrine transporter and dopamine transporter, respectively. Biodistribution of 4-(18)F-ADAM in rats showed a high initial uptake and slow clearance in the brain (2.13%, 1.90%, and 0.95% injected dose per organ at 2, 30, and 60 min after intravenous injection, respectively), with the specific binding peaking at 2 h after injection (hypothalamus/cerebellum = 12.49). The uptake in blood, muscle, lung, kidney, and liver was also initially high but cleared rapidly. The radioactivity in the femur increases with time for 4-(18)F-ADAM, indicating that in vivo defluorination may occur. In vivo metabolism studies in rats showed that 4-(18)F-ADAM was not metabolized in

Synthesis of 2'-deoxy-2'-[.sup.18F]fluoro-5-methyl-1-B-D-arabinofuranosyluracil (.sup.18F-FMAU)

DOEpatents

Li, Zibo; Cai, Hancheng; Conti, Peter S

2014-12-16

The present invention relates to methods of synthesizing .sup.18F-FMAU. In particular, .sup.18F-FMAU is synthesized using one-pot reaction conditions in the presence of Friedel-Crafts catalysts. The one-pot reaction conditions are incorporated into a fully automated cGMP-compliant radiosynthesis module, which results in a reduction in synthesis time and simplifies reaction conditions. The one-pot reaction conditions are also suitable for the production of 5-substituted thymidine or cytidine analogs. The products from the one-pot reaction (e.g. the labeled thymidine or cytidine analogs) can be used as probes for imaging tumor proliferative activity. More specifically, these [.sup.18F]-labeled thymidine or cytidine analogs can be used as a PET tracer for certain medical conditions, including, but not limited to, cancer disease, autoimmunity inflammation, and bone marrow transplant.

Automated synthesis of N-(2-[18 F]Fluoropropionyl)-l-glutamic acid as an amino acid tracer for tumor imaging on a modified [18 F]FDG synthesis module.

PubMed

Liu, Shaoyu; Sun, Aixia; Zhang, Zhanwen; Tang, Xiaolan; Nie, Dahong; Ma, Hui; Jiang, Shende; Tang, Ganghua

2017-06-15

N-(2-[ 18 F]Fluoropropionyl)-l-glutamic acid ([ 18 F]FPGLU) is a potential amino acid tracer for tumor imaging with positron emission tomography. However, due to the complicated multistep synthesis, the routine production of [ 18 F]FPGLU presents many challenging laboratory requirements. To simplify the synthesis process of this interesting radiopharmaceutical, an efficient automated synthesis of [ 18 F]FPGLU was performed on a modified commercial fluorodeoxyglucose synthesizer via a 2-step on-column hydrolysis procedure, including 18 F-fluorination and on-column hydrolysis reaction. [ 18 F]FPGLU was synthesized in 12 ± 2% (n = 10, uncorrected) radiochemical yield based on [ 18 F]fluoride using the tosylated precursor 2. The radiochemical purity was ≥98%, and the overall synthesis time was 35 minutes. To further optimize the radiosynthesis conditions of [ 18 F]FPGLU, a brominated precursor 3 was also used for the preparation of [ 18 F]FPGLU, and the improved radiochemical yield was up to 20 ± 3% (n = 10, uncorrected) in 35 minutes. Moreover, all these results were achieved using the similar on-column hydrolysis procedure on the modified fluorodeoxyglucose synthesis module. Copyright © 2017 John Wiley & Sons, Ltd.

Multiparametric [18F]Fluorodeoxyglucose/ [18F]Fluoromisonidazole Positron Emission Tomography/ Magnetic Resonance Imaging of Locally Advanced Cervical Cancer for the Non-Invasive Detection of Tumor Heterogeneity: A Pilot Study

PubMed Central

Andrzejewski, Piotr; Baltzer, Pascal; Polanec, Stephan H.; Sturdza, Alina; Georg, Dietmar; Helbich, Thomas H.; Karanikas, Georgios; Grimm, Christoph; Polterauer, Stephan; Poetter, Richard; Wadsak, Wolfgang; Mitterhauser, Markus; Georg, Petra

2016-01-01

Objectives To investigate fused multiparametric positron emission tomography/magnetic resonance imaging (MP PET/MRI) at 3T in patients with locally advanced cervical cancer, using high-resolution T2-weighted, contrast-enhanced MRI (CE-MRI), diffusion-weighted imaging (DWI), and the radiotracers [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoromisonidazol ([18F]FMISO) for the non-invasive detection of tumor heterogeneity for an improved planning of chemo-radiation therapy (CRT). Materials and Methods Sixteen patients with locally advanced cervix were enrolled in this IRB approved and were examined with fused MP [18F]FDG/ [18F]FMISO PET/MRI and in eleven patients complete data sets were acquired. MP PET/MRI was assessed for tumor volume, enhancement (EH)-kinetics, diffusivity, and [18F]FDG/ [18F]FMISO-avidity. Descriptive statistics and voxel-by-voxel analysis of MRI and PET parameters were performed. Correlations were assessed using multiple correlation analysis. Results All tumors displayed imaging parameters concordant with cervix cancer, i.e. type II/III EH-kinetics, restricted diffusivity (median ADC 0.80x10-3mm2/sec), [18F]FDG- (median SUVmax16.2) and [18F]FMISO-avidity (median SUVmax3.1). In all patients, [18F]FMISO PET identified the hypoxic tumor subvolume, which was independent of tumor volume. A voxel-by-voxel analysis revealed only weak correlations between the MRI and PET parameters (0.05–0.22), indicating that each individual parameter yields independent information and the presence of tumor heterogeneity. Conclusion MP [18F]FDG/ [18F]FMISO PET/MRI in patients with cervical cancer facilitates the acquisition of independent predictive and prognostic imaging parameters. MP [18F]FDG/ [18F]FMISO PET/MRI enables insights into tumor biology on multiple levels and provides information on tumor heterogeneity, which has the potential to improve the planning of CRT. PMID:27167829

Multiparametric [18F]Fluorodeoxyglucose/ [18F]Fluoromisonidazole Positron Emission Tomography/ Magnetic Resonance Imaging of Locally Advanced Cervical Cancer for the Non-Invasive Detection of Tumor Heterogeneity: A Pilot Study.

PubMed

Pinker, Katja; Andrzejewski, Piotr; Baltzer, Pascal; Polanec, Stephan H; Sturdza, Alina; Georg, Dietmar; Helbich, Thomas H; Karanikas, Georgios; Grimm, Christoph; Polterauer, Stephan; Poetter, Richard; Wadsak, Wolfgang; Mitterhauser, Markus; Georg, Petra

2016-01-01

To investigate fused multiparametric positron emission tomography/magnetic resonance imaging (MP PET/MRI) at 3T in patients with locally advanced cervical cancer, using high-resolution T2-weighted, contrast-enhanced MRI (CE-MRI), diffusion-weighted imaging (DWI), and the radiotracers [18F]fluorodeoxyglucose ([18F]FDG) and [18F]fluoromisonidazol ([18F]FMISO) for the non-invasive detection of tumor heterogeneity for an improved planning of chemo-radiation therapy (CRT). Sixteen patients with locally advanced cervix were enrolled in this IRB approved and were examined with fused MP [18F]FDG/ [18F]FMISO PET/MRI and in eleven patients complete data sets were acquired. MP PET/MRI was assessed for tumor volume, enhancement (EH)-kinetics, diffusivity, and [18F]FDG/ [18F]FMISO-avidity. Descriptive statistics and voxel-by-voxel analysis of MRI and PET parameters were performed. Correlations were assessed using multiple correlation analysis. All tumors displayed imaging parameters concordant with cervix cancer, i.e. type II/III EH-kinetics, restricted diffusivity (median ADC 0.80x10-3mm2/sec), [18F]FDG- (median SUVmax16.2) and [18F]FMISO-avidity (median SUVmax3.1). In all patients, [18F]FMISO PET identified the hypoxic tumor subvolume, which was independent of tumor volume. A voxel-by-voxel analysis revealed only weak correlations between the MRI and PET parameters (0.05-0.22), indicating that each individual parameter yields independent information and the presence of tumor heterogeneity. MP [18F]FDG/ [18F]FMISO PET/MRI in patients with cervical cancer facilitates the acquisition of independent predictive and prognostic imaging parameters. MP [18F]FDG/ [18F]FMISO PET/MRI enables insights into tumor biology on multiple levels and provides information on tumor heterogeneity, which has the potential to improve the planning of CRT.

A multicenter clinical trial on the diagnostic value of dual-tracer PET/CT in pulmonary lesions using 3'-deoxy-3'-18F-fluorothymidine and 18F-FDG.

PubMed

Tian, Jiahe; Yang, Xiaofeng; Yu, Lijuan; Chen, Ping; Xin, Jun; Ma, Liming; Feng, Huiru; Tan, Yieyin; Zhao, Zhoushe; Wu, Wenkai

2008-02-01

Some new radiotracers might add useful information and improve diagnostic confidence of (18)F-FDG imaging in tumors. A multicenter clinical trial was designed to investigate the diagnostic performance of dual-tracer ((18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine [(18)F-FLT]) PET/CT in pulmonary nodules. Fifty-five patients underwent dual-tracer imaging in 6 imaging centers using the same models of equipment and standardized protocols. The images were interpreted by a collective group of readers who were unaware of the clinical data. The diagnostic performance using either tracer alone or dual-tracers together, with or without CT, was compared. The histological diagnosis or clinical findings in a 12-mo follow-up period served as the standard of truth. In 16 patients with malignant tumor, 16 with tuberculosis, and 23 with other benign lesions, the sensitivity and specificity of (18)F-FDG and (18)F-FLT were 87.5% and 58.97% and 68.75% and 76.92%, respectively. The combination of dual-tracer PET/CT improved the sensitivity and specificity up to 100% and 89.74%. The 3 subgroups of patients could be best separated when the (18)F-FLT/(18)F-FDG standardized uptake value ratio of 0.4-0.90 was used as the threshold. By reflecting different biologic features, the dual-tracer PET/CT using (18)F-FDG and (18)F-FLT favorably affected the diagnosis of lung nodules.

Mapping the binding domain of the F18 fimbrial adhesin.

PubMed

Smeds, A; Pertovaara, M; Timonen, T; Pohjanvirta, T; Pelkonen, S; Palva, A

2003-04-01

F18 fimbrial Esherichia coli strains are associated with porcine postweaning diarrhea and pig edema disease. Recently, the FedF subunit was identified as the adhesin of the F18 fimbriae. In this study, adhesion domains of FedF were further studied by constructing deletions within the fedF gene and expressing FedF proteins with deletions either together with the other F18 fimbrial subunits or as fusion proteins tagged with maltose binding protein. The region essential for adhesion to porcine intestinal epithelial cells was mapped between amino acid residues 60 and 109 of FedF. To map the binding domain even more closely, all eight charged amino acid residues within this region were independently replaced by alanine. Three of these single point mutants expressing F18 fimbriae exhibited significantly diminished capabilities to adhere to porcine epithelial cells in vitro. In addition, a triple point mutation and a double point mutation completely abolished receptor adhesiveness. The result further confirmed that the region between amino acid residues 60 and 109 is essential for the binding of F18 fimbriae to their receptor. In addition, the adhesion capability of the binding domain was eliminated after treatment with iodoacetamide, suggesting the formation of a disulfide bridge between Cys-63 and Cys-83, whereas Cys-111 and Cys-116 could be deleted without affecting the binding ability of FedF.

F18-FDG coincidence-PET in patients with suspected gynecological malignancy.

PubMed

Zor, E; Stokkel, M P; Ozalp, S; Vardareli, E; Yalçin, O Tarik; Ak, I

2006-07-01

To assess the role of F18-FDG imaging with a dual-head coincidence mode gamma camera (Co-PET) in identifying malignant tumors in patients with a suspicious adnexal mass depicted by conventional imaging methods. F18-FDG Co-PET was performed preoperatively in 18 women (mean age 56.38 years) with suspected malignant gynecologic tumors according to clinical and abdomino-pelvic/transvaginal ultrasound or computed tomography findings. Exploratory laparotomy was performed in all patients within the 10 days post-F18-FDG Co-PET study, and the definitive diagnosis of the adnexal masses was established by histopathological examination. Histopathological examinations of the surgically excised adnexal masses revealed eight malignant, one borderline, and nine benign neoplastic tumors. Four benign tumors had no F18-FDG uptake, while the remaining five tumors, all leiomyomas, showed mild FDG accumulation. Eight malignant tumors showed intense F18-FDG uptake. Sensitivity, specificity, PPV, and NPV of F18-FDG co-PET in differentiating benign from malign adnexal masses were 88%, 44%, 61%, and 80%, respectively. Tumor to background ratios (T/B) in benign lesions (2.04 +/- 0.27) were significantly lower than in malignant lesions (7.4 +/- 0.99). F18-FDG Co-PET is of clinical value when assessing suspicious malignant adnexal masses. False-negative F18-FDG results might arise from borderline disease. Moderate F18-FDG uptake in leiomyomas can result false-positive, but T/B ratios may be helpful in such cases.

Sulfonyl fluoride-based prosthetic compounds as potential 18F labelling agents.

PubMed

Inkster, James A H; Liu, Kate; Ait-Mohand, Samia; Schaffer, Paul; Guérin, Brigitte; Ruth, Thomas J; Storr, Tim

2012-08-27

Nucleophilic incorporation of [(18)F]F(-) under aqueous conditions holds several advantages in radiopharmaceutical development, especially with the advent of complex biological pharmacophores. Sulfonyl fluorides can be prepared in water at room temperature, yet they have not been assayed as a potential means to (18)F-labelled biomarkers for PET chemistry. We developed a general route to prepare bifunctional 4-formyl-, 3-formyl-, 4-maleimido- and 4-oxylalkynl-arylsulfonyl [(18)F]fluorides from their sulfonyl chloride analogues in 1:1 mixtures of acetonitrile, THF, or tBuOH and Cs[(18)F]F/Cs(2)CO(3(aq.)) in a reaction time of 15 min at room temperature. With the exception of 4-N-maleimide-benzenesulfonyl fluoride (3), pyridine could be used to simplify radiotracer purification by selectively degrading the precursor without significantly affecting observed yields. The addition of pyridine at the start of [(18)F]fluorination (1:1:0.8 tBuOH/Cs(2)CO(3(aq.))/pyridine) did not negatively affect yields of 3-formyl-2,4,6-trimethylbenzenesulfonyl [(18)F]fluoride (2) and dramatically improved the yields of 4-(prop-2-ynyloxy)benzenesulfonyl [(18)F]fluoride (4). The N-arylsulfonyl-4-dimethylaminopyridinium derivative of 4 (14) can be prepared and incorporates (18)F efficiently in solutions of 100 % aqueous Cs(2)CO(3) (10 mg mL(-1)). As proof-of-principle, [(18)F]2 was synthesised in a preparative fashion [88(±8) % decay corrected (n=6) from start-of-synthesis] and used to radioactively label an oxyamino-modified bombesin(6-14) analogue [35(±6) % decay corrected (n=4) from start-of-synthesis]. Total preparation time was 105-109 min from start-of-synthesis. Although the (18)F-peptide exhibited evidence of proteolytic defluorination and modification, our study is the first step in developing an aqueous, room temperature (18)F labelling strategy. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): a novel vesicular monoamine transporter 2 imaging agent.

PubMed

Lin, Kun-Ju; Weng, Yi-Hsin; Wey, Shiaw-Pyng; Hsiao, Ing-Tsung; Lu, Chin-Song; Skovronsky, Daniel; Chang, Hsiu-Ping; Kung, Mei-Ping; Yen, Tzu-Chen

2010-09-01

Vesicular monoamine transporter 2 (VMAT2) is highly expressed in the endocrine cells and brain. We investigated the biodistribution and radiation dosimetry of (2R,3R,11bR)-9-(3-(18)F-fluoropropoxy)-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol ((18)F-FP-(+)-dihydrotetrabenazine [DTBZ] or (18)F-AV-133), a potential VMAT2 imaging agent showing encouraging results in humans, to facilitate its future clinical use. Nine healthy human subjects (mean age +/- SD, 58.6 +/- 4.2 y) were enrolled for the whole-body PET scan. Serial images were acquired for 3 h immediately after a bolus injection of 390.7 +/- 22.9 MBq of (18)F-AV-133 per individual. The source organs were delineated on PET/CT images. The OLINDA/EXM application was used to determine the equivalent dose for individual organs. The radiotracer did not show any noticeable adverse effects for the 9 subjects examined. The radioactivity uptake in the brain was the highest at 7.5% +/- 0.6% injected dose at 10 min after injection. High absorbed doses were found in the pancreas, liver, and upper large intestine wall. The highest-dosed organ, which received 153.3 +/- 23.8 microGy/MBq, was the pancreas. The effective dose equivalent and effective dose for (18)F-AV-133 were 36.5 +/- 2.8 and 27.8 +/- 2.5 microSv/MBq, respectively. These values are comparable to those reported for any other (18)F-labeled radiopharmaceutical. (18)F-AV-133 is safe, with appropriate biodistribution and radiation dosimetry for imaging VMAT2 sites in humans.

Utility of 18F-fluoro-deoxyglucose emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in combination with ultrasonography for axillary staging in primary breast cancer.

PubMed

Ueda, Shigeto; Tsuda, Hitoshi; Asakawa, Hideki; Omata, Jiro; Fukatsu, Kazuhiko; Kondo, Nobuo; Kondo, Tadaharu; Hama, Yukihiro; Tamura, Katsumi; Ishida, Jiro; Abe, Yoshiyuki; Mochizuki, Hidetaka

2008-06-09

Accurate evaluation of axillary lymph node (ALN) involvement is mandatory before treatment of primary breast cancer. The aim of this study is to compare preoperative diagnostic accuracy between positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (18F-FDG PET/CT) and axillary ultrasonography (AUS) for detecting ALN metastasis in patients having operable breast cancer, and to assess the clinical management of axillary 18F-FDG PET/CT for therapeutic indication of sentinel node biopsy (SNB) and preoperative systemic chemotherapy (PSC). One hundred eighty-three patients with primary operable breast cancer were recruited. All patients underwent 18F-FDG PET/CT and AUS followed by SNB and/or ALN dissection (ALND). Using 18F-FDG PET/CT, we studied both a visual assessment of 18F-FDG uptake and standardized uptake value (SUV) for axillary staging. In a visual assessment of 18F-FDG PET/CT, the diagnostic accuracy of ALN metastasis was 83% with 58% in sensitivity and 95% in specificity, and when cut-off point of SUV was set at 1.8, sensitivity, specificity, and accuracy were 36, 100, and 79%, respectively. On the other hand, the diagnostic accuracy of AUS was 85% with 54% in sensitivity and 99% in specificity. By the combination of 18F-FDG PET/CT and AUS to the axilla, the sensitivity, specificity, and accuracy were 64, 94, and 85%, respectively. If either 18F-FDG PET uptake or AUS was positive in allixa, the probability of axillary metastasis was high; 50% (6 of 12) in 18F-FDG PET uptake only, 80% (4 of 5) in AUS positive only, and 100% (28 of 28) in dual positive. By the combination of AUS and 18F-FDG PET/CT, candidates of SNB were more appropriately selected. The axillary 18F-FDG uptake was correlated with the maximum size and nuclear grade of metastatic foci (p = 0.006 and p = 0.03). The diagnostic accuracy of 18F-FDG PET/CT was shown to be nearly equal to ultrasound, and considering their limited sensitivities, the high radiation exposure by 18F

Integrated whole-body PET/MR imaging with 18F-FDG, 18F-FDOPA, and 18F-fluorodopamine in paragangliomas, in comparison to PET/CT: NIH first clinical experience with a single-injection, dual-modality imaging protocol

PubMed Central

Blanchet, Elise M.; Millo, Corina; Martucci, Victoria; Maass-Moreno, Roberto; Bluemke, David A.; Pacak, Karel

2017-01-01

Purpose Paragangliomas (PGLs) are tumors that can metastasize and recur; therefore, lifelong imaging follow-up is required. Hybrid positron emission tomography (PET)/computed tomography (/CT) is an essential tool to image PGLs. Novel hybrid PET/magnetic resonance (/MR) scanners are currently being studied in clinical oncology. We studied the feasibility of simultaneous whole-body PET/MR imaging to evaluate patients with PGLs. Methods Fifty-three PGLs or PGL-related lesions from eight patients were evaluated. All patients underwent a single-injection, dual-modality imaging protocol consisting of a PET/CT and subsequent PET/MR scan. Four patients were evaluated with 18F-fluorodeoxyglucose (18F-FDG), two with 18F-fluorodihydroxyphenylalanine (18F-FDOPA), and two with 18F-fluorodopamine (18F-FDA). PET/MR data were acquired using a hybrid whole-body 3-Tesla integrated PET/MR scanner. PET and MR data (DIXON images for attenuation correction and T2-weighted sequences for anatomic allocation) were acquired simultaneously. Imaging workflow and imaging times were documented. PET/MR and PET/CT data were visually assessed (blindly) in regards to image quality, lesion detection, and anatomic allocation and delineation of the PET findings. Results With hybrid PET/MR, we obtained high quality images in an acceptable acquisition time (median: 31 min, range: 25–40 min) with good patient compliance. A total of 53 lesions, located in the head-and-neck area (6), mediastinum (2), abdomen and pelvis (13), lungs (2), liver (4), and bone (26) were evaluated. 51 lesions were detected with PET/MR and confirmed by PET/CT. Two bone lesions (L4 body (8 mm) and sacrum (6 mm)) were not detectable on an 18F-FDA scan PET/MR, likely due to washout of the 18F-FDA. Co-registered MR tended to be superior to co-registered CT for head-and-neck, abdomen, pelvis, and liver lesions for anatomic allocation and delineation. Conclusions Clinical PGL evaluation with hybrid PET/MR is feasible with high image

Evaluation of the Outcome of Lung Nodules Missed on 18F-FDG PET/MRI Compared with 18F-FDG PET/CT in Patients with Known Malignancies.

PubMed

Sawicki, Lino M; Grueneisen, Johannes; Buchbender, Christian; Schaarschmidt, Benedikt M; Gomez, Benedikt; Ruhlmann, Verena; Umutlu, Lale; Antoch, Gerald; Heusch, Philipp

2016-01-01

The lower detection rate of (18)F-FDG PET/MRI than (18)F-FDG PET/CT regarding small lung nodules should be considered in the staging of malignant tumors. The purpose of this study was to evaluate the outcome of these small lung nodules missed by (18)F-FDG PET/MRI. Fifty-one oncologic patients (mean age ± SD, 56.6 ± 14.0 y; 29 women, 22 men; tumor stages, I [n = 7], II [n = 7], III [n = 9], IV [n = 28]) who underwent (18)F-FDG PET/CT and subsequent (18)F-FDG PET/MRI on the same day were retrospectively enrolled. Images were analyzed by 2 interpreters in random order and separate sessions with a minimum of 4 wk apart. A maximum of 10 lung nodules was identified for each patient on baseline imaging. The presence, size, and presence of focal tracer uptake was noted for each lung nodule detected on (18)F-FDG PET/CT and (18)F-FDG PET/MRI using a postcontrast T1-weighted 3-dimensional gradient echo volume-interpolated breath-hold examination sequence with fat suppression as morphologic dataset. Follow-up CT or (18)F-FDG PET/CT (mean time to follow-up, 11 mo; range, 3-35 mo) was used as a reference standard to define each missed nodule as benign or malignant based on changes in size and potential new tracer uptake. Nodule-to-nodule comparison between baseline and follow-up was performed using descriptive statistics. Out of 134 lung nodules found on (18)F-FDG PET/CT, (18)F-FDG PET/MRI detected 92 nodules. Accordingly, 42 lung nodules (average size ± SD, 3.9 ± 1.3 mm; range, 2-7 mm) were missed by (18)F-FDG PET/MRI. None of the missed lung nodules presented with focal tracer uptake on baseline imaging or follow-up (18)F-FDG PET/CT. Thirty-three out of 42 missed lung nodules (78.6%) in 26 patients were rated benign, whereas 9 nodules (21.4%) in 4 patients were rated malignant. As a result, 1 patient required upstaging from tumor stage I to IV. Although most small lung nodules missed on (18)F-FDG PET/MRI were found to be benign, there was a relevant number of undetected

Cranberry extract inhibits in vitro adhesion of F4 and F18+Escherichia coli to pig intestinal epithelium and reduces in vivo excretion of pigs orally challenged with F18+ verotoxigenic E. coli.

PubMed

Coddens, Annelies; Loos, Michaela; Vanrompay, Daisy; Remon, Jean Paul; Cox, Eric

2017-04-01

F4 + E. coli and F18 + E. coli infections are an important threat for pig industry worldwide. Antibiotics are commonly used to treat infected piglets, but the emerging development of resistance against antibiotics raises major concerns. Hence, alternative therapies to prevent pigs from F4 + E. coli and F18 + E. coli infections need to be developed. Since cranberry previously showed anti-adhesive activity against uropathogenic E. coli, we aimed to investigate whether cranberry extract could also inhibit binding of F4 + E. coli and F18 + E. coli to pig intestinal epithelium. Using the in vitro villus adhesion assay, we found that low concentrations of cranberry extract (20μg or 100μg/ml) have strong inhibitory activity on F4 + E. coli (75.3%, S.D.=9.31 or 95.8%, S.D.=2.56, respectively) and F18 + E. coli adherence (100% inhibition). This effect was not due to antimicrobial activity. Moreover, cranberry extract (10mg or 100mg) could also abolish in vivo binding of F4 and F18 fimbriae to the pig intestinal epithelium in ligated loop experiments. Finally, two challenge experiments with F18 + E. coli were performed to address the efficacy of in-feed or water supplemented cranberry extract. No effect could be observed in piglets that received cranberry extract only in feed (1g/kg or 10g/kg). However, supplementation of feed (10g/kg) and drinking water (1g/L) significantly decreased excretion and diarrhea. The decreased infection resulted in a decreased serum antibody response indicating reduced exposure to F18 + E. coli. Copyright © 2017 Elsevier B.V. All rights reserved.

Dose calibrator linearity test: 99mTc versus 18F radioisotopes*

PubMed Central

Willegaignon, José; Sapienza, Marcelo Tatit; Coura-Filho, George Barberio; Garcez, Alexandre Teles; Alves, Carlos Eduardo Gonzalez Ribeiro; Cardona, Marissa Anabel Rivera; Gutterres, Ricardo Fraga; Buchpiguel, Carlos Alberto

2015-01-01

Objective The present study was aimed at evaluating the viability of replacing 18F with 99mTc in dose calibrator linearity testing. Materials and Methods The test was performed with sources of 99mTc (62 GBq) and 18F (12 GBq) whose activities were measured up to values lower than 1 MBq. Ratios and deviations between experimental and theoretical 99mTc and 18F sources activities were calculated and subsequently compared. Results Mean deviations between experimental and theoretical 99mTc and 18F sources activities were 0.56 (± 1.79)% and 0.92 (± 1.19)%, respectively. The mean ratio between activities indicated by the device for the 99mTc source as measured with the equipment pre-calibrated to measure 99mTc and 18F was 3.42 (± 0.06), and for the 18F source this ratio was 3.39 (± 0.05), values considered constant over the measurement time. Conclusion The results of the linearity test using 99mTc were compatible with those obtained with the 18F source, indicating the viability of utilizing both radioisotopes in dose calibrator linearity testing. Such information in association with the high potential of radiation exposure and costs involved in 18F acquisition suggest 99mTc as the element of choice to perform dose calibrator linearity tests in centers that use 18F, without any detriment to the procedure as well as to the quality of the nuclear medicine service. PMID:25798005

A novel facile method of labeling octreotide with (18)F-fluorine.

PubMed

Laverman, Peter; McBride, William J; Sharkey, Robert M; Eek, Annemarie; Joosten, Lieke; Oyen, Wim J G; Goldenberg, David M; Boerman, Otto C

2010-03-01

Several methods have been developed to label peptides with (18)F. However, in general these are laborious and require a multistep synthesis. We present a facile method based on the chelation of (18)F-aluminum fluoride (Al(18)F) by 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The method is characterized by the labeling of NOTA-octreotide (NOTA-d-Phe-cyclo[Cys-Phe-d-Trp-Lys-Thr-Cys]-Throl (MH(+) 1305) [IMP466]) with (18)F. Octreotide was conjugated with the NOTA chelate and labeled with (18)F in a 2-step, 1-pot method. The labeling procedure was optimized with regard to the labeling buffer, peptide, and aluminum concentration. Radiochemical yield, specific activity, in vitro stability, and receptor affinity were determined. Biodistribution of (18)F-IMP466 was studied in AR42J tumor-bearing mice and compared with that of (68)Ga-labeled IMP466. In addition, small-animal PET/CT images were acquired. IMP466 was labeled with Al(18)F in a single step with 50% yield. The labeled product was purified by high-performance liquid chromatography to remove unbound Al(18)F and unlabeled peptide. The radiolabeling, including purification, was performed in 45 min. The specific activity was 45,000 GBq/mmol, and the peptide was stable in serum for 4 h at 37 degrees C. Labeling was performed at pH 4.1 in sodium citrate, sodium acetate, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, and 2-(N-morpholino)ethanesulfonic acid buffer and was optimal in sodium acetate buffer. The apparent 50% inhibitory concentration of the (19)F-labeled IMP466 determined on AR42J cells was 3.6 nM. Biodistribution studies at 2 h after injection showed a high tumor uptake of (18)F-IMP466 (28.3 +/- 5.2 percentage injected dose per gram [%ID/g]; tumor-to-blood ratio, 300 +/- 90), which could be blocked by an excess of unlabeled peptide (8.6 +/- 0.7 %ID/g), indicating that the accumulation in the tumor was receptor-mediated. Biodistribution of (68)Ga-IMP466 was similar to that of (18)F-IMP466. (18)F

(R)-N-Methyl-3-(3′-[18F]fluoropropyl)phenoxy)-3-phenylpropanamine (18F-MFP3) as a potential PET imaging agent for norepinephrine transporter

PubMed Central

Nguyen, Vivien L.; Pichika, Rama; Bhakta, Paayal H.; Kant, Ritu; Mukherjee, Jogeshwar

2010-01-01

A decline of norepinephrine transporter (NET) level is associated with several psychiatric and neurological disorders. Therefore positron emission tomography (PET) imaging agents are greatly desired to study the NET pathway. We have developed a C-fluoropropyl analog of nisoxetine: (R)-N-methyl-3-(3′-[18F]fluoropropyl)phenoxy)-3-phenylpropanamine (18F-MFP3) as a new potential PET radiotracer for NET with the advantage of the longer half-life of fluorine-18 (110 min compared with carbon-11 (20 min). Synthesis of (R)-N-methyl-3-(3′-fluoropropyl)phenoxy)-3-phenylpropanamine (MFP3) was achieved in five steps starting from (S)-N-methyl-3-ol-3-phenylpropanamine in approx. 3–5% overall yields. In vitro binding affinity of nisoxetine and MFP3 in rat brain homogenates labeled with 3H-nisoxetine gave Ki values of 8.02 nM and 23 nM, respectively. For radiosynthesis of 18F-MFP3, fluorine-18 was incorporated into a tosylate precursor, followed by the deprotection of the N-BOC-protected amine group with a 15% decay corrected yield in 2.5 h. Reverse-phase chromatographic purification provided 18F-MFP3 in specific activities of >2000 Ci/mmol. Fluorine-18 labeled 18F-MFP3 has been produced in modest radiochemical yields and in high specific activities. Evaluation of 18F-MFP3 in animal imaging studies is in progress in order to validate this new fluorine-18 radiotracer for PET imaging of NET. PMID:20495670

18F-FDOPA PET/CT imaging of MAX-related pheochromocytoma.

PubMed

Taïeb, David; Jha, Abhishek; Guerin, Carole; Pang, Ying; Adams, Karen T; Chen, Clara C; Romanet, Pauline; Roche, Philippe; Essamet, Wassim; Ling, Alexander; Quezado, Martha M; Castinetti, Frédéric; Sebag, Fréderic; Pacak, Karel

2018-03-08

MYC associated factor X (MAX) has been recently described as a new susceptibility pheochromocytoma (PHEO) gene with a total of approximately 40 reported cases. At present, no study has specifically described the functional imaging phenotype of MAX-related PHEO. The objective of this study was to present our experience with contrast-enhanced CT and 18F-FDOPA PET/CT imaging in 6 consecutive patients (4 at initial diagnosis and 2 at follow-up evaluation) with rare but clinically important MAX-related PHEOs. In 5 patients, 18F-FDOPA was also compared to other radiopharmaceuticals. Patients had 5 different mutations in the MAX gene that caused disruption of Max/Myc interaction and/or abolished interaction with DNA based on in-silico analyses. All but one patient developed bilateral PHEOs during their lifetime. In all cases, 18F-FDOPA PET/CT accurately visualized PHEOs that were often multiple within the same gland or bilateral and detected more adrenal and extradrenal lesions than CT (per lesion sensitivity 90.5% vs 52.4% for CT/MRI). The 2 missed PHEO on 18F-FDOPA PET/CT were <1cm, corresponding to nodular adrenomedullary hyperplasia. 68Ga-DOTATATE PET/CT detected fewer lesions than 18F-FDOPA PET/CT in 1/3 patients and 18F-FDG PET/CT was only faintly positive in 2/4 patients with underestimation of extraadrenal lesions in 1 patient. MAX-related PHEO exihibit a marked 18F-FDOPA uptake, a finding that illustrates the common well-differentiated chromaffin pattern of PHEO associated with activation of kinase signaling pathways. 18F-FDOPA PET/CT should be considered as the first-line functional imaging modality for diagnostic or follow-up evaluation in these patients.

No-carrier-added (18F)-N-methylspiroperidol

DOEpatents

Shiue, Chyng-Yann; Fowler, Joanna S.; Wolf, Alfred P.

1993-01-01

There is disclosed a radioligand labeled with a positron emitting radionuclide suitable for dynamic study in living humans with positron emission transaxial tomography. [.sup.18 F]-N-methylspiroperidol, exhibiting extremely high affinity for the dopamine receptors, provides enhanced uptake and retention in the brain concomitant with reduced radiation burden. These characteristics all combine to provide [.sup.18 F]-N-methylspiroperidol as a radioligand superior to known radioligands for mapping dopamine receptors in normal and disease states in the living brain. Additionally, a new synthetic procedure for this material is disclosed.

No-carrier-added (18F)-N-methylspiroperidol

DOEpatents

Shiue, Chyng-Yann; Fowler, Joanna S.; Wolf, Alfred P.

1993-07-06

There is disclosed a radioligand labeled with a positron emitting radionuclide suitable for dynamic study in living humans with positron emission transaxial tomography. [.sup.18 F]-N-methylspiroperidol, exhibiting extremely high affinity for the dopamine receptors, provides enhanced uptake and retention in the brain concomitant with reduced radiation burden. These characteristics all combine to provide [.sup.18 F]-N-methylspiroperidol as a radioligand superior to known radioligands for mapping dopamine receptors in normal and disease states in the living brain. Additionally, a new synthetic procedure for this material is disclosed.

Synthesis, Bioconjugation and Stability Studies of [18 F] Ethenesulfonyl Fluoride.

PubMed

Zhang, Bo; Pascali, Giancarlo; Wyatt, Naomi; Matesic, Lidia; Klenner, Mitchell A; Sia, Tiffany R; Guastella, Adam J; Massi, Massimiliano; Robinson, Andrea J; Fraser, Benjamin H

2018-06-20

Fluorine-18 labelled prosthetic groups (PGs) are often necessary for radiolabelling sensitive biological molecules such as peptides and proteins. Several shortcomings, however, often diminish the final yield of radiotracer. In an attempt to provide higher yielding and operationally efficient tools for radiolabelling biological molecules, we describe herein the first radiochemical synthesis of [ 18 F] ethenesulfonylfluoride ([ 18 F] ESF) and its Michael conjugation with amino acids and proteins. The synthesis of [ 18 F] ESF was optimised using a microfluidic reactor under both carrier-added (c.a.) and no-carrier-added (n.c.a.) conditions, affording, in a straightforward procedure, 30-50% radiochemical yield (RCY) for c.a. [ 18 F] ESF and 60-70% RCY for n.c.a. [ 18 F] ESF. The conjugation reactions were performed at room temperature using 10 mg/mL precursor in aqueous/organic solvent mixtures for 15 min. The radiochemical stability of the final conjugates was evaluated in injectable formulation and rat serum, and resulted strongly substrate dependent and generally poor in rat serum. Therefore, in this work we have optimised a straightforward synthesis of [ 18 F] ESF and its Michael conjugation with model compounds, without requiring chromatographic purification. However, given the general low stability of the final products, further studies will be required for improving conjugate stability, before assessing the use of this PG for PET imaging. This article is protected by copyright. All rights reserved.

Measurement of 17F(d ,n )18Ne and the impact on the 17F(p ,γ )18Ne reaction rate for astrophysics

NASA Astrophysics Data System (ADS)

Kuvin, S. A.; Belarge, J.; Baby, L. T.; Baker, J.; Wiedenhöver, I.; Höflich, P.; Volya, A.; Blackmon, J. C.; Deibel, C. M.; Gardiner, H. E.; Lai, J.; Linhardt, L. E.; Macon, K. T.; Rasco, B. C.; Quails, N.; Colbert, K.; Gay, D. L.; Keeley, N.

2017-10-01

Background: The 17F(p ,γ )18Ne reaction is part of the astrophysical "hot CNO" cycles that are important in astrophysical environments like novas. Its thermal reaction rate is low owing to the relatively high energy of the resonances and therefore is dominated by direct, nonresonant capture in stellar environments at temperatures below 0.4 GK. Purpose: An experimental method is established to extract the proton strength to bound and unbound states in experiments with radioactive ion beams and to determine the parameters of direct and resonant capture in the 17F(p ,γ )18Ne reaction. Method: The 17F(d ,n )18Ne reaction is measured in inverse kinematics using a beam of the short-lived isotope 17F and a compact setup of neutron, proton, γ -ray, and heavy-ion detectors called resoneut. Results: The spectroscopic factors for the lowest l =0 proton resonances at Ec .m .=0.60 and 1.17 MeV are determined, yielding results consistent within 1.4 σ of previous proton elastic-scattering measurements. The asymptotic normalization coefficients of the bound 21+ and 22+ states in 18Ne are determined and the resulting direct-capture reaction rates are extracted. Conclusions: The direct-capture component of the 17F(p ,γ )18Ne reaction is determined for the first time from experimental data on 18Ne.

Optimizing Maintenance Manpower for USMC F/A-18 Squadrons

DTIC Science & Technology

2016-06-01

experience level, with the requirement of keeping a standard number of aircraft operationally ready. MVP results show areas of deficit, either manpower ...MAINTENANCE MANPOWER FOR USMC F/A-18 SQUADRONS by Kevin J. Goodwin June 2016 Thesis Co-Advisors: W. Matthew Carlyle Robert F. Dell Second...REPORT TYPE AND DATES COVERED Master’s thesis 4. TITLE AND SUBTITLE OPTIMIZING MAINTENANCE MANPOWER FOR USMC F/A-18 SQUADRONS 5. FUNDING NUMBERS 6

Automated production at the curie level of no-carrier-added 6-[(18)F]fluoro-L-dopa and 2-[(18)F]fluoro-L-tyrosine on a FASTlab synthesizer.

PubMed

Lemaire, C; Libert, L; Franci, X; Genon, J-L; Kuci, S; Giacomelli, F; Luxen, A

2015-06-15

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and 2-[(18)F]fluoro-L-tyrosine ([(18)F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high- performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand-alone HPLC. [(18)F]FDOPA and [(18)F]FTYR were produced in 36.3 ± 3.0% (n = 8) and 50.5 ± 2.7% (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95%, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [(18)F]FDOPA and [(18)F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment. Copyright © 2015 John Wiley & Sons, Ltd.

Comparative assessment of 6-[18 F]fluoro-L-m-tyrosine and 6-[18 F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

PubMed

Becker, Guillaume; Bahri, Mohamed Ali; Michel, Anne; Hustadt, Fabian; Garraux, Gaëtan; Luxen, André; Lemaire, Christian; Plenevaux, Alain

2017-05-01

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [ 18 F]fluoro-3,4-dihydroxyphenyl-L-alanine ([ 18 F]FDOPA) and 6-[ 18 F]fluoro-L-m-tyrosine ([ 18 F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [ 18 F]FMT and [ 18 F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [ 18 F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [ 18 F]FMT and [ 18 F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant K c . However, only [ 18 F]FMT K c succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [ 18 F]FMT could be more sensitive, with respect of [ 18 F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L

Comparison of 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) and 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) PET/CT in human brain glioma imaging.

PubMed

Toyota, Yasunori; Miyake, Keisuke; Kawai, Nobuyuki; Hatakeyama, Tetsuhiro; Yamamoto, Yuka; Toyohara, Jun; Nishiyama, Yoshihiro; Tamiya, Takashi

2015-01-01

3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, (18)F-FLT has several limitations in clinical use. Recently, (11)C-labeled thymidine analogue, 4'-[methyl-(11)C]thiothymidine ((11)C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of (11)C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of (18)F-FLT PET. Twenty patients with primary and recurrent brain gliomas underwent (18)F-FLT and (11)C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of (11)C-4DST and (18)F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual (18)F-FLT and (11)C-4DST uptake values in the tumors was also examined. (11)C-4DST uptake was significantly higher than that of (18)F-FLT in the normal brain. The uptake values of (11)C-4DST in the tumor were similar to those of (18)F-FLT resulting in better visualization with (18)F-FLT. No significant differences in the uptake values of (18)F-FLT and (11)C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of (11)C-4DST (r = 0.50, P < 0.05) and (18)F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of (11)C-4DST (r = 0.52, P < 0.05) and (18)F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of (11)C-4DST and (18)F-FLT in the tumor (r�

Novel 18F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates.

PubMed

Li, Songye; Cai, Zhengxin; Zheng, Ming-Qiang; Holden, Daniel; Naganawa, Mika; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Kapinos, Michael; Lara-Jaime, Teresa; Navarro, Antonio; Huang, Yiyun

2018-01-01

The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11 C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18 F-LY2459989 as the first 18 F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11 C-LY2459989. Methods: The novel radioligand 18 F-LY2459989 was synthesized by 18 F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time-activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18 F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18 F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18 F-LY2459989 in vivo. Regional time-activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain

(S)-4-(3-18F-fluoropropyl)-L-glutamic acid: an 18F-labeled tumor-specific probe for PET/CT imaging--dosimetry.

PubMed

Smolarz, Kamilla; Krause, Bernd Joachim; Graner, Frank-Philipp; Wagner, Franziska Martina; Hultsch, Christina; Bacher-Stier, Claudia; Sparks, Richard B; Ramsay, Susan; Fels, Lüder M; Dinkelborg, Ludger M; Schwaiger, Markus

2013-06-01

The glutamic acid derivative (S)-4-(3-(18)F-Fluoropropyl)-l-glutamic acid ((18)F-FSPG, alias BAY 94-9392), a new PET tracer for the detection of malignant diseases, displayed promising results in non-small cell lung cancer patients. The aim of this study was to provide dosimetry estimates for (18)F-FSPG based on human whole-body PET/CT measurements. (18)F-FSPG was prepared by a fully automated 2-step procedure and purified by a solid-phase extraction method. PET/CT scans were obtained for 5 healthy volunteers (mean age, 59 y; age range, 51-64 y; 2 men, 3 women). Human subjects were imaged for up to 240 min using a PET/CT scanner after intravenous injection of 299 ± 22.5 MBq of (18)F-FSPG. Image quantification, time-activity data modeling, estimation of normalized number of disintegrations, and production of dosimetry estimates were performed using the RADAR (RAdiation Dose Assessment Resource) method for internal dosimetry and in general concordance with the methodology and principles as presented in the MIRD 16 document. Because of the renal excretion of the tracer, the absorbed dose was highest in the urinary bladder wall and kidneys, followed by the pancreas and uterus. The individual organ doses (mSv/MBq) were 0.40 ± 0.058 for the urinary bladder wall, 0.11 ± 0.011 for the kidneys, 0.077 ± 0.020 for the pancreas, and 0.030 ± 0.0034 for the uterus. The calculated effective dose was 0.032 ± 0.0034 mSv/MBq. Absorbed dose to the bladder and the effective dose can be reduced significantly by frequent bladder-voiding intervals. For a 0.75-h voiding interval, the bladder dose was reduced to 0.10 ± 0.012 mSv/MBq, and the effective dose was reduced to 0.015 ± 0.0010 mSv/MBq. On the basis of the distribution and biokinetic data, the determined radiation dose for (18)F-FSPG was calculated to be 9.5 ± 1.0 mSv at a patient dose of 300 MBq, which is of similar magnitude to that of (18)F-FDG (5.7 mSv). The effective dose can be reduced to 4.5 ± 0.30 mSv (at 300 MBq

A broadly applicable [18F]trifluoromethylation of aryl and heteroaryl iodides for PET imaging

NASA Astrophysics Data System (ADS)

Huiban, Mickael; Tredwell, Matthew; Mizuta, Satoshi; Wan, Zehong; Zhang, Xiaomin; Collier, Thomas Lee; Gouverneur, Véronique; Passchier, Jan

2013-11-01

Molecules labelled with the unnatural isotope fluorine-18 are used for positron emission tomography. Currently, this molecular imaging technology is not exploited at its full potential because many 18F-labelled probes are inaccessible or notoriously difficult to produce. Typical challenges associated with 18F radiochemistry are the short half-life of 18F (<2 h), the use of sub-stoichiometric amounts of 18F, relative to the precursor and other reagents, as well as the limited availability of parent 18F sources of suitable reactivity ([18F]F- and [18F]F2). There is a high-priority demand for general methods allowing access to [18F]CF3-substituted molecules for application in pharmaceutical discovery programmes. We report the development of a process for the late-stage [18F]trifluoromethylation of (hetero)arenes from [18F]fluoride using commercially available reagents and (hetero)aryl iodides. This [18F]CuCF3-based protocol benefits from a large substrate scope and is characterized by its operational simplicity.

18F-FDG positron emission tomography/computed tomography in infective endocarditis.

PubMed

Salomäki, Soile Pauliina; Saraste, Antti; Kemppainen, Jukka; Bax, Jeroen J; Knuuti, Juhani; Nuutila, Pirjo; Seppänen, Marko; Roivainen, Anne; Airaksinen, Juhani; Pirilä, Laura; Oksi, Jarmo; Hohenthal, Ulla

2017-02-01

The diagnosis of infective endocarditis (IE), especially the diagnosis of prosthetic valve endocarditis (PVE) is challenging since echocardiographic findings are often scarce in the early phase of the disease. We studied the use of 2-[ 18 F]fluoro-2-deoxy-D-glucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in IE. Sixteen patients with suspected PVE and 7 patients with NVE underwent visual evaluation of 18 F-FDG-PET/CT. 18 F-FDG uptake was measured also semiquantitatively as maximum standardized uptake value (SUV max ) and target-to-background ratio (TBR). The modified Duke criteria were used as a reference. There was strong, focal 18 F-FDG uptake in the area of the affected valve in all 6 cases of definite PVE, in 3 of 5 possible PVE cases, and in 2 of 5 rejected cases. In all patients with definite PVE, SUV max of the affected valve was higher than 4 and TBR higher than 1.8. In contrast to PVE, only 1 of 7 patients with NVE had uptake of 18 F-FDG by PET/CT in the valve area. Embolic infectious foci were detected in 58% of the patients with definite IE. 18 F-FDG-PET/CT appears to be a sensitive method for the detection of paravalvular infection associated with PVE. Instead, the sensitivity of PET/CT is limited in NVE.

Two years of experience with the [ 18F]FDG production module

NASA Astrophysics Data System (ADS)

Kim, Sang Wook; Hur, Min Goo; Chai, Jong-Seo; Park, Jeong Hoon; Yu, Kook Hyun; Jeong, Cheol Ki; Lee, Goung Jin; Min, Young Don; Yang, Seung Dae

2007-08-01

Chemistry module for a conventional [18F]FDG production by using tetrabutylammonium bicarbonate (TBA) and an acidic hydrolysis has been manufactured and evaluated. In this experiment, 75 mM (pH 7.5-7.8) of TBA solution and a ca. 2-curies order of [18F]-fluoride have been used for the evaluation. The commercial acidic purification cartridge was purchased from GE or UKE. The operation system (OS) was programmed with Lab-View which was selected because of its easy customization of the OS. Small sized solenoid valves (Burkert; type 6124) were selected to reduce the module dimensions (W 350 × D 270 × H 250). The total time for the synthesis of [18F]FDG was 30 ± 3 min. The production yield of [18F]FDG was 60 ± 2% on an average at EOS, with the decay uncorrected. This experimental data show that the traditional chemistry module can provide a good [18F]FDG production yield by optimizing the operational conditions. The radiochemical purity, radionuclidic purity, acidity, residual solvent, osmolality and endotoxin were determined to assess the quality of [18F]FDG. The examined contents for the quality control of [18F]FDG were found to be suitable for a clinical application.

New Chelators for Low Temperature Al(18)F-Labeling of Biomolecules.

PubMed

Cleeren, Frederik; Lecina, Joan; Billaud, Emilie M F; Ahamed, Muneer; Verbruggen, Alfons; Bormans, Guy M

2016-03-16

The Al(18)F labeling method is a relatively new approach that allows radiofluorination of biomolecules such as peptides and proteins in a one-step procedure and in aqueous solution. However, the chelation of the {Al(18)F}(2+) core with the macrocyclic chelators NOTA or NODA requires heating to 100-120 °C. Therefore, we have developed new polydentate ligands for the complexation of {Al(18)F}(2+) with good radiochemical yields at a temperature of 40 °C. The stability of the new Al(18)F-complexes was tested in phosphate buffered saline (PBS) at pH 7.4 and in rat serum. The stability of the Al(18)F-L3 complex was found to be comparable to that of the previously reported Al(18)F-NODA complex up to 60 min in rat serum. Moreover, the biodistribution of Al(18)F-L3 in healthy mice showed the absence of in vivo defluorination since no significant bone uptake was observed, whereas the major fraction of activity at 60 min p.i. was observed in liver and intestines, indicating hepatobiliary clearance of the radiolabeled ligand. The acyclic chelator H3L3 proved to be a good lead candidate for labeling of heat-sensitive biomolecules with fluorine-18. In order to obtain a better understanding of the different factors influencing the formation and stability of the complex, we carried out more in-depth experiments with ligand H3L3. As a proof of concept, we successfully conjugated the new AlF-chelator with the urea-based PSMA inhibitor Glu-NH-CO-NH-Lys to form Glu-NH-CO-NH-Lys(Ahx)L3, and a biodistribution study in healthy mice was performed with the Al(18)F-labeled construct. This new class of AlF-chelators may have a great impact on PET radiochemical space as it will stimulate the rapid development of new fluorine-18 labeled peptides and other heat-sensitive biomolecules.

18F-FPYBF-2, a new F-18-labelled amyloid imaging PET tracer: first experience in 61 volunteers and 55 patients with dementia.

PubMed

Higashi, Tatsuya; Nishii, Ryuichi; Kagawa, Shinya; Kishibe, Yoshihiko; Takahashi, Masaaki; Okina, Tomoko; Suzuki, Norio; Hasegawa, Hiroshi; Nagahama, Yasuhiro; Ishizu, Koichi; Oishi, Naoya; Kimura, Hiroyuki; Watanabe, Hiroyuki; Ono, Masahiro; Saji, Hideo; Yamauchi, Hiroshi

2018-04-01

Recently, we developed a benzofuran derivative for the imaging of β-amyloid plaques, 5-(5-(2-(2-(2- 18 F-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N-methylpyridin-2-amine ( 18 F-FPYBF-2) (Ono et al., J Med Chem 54:2971-9, 2011). The aim of this study was to assess the feasibility of 18 F-FPYBF-2 as an amyloid imaging PET tracer in a first clinical study with healthy volunteers and patients with various dementia and in comparative dual tracer study using 11 C-Pittsburgh Compound B ( 11 C-PiB). 61 healthy volunteers (age: 53.7 ± 13.1 years old; 19 male and 42 female; age range 24-79) and 55 patients with suspected dementia [Alzheimer's Disease (AD); early AD: n = 19 and moderate stage AD: n = 8, other dementia: n = 9, mild cognitive impairment (MCI): n = 16, cognitively normal: n = 3] for first clinical study underwent static head PET/CT scan using 18 F - FPYBF-2 at 50-70 min after injection. 13 volunteers and 14 patients also underwent dynamic PET scan at 0-50 min at the same instant. 16 subjects (volunteers: n = 5, patients with dementia: n = 11) (age: 66.3 ± 14.2 years old; 10 males and 6 females) were evaluated for comparative study (50-70 min after injection) using 18 F-FPYBF-2 and 11 C-PiB on separate days, respectively. Quantitative analysis of mean cortical uptake was calculated using Mean Cortical Index of SUVR (standardized uptake value ratio) based on the established method for 11 C-PiB analysis using cerebellar cortex as control. Studies with healthy volunteers showed that 18 F-FPYBF-2 uptake was mainly observed in cerebral white matter and that average Mean Cortical Index at 50-70 min was low and stable (1.066 ± 0.069) basically independent from age or gender. In patients with AD, 18 F-FPYBF-2 uptake was observed both in cerebral white and gray matter, and Mean Cortical Index was significantly higher (early AD: 1.288 ± 0.134, moderate AD: 1.342 ± 0.191) than those of volunteers and other

Water-tunnel study results of a TF/A-18 and F/A-18 canopy flow visualization

NASA Technical Reports Server (NTRS)

Johnson, Steven A.; Fisher, David F.

1990-01-01

A water tunnel study examining the influence of canopy shape on canopy and leading edge extension flow patterns was initiated. The F/A-18 single-place canopy model and the TF/A-18 two place canopy model were the study subjects. Plan view and side view photographs showing the flow patterns created by injected colored dye are presented for 0 deg and 5 deg sideslip angles. Photographs taken at angle of attack and sideslip conditions correspond to test departure points found in flight test. Flight experience has shown that the TF/A-18 airplane departs in regions where the F/A-18 airplane is departure-resistant. The study results provide insight into the differences in flow patterns which may influence the resulting aerodynamics of the TF/A-18 and F/A-18 aircraft. It was found that at 0 deg sideslip, the TF/A-18 model has more downward flow on the sides of the canopy than the F/A-18 model. This could be indicative of flow from the leading edge extension (LEX) vortexes impinging on the sides of the wider TF/A-18 canopy. In addition, the TF/A-18 model has larger areas of asymmetric separated and unsteady flow on the LEXs and fuselage, possibly indicating a lateral and directional destabilizing effect at the conditions studied.

Benefit of 18F-fluorocholine PET imaging in parathyroid surgery.

PubMed

Huber, G F; Hüllner, M; Schmid, C; Brunner, A; Sah, B; Vetter, D; Kaufmann, P A; von Schulthess, G K

2018-06-01

To assess the additional diagnostic value of 18 F-fluorocholine PET imaging in preoperative localization of pathologic parathyroid glands in clinically manifest hyperparathyroidism in case of negative or conflicting ultrasound and scintigraphy results. A retrospective, single-institution study of 26 patients diagnosed with hyperparathyroidism. In cases where ultrasound and scintigraphy failed to detect the location of an adenoma in order to allow a focused surgical approach, an additional 18 F-fluorocholine PET scan was performed and its results were compared with the intraoperative findings. A total of 26 patients underwent 18 F-fluorocholine PET/CT (n = 11) or PET/MRI (n = 15). Adenomas were detected in 25 patients (96.2%). All patients underwent surgery, and the location predicted by PET hybrid imaging was confirmed intraoperatively by frozen section and adequate parathyroid hormone drop after removal. None of the patients needed revision surgery during follow-up. These results demonstrate that 18 F-fluorocholine PET imaging is a highly accurate method to detect parathyroid adenomas even in case of previous localization failure by other imaging examinations. • With 18 F-fluorocholine PET imaging, parathyroid adenomas could be detected in 96.2%. • 18 F-fluorocholine imaging is a highly accurate method to detect parathyroid adenomas. • We encourage its use, where ultrasound fails to detect an adenoma.

Human radiation dosimetry of 6-[{sup 18}F]FDG predicted from preclinical studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Muzic, Raymond F., E-mail: raymond.muzic@case.edu; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106; Case Center for Imaging Research, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106

Purpose: The authors are developing 6-[{sup 18}F]fluoro-6-deoxy-D-glucose (6-[{sup 18}F]FDG) as an in vivo tracer of glucose transport. While 6-[{sup 18}F]FDG has the same radionuclide half-life as 2-[{sup 18}F]fluoro-2-deoxy-D-glucose (2-[{sup 18}F]FDG) which is ubiquitously used for PET imaging, 6-[{sup 18}F]FDG has special biologic properties and different biodistributions that make it preferable to 2-[{sup 18}F]FDG for assessing glucose transport. In preparation for 6-[{sup 18}F]FDG use in human PET scanning, the authors would like to determine the amount of 6-[{sup 18}F]FDG to inject while maintaining radiation doses in a safe range. Methods: Rats were injected with 6-[{sup 18}F]FDG, euthanized at specified times, andmore » tissues were collected and assayed for activity content. For each tissue sample, the percent of injected dose per gram was calculated and extrapolated to that for humans in order to construct predicted time-courses. Residence times were calculated as areas under the curves and were used as inputs to OLINDA/EXM in order to calculate the radiation doses. Results: Unlike with 2-[{sup 18}F]FDG for which the urinary bladder wall receives the highest absorbed dose due to urinary excretion, with 6-[{sup 18}F]FDG there is little urinary excretion and osteogenic cells and the liver are predicted to receive the highest absorbed doses: 0.027 mGy/MBq (0.100 rad/mCi) and 0.018 mGy/MBq (0.066 rad/mCi), respectively. Also, the effective dose from 6-[{sup 18}F]FDG, i.e., 0.013 mSv/MBq (0.046 rem/mCi), is predicted to be approximately 30% lower than that from 2-[{sup 18}F]FDG. Conclusions: 6-[{sup 18}F]FDG will be safe for use in the PET scanning of humans.« less

Predicting chemotherapy response to paclitaxel with 18F-Fluoropaclitaxel and PET.

PubMed

Hsueh, Wei-Ann; Kesner, Amanda L; Gangloff, Anne; Pegram, Mark D; Beryt, Malgorzata; Czernin, Johannes; Phelps, Michael E; Silverman, Daniel H S

2006-12-01

Paclitaxel is used as a chemotherapy drug for the treatment of various malignancies, including breast, ovarian, and lung cancers. To evaluate the potential of a noninvasive prognostic tool for specifically predicting the resistance of tumors to paclitaxel therapy, we examined the tumoral uptake of (18)F-fluoropaclitaxel ((18)F-FPAC) in mice bearing human breast cancer xenografts by using small-animal-dedicated PET and compared (18)F-FPAC uptake with the tumor response to paclitaxel treatment. PET data were acquired after tail vein injection of approximately 9 MBq of (18)F-FPAC in anesthetized nude mice bearing breast cancer xenografts. Tracer uptake in reconstructed images was quantified by region-of-interest analyses and compared with the tumor response, as measured by changes in tumor volume, after treatment with paclitaxel. Mice with tumors that progressed demonstrated lower tumoral uptake of (18)F-FPAC than mice with tumors that did not progress or that regressed (r = 0.55, P < 0.02; n = 19), indicating that low (18)F-FPAC uptake was a significant predictor of chemoresistance. Conversely, high (18)F-FPAC uptake predicted tumor regression. This relationship was found for mice bearing xenografts from cell lines selected to be either sensitive or intrinsically resistant to paclitaxel in vitro. PET data acquired with (18)F-FPAC suggest that this tracer holds promise for the noninvasive quantification of its distribution in vivo in a straightforward manner. In combination with approaches for examining other aspects of resistance, such quantification could prove useful in helping to predict subsequent resistance to paclitaxel chemotherapy of breast cancer.

Fully automated synthesis of 4-[18F]fluorobenzylamine based on borohydride/NiCl2 reduction.

PubMed

Way, Jenilee; Wuest, Frank

2013-04-01

4-[(18)F]Fluorobenzylamine ([(18)F]FBA) is an important building block for the synthesis of (18)F-labeled compounds. Synthesis of [(18)F]FBA usually involves application of strong reducing agents like LiAlH4 which is challenging to handle in automated synthesis units (ASUs). Therefore, alternative methods for the preparation of [(18)F]FBA compatible with remotely-controlled syntheses in ASUs are needed. (18)F]FBA was prepared in a remotely-controlled synthesis unit (GE TRACERlab™ FX) based on Ni(II)-mediated borohydride exchange resin (BER) reduction of 4-[(18)F]fluorobenzonitrile ([(18)F]FBN). [(18)F]FBA was used for the synthesis of novel thiol-reactive prosthetic group 4-[(18)F]fluorobenzyl)maleimide [(18)F]FBM and Hsp90 inhibitor 17-(4-[(18)F]fluorobenzylamino)-17-demethoxy-geldanamycin [(18)F] GA. [(18)F]FBA could be prepared in high radiochemical yield greater than 80% (decay-corrected) within 60min. In a typical experiment, 7.4GBq of [(18)F]FBA could be obtained in high radiochemical purity of greater than 95% starting from 10GBq of cyclotron-produced n.c.a. [(18)F]fluoride. [(18)F]FBA was used for the preparation of 4-[(18)F]fluorobenzyl)maleimide as a novel prosthetic group for labeling of thiol groups as demonstrated with tripeptide glutathione. [(18)F]FBA was also used as building block for the syntheses of small molecules as exemplified by the preparation of Hsp90 inhibitor 17-(4-[(18)F]fluorobenzylamino)-17-demethoxy-geldanamycin. The described remotely-controlled synthesis of [(18)F]FBA will significantly improve the availability of [(18)F]FBA as an important and versatile building block for the development of novel (18)F-labeled compounds containing a fluorobenzylamine moiety. Copyright © 2013 Elsevier Inc. All rights reserved.

Imaging Bone–Cartilage Interactions in Osteoarthritis Using [18F]-NaF PET-MRI

PubMed Central

Pedoia, Valentina; Seo, Youngho; Yang, Jaewon; Bucknor, Matt; Franc, Benjamin L.; Majumdar, Sharmila

2016-01-01

Purpose: Simultaneous positron emission tomography–magnetic resonance imaging (PET-MRI) is an emerging technology providing both anatomical and functional images without increasing the scan time. Compared to the traditional PET/computed tomography imaging, it also exposes the patient to significantly less radiation and provides better anatomical images as MRI provides superior soft tissue characterization. Using PET-MRI, we aim to study interactions between cartilage composition and bone function simultaneously, in knee osteoarthritis (OA). Procedures: In this article, bone turnover and remodeling was studied using [18F]-sodium fluoride (NaF) PET data. Quantitative MR-derived T1ρ relaxation times characterized the biochemical cartilage degeneration. Sixteen participants with early signs of OA of the knee received intravenous injections of [18F]-NaF at the onset of PET-MR image acquisition. Regions of interest were identified, and kinetic analysis of dynamic PET data provided the rate of uptake (Ki) and the normalized uptake (standardized uptake value) of [18F]-NaF in the bone. Morphological MR images and quantitative voxel-based T1ρ maps of cartilage were obtained using an atlas-based registration technique to segment cartilage automatically. Voxel-by-voxel statistical parameter mapping was used to investigate the relationship between bone and cartilage. Results: Increases in cartilage T1ρ, indicating degenerative changes, were associated with increased turnover in the adjoining bone but reduced turnover in the nonadjoining compartments. Associations between pain and increased bone uptake were seen in the absence of morphological lesions in cartilage, but the relationship was reversed in the presence of incident cartilage lesions. Conclusion: This study shows significant cartilage and bone interactions in OA of the knee joint using simultaneous [18F]-NaF PET-MR, the first in human study. These observations highlight the complex biomechanical and biochemical

18F-choline PET/MRI in suspected recurrence of prostate carcinoma.

PubMed

Riola-Parada, C; Carreras-Delgado, J L; Pérez-Dueñas, V; Garcerant-Tafur, M; García-Cañamaque, L

2018-05-21

To evaluate the usefulness of simultaneous 18 F-choline PET/MRI in the suspicion of prostate cancer recurrence and to relate 18 F-choline PET/MRI detection rate with analytical and pathological variables. 27 patients with prostate cancer who received local therapy as primary treatment underwent a 18 F-choline PET/MRI due to suspicion of recurrence (persistently rising serum PSA level). 18 F-choline PET/MRI findings were validated by anatomopathological analysis, other imaging tests or by biochemical response to oncological treatment. 18 F-choline PET/MRI detected disease in 15 of 27 patients (detection rate 55.56%). 4 (15%) presented exclusively local recurrence, 5 (18%) lymph node metastases and 7 (26%) bone metastases. Mean PSA (PSA med ) at study time was 2.94ng/mL (range 0.18-10ng/mL). PSA med in patients with positive PET/MRI was 3.70ng/mL (range 0.24-10ng/mL), higher than in patients with negative PET/MRI, PSA med 1.97ng/mL (range 0.18-4.38ng/mL), although without statistically significant differences. Gleason score at diagnosis in patients with a positive study was 7.33 (range 6-9) and in patients with a negative study was 7 (range 6-9), without statistically significant differences. 18 F-choline PET/MRI detection rate was considerable despite the relatively low PSA values in our sample. The influence of Gleason score and PSA level on 18 F-choline PET/MRI detection rate was not statistically significant. Copyright © 2018 Sociedad Española de Medicina Nuclear e Imagen Molecular. Publicado por Elsevier España, S.L.U. All rights reserved.

Comparison of the biological effects of {sup 18}F at different intracellular levels

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kashino, Genro, E-mail: kashino@oita-u.ac.jp; Hayashi, Kazutaka; Douhara, Kazumasa

Highlights: • We estimated the inductions of DNA DSB in cell treated with {sup 18}F-FDG. • We found that inductions of DNA DSB are dependent on accumulation of {sup 18}F in cell. • Accumulation of {sup 18}F in cell may be indispensable for risk estimation of PET. - Abstract: We herein examined the biological effects of cells treated with {sup 18}F labeled drugs for positron emission tomography (PET). The relationship between the intracellular distribution of {sup 18}F and levels of damaged DNA has yet to be clarified in detail. We used culture cells (Chinese Hamster Ovary cells) treated with twomore » types of {sup 18}F labeled drugs, fluorodeoxyglucose (FDG) and fluorine ion (HF). FDG efficiently accumulated in cells, whereas HF did not. To examine the induction of DNA double strand breaks (DSB), we measured the number of foci for 53BP1 that formed at the site of DNA DSB. The results revealed that although radioactivity levels were the same, the induction of 53BP1 foci was stronger in cells treated with {sup 18}F-FDG than in those treated with {sup 18}F-HF. The clonogenic survival of cells was significantly lower with {sup 18}F-FDG than with {sup 18}F-HF. We concluded that the efficient accumulation of {sup 18}F in cells led to stronger biological effects due to more severe cellular lethality via the induction of DNA DSB.« less

Automated radiosynthesis of Al[18F]PSMA-11 for large scale routine use.

PubMed

Kersemans, Ken; De Man, Kathia; Courtyn, Jan; Van Royen, Tessa; Piron, Sarah; Moerman, Lieselotte; Brans, Boudewijn; De Vos, Filip

2018-05-01

We report a reproducible automated radiosynthesis for large scale batch production of clinical grade Al[ 18 F]PSMA-11. A SynthraFCHOL module was optimized to synthesize Al[ 18 F]PSMA-11 by Al[ 18 F]-chelation. Results Al[ 18 F]PSMA-11 was synthesized within 35min in a yield of 21 ± 3% (24.0 ± 6.0GBq) and a radiochemical purity > 95%. Batches were stable for 4h and conform the European Pharmacopeia guidelines. The automated synthesis of Al[ 18 F]PSMA-11 allows for large scale production and distribution of Al[ 18 F]PSMA-11. Copyright © 2018 Elsevier Ltd. All rights reserved.

PET/CT with 18F-FDG- and 18F-FBEM-labeled leukocytes for metabolic activity and leukocyte recruitment monitoring in a mouse model of pulmonary fibrosis.

PubMed

Bondue, Benjamin; Sherer, Félicie; Van Simaeys, Gaetan; Doumont, Gilles; Egrise, Dominique; Yakoub, Yousof; Huaux, François; Parmentier, Marc; Rorive, Sandrine; Sauvage, Sébastien; Lacroix, Simon; Vosters, Olivier; De Vuyst, Paul; Goldman, Serge

2015-01-01

Idiopathic pulmonary fibrosis is characterized by a progressive and irreversible respiratory failure. Validated noninvasive methods able to assess disease activity are essential for prognostic purposes as well as for the evaluation of emerging antifibrotic treatments. C57BL/6 mice were used in a murine model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (control mice were instilled with a saline solution). At different times after instillation, PET/CT with (18)F-FDG- or (18)F-4-fluorobenzamido-N-ethylamino-maleimide ((18)F-FBEM)-labeled leukocytes was performed to assess metabolic activity and leukocyte recruitment, respectively. In bleomycin-treated mice, a higher metabolic activity was measured on (18)F-FDG PET/CT scans from day 7 to day 24 after instillation, with a peak of activity measured at day 14. Of note, lung mean standardized uptake values correlated with bleomycin doses, histologic score of fibrosis, lung hydroxyproline content, and weight loss. Moreover, during the inflammatory phase of the model (day 7), but not the fibrotic phase (day 23), bleomycin-treated mice presented with an enhanced leukocyte recruitment as assessed by (18)F-FBEM-labeled leukocyte PET/CT. Autoradiographic analysis of lung sections and CD45 immunostaining confirm the higher and early recruitment of leukocytes in bleomycin-treated mice, compared with control mice. (18)F-FDG- and (18)F-FBEM-labeled leukocyte PET/CT enable monitoring of metabolic activity and leukocyte recruitment in a mouse model of pulmonary fibrosis. Implications for preclinical evaluation of antifibrotic therapy are expected. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study.

PubMed

Derlin, Thorsten; Tóth, Zoltán; Papp, László; Wisotzki, Christian; Apostolova, Ivayla; Habermann, Christian R; Mester, Janos; Klutmann, Susanne

2011-07-01

Formation and progression of atherosclerotic plaque is a dynamic and complex process involving various pathophysiologic steps including inflammation and calcification. The purpose of this study was to compare macrophage activity as determined by (18)F-FDG PET and ongoing mineral deposition as measured by (18)F-sodium fluoride PET in atherosclerotic plaque and to correlate these findings with calcified plaque burden as assessed by CT. Forty-five patients were examined by whole-body (18)F-FDG PET, (18)F-sodium fluoride PET, and CT. Tracer uptake in various arterial segments was analyzed both qualitatively and semiquantitatively by measuring the blood-pool-corrected standardized uptake value (target-to-background ratio [TBR]). The pattern of tracer uptake in atherosclerotic lesions was compared after color-coded multistudy image fusion of PET and CT studies. The Fisher exact test and the Spearman correlation coefficient r(s) were used for statistical analysis of image-based results and cardiovascular risk factors. Intra- and interrater reproducibility were evaluated using the Cohen κ. (18)F-sodium fluoride uptake was observed at 105 sites in 27 (60%) of the 45 study patients, and mean TBR was 2.3 ± 0.7. (18)F-FDG uptake was seen at 124 sites in 34 (75.6%) patients, and mean TBR was 1.5 ± 0.3. Calcified atherosclerotic lesions were observed at 503 sites in 34 (75.6%) patients. Eighty-one (77.1%) of the 105 lesions with marked (18)F-sodium fluoride uptake and only 18 (14.5%) of the 124 lesions with (18)F-FDG accumulation were colocalized with arterial calcification. Coincident uptake of both (18)F-sodium fluoride and (18)F-FDG was observed in only 14 (6.5%) of the 215 arterial lesions with radiotracer accumulation. PET/CT with (18)F-FDG and (18)F-sodium fluoride may allow evaluation of distinct pathophysiologic processes in atherosclerotic lesions and might provide information on the complex interactions involved in formation and progression of atherosclerotic plaque.

18F-FNDP for PET Imaging of Soluble Epoxide Hydrolase.

PubMed

Horti, Andrew G; Wang, Yuchuan; Minn, Il; Lan, Xi; Wang, Jian; Koehler, Raymond C; Alkayed, Nabil J; Dannals, Robert F; Pomper, Martin G

2016-11-01

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which are generated in the brain to couple neuronal activity and cerebral blood flow in normal and pathologic states. Altered regulation of sEH was observed previously in various neuropathologic disorders including vascular dementia and stroke. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6- 18 F-fluoronicotinamide ( 18 F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET. 18 F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18 F-FNDP was measured using an sEH inhibitor screening assay kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pretreatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in 3 baboons, with regional tracer binding quantified using distribution volume. The metabolism of 18 F-FNDP in baboons was assessed using high-performance liquid chromatography. 18 F-FNDP (inhibition binding affinity constant, 1.73 nM) was prepared in 1 step in a radiochemical yield of 14% ± 7%, specific radioactivity in the range of 888-3,774 GBq/μmol, and a radiochemical purity greater than 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice, regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2% injected dose per gram of tissue at peak uptake. Blockade of 80%-90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH knock-out mice. PET baboon

Induction of Th1 polarized immune responses by thiolated Eudragit-coated F4 and F18 fimbriae of enterotoxigenic Escherichia coli.

PubMed

Lee, Won-Jung; Cha, Seungbin; Shin, Minkyoung; Islam, Mohammad Ariful; Cho, Chong-su; Yoo, Han Sang

2011-10-01

Diarrhea in newborn and weaned piglets is mainly induced by enterotoxigenic Escherichia coli (ETEC) with fimbriae F4 (K88) and F18 (F107). In this study, we evaluated F4 and F18 coated with thiolated Eudragit microspheres (TEMS) as a candidate for an oral vaccine. The average particle sizes of TEMS, F4-loaded TEMS, and F18-loaded TEMS were measured as 4.2±0.75 μm, 4.7±0.50 μm, and 4.5±0.37 μm, respectively. F4 is more efficiently encapsulated than F18 in the loading with TEMS. In the release test, F4 and F18 fimbriae were protected in acidic circumstances, whereas most were released at pH 7.4 of intestine circumstances. Production of TNF-α and NO from RAW 264.7 cells was increased in a time-dependent manner after exposure to all groups, whereas only F4- or F18-loaded TEMS-stimulated IL-6 secretion. The levels of IFN-γ from mouse splenocytes after exposure to F4 or F18 were increased while IL-4 was not detectable. These results suggest that F4- and F18-loaded TEMS may effectively induce immune response with the efficient release of antigens to appropriate target sites. Copyright © 2011 Elsevier B.V. All rights reserved.

A rapid solid-phase extraction method for measurement of non-metabolised peripheral benzodiazepine receptor ligands, [(18)F]PBR102 and [(18)F]PBR111, in rat and primate plasma.

PubMed

Katsifis, Andrew; Loc'h, Christian; Henderson, David; Bourdier, Thomas; Pham, Tien; Greguric, Ivan; Lam, Peter; Callaghan, Paul; Mattner, Filomena; Eberl, Stefan; Fulham, Michael

2011-01-01

To develop a rapid and reliable method for estimating non-metabolised PBR ligands fluoroethoxy ([(18)F]PBR102)- and fluoropropoxy ([(18)F]PBR111)-substituted 2-(6-chloro-2-phenyl)imidazo[1,2-a]pyridine-3-yl)-N,N-diethylacetamides in plasma. Rats and baboons were imaged with PET up to 2 h postinjection of [(18)F]PBR102 and [(18)F]PBR111 under baseline conditions, after pre-blocking or displacement with PK11195. Arterial plasma samples were directly analysed by reverse-phase solid-phase extraction (RP-SPE) and RP-HPLC and by normal-phase TLC. SPE cartridges were successively washed with acetonitrile/water mixtures. SPE eluant radioactivity was measured in a γ-counter to determine the parent compound fraction and then analysed by HPLC and TLC for validation. In SPE, hydrophilic and lipophilic radiolabelled metabolites were eluted in water and 20% acetonitrile/water. All non-metabolised [(18)F]PBR102 and [(18)F]PBR111 were in SPE acetonitrile fraction as confirmed by HPLC and TLC analysis. Unchanged (%) [(18)F]PBR102 and [(18)F]PBR111 from SPE analysis in rat and baboon plasma agreed with those from HPLC and TLC analysis. In rats and baboons, the fraction of unchanged tracer followed a bi-exponential decrease, with half-lives of 7 to 10 min for the fast component and >80 min for the slow component for both tracers. Direct plasma SPE analysis of [(18)F]PBR102 and [(18)F]PBR111 can reliably estimate parent compound fraction. SPE was superior to HPLC for samples with low activity; it allows rapid and accurate metabolite analysis of a large number of plasma samples for improved estimation of metabolite-corrected input function during quantitative PET imaging studies. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Fast and repetitive in-capillary production of [18F]FDG.

PubMed

Wester, Hans-Jürgen; Schoultz, Bent Wilhelm; Hultsch, Christina; Henriksen, Gjermund

2009-04-01

The increasing demand for radiopharmaceuticals to be provided reproducibly and flexibly with high frequency for clinical application and animal imaging would be better met by improved or even new strategies for automated tracer production. Radiosynthesis in microfluidic systems, i.e. narrow tubing with a diameter of approximately 50-500 microm, holds promise for providing the means for repetitive multidose and multitracer production. In this study, the performance of a conceptually simple microfluidic device integrated into a fully automated synthesis procedure for in-capillary radiosynthesis (ICR) of clinical grade [(18)F]FDG was evaluated. The instrumental set-up consisted of pumps for reagent and solvent delivery into small mixing chambers, micro-fluidic capillaries, in-process radioactivity monitoring, solid-phase extraction and on-column deprotection of the (18)F-labelled intermediate followed by on-line formulation of [(18)F]FDG. In-capillary(18)F-fluorination of 2.1 micromol 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulphonyl-beta-D-mannopyranose (TATM; precursor for [(18)F]FDG) in acetonitrile (MeCN) at a flow rate of 0.3 ml/min within 40 s and subsequent on-line hydrolysis of the intermediate by treatment with 0.3 M NaOH for 1 min at 40 degrees C resulted in a radiochemical yield of 88 +/- 4% within <7 min. Reproducibility, robustness and suitability as a fast and efficient radiopharmaceutical research tool for (18)F-fluorination was demonstrated by eight independent, sequentially performed ICRs which provided identical tracer quality (radiochemical purity >97%, MeCN <5 microg/ml) and similar absolute yields (approximately 1.4 GBq). The described ICR process is a simple and efficient alternative to classic radiotracer production systems and provides a comparatively cheap instrumental methodology for the repetitive production of [(18)F]FDG with remarkably high efficiency and high yield under fully automated conditions. Although the results concerning the

Selective 2-( sup 18 F)fluorodopa uptake for melanogenesis in murine metastatic melanomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ishiwata, K.; Kubota, K.; Kubota, R.

The relationship between 3,4-dihydroxy-2-({sup 18}F)fluoro-L-phenylalanine (2-({sup 18}F)FDOPA) uptake and melanogenesis was studied using mice bearing two B16 melanomas: B16-F1 has a higher melanin synthesis ability and a slower growing rate than the higher metastatic B16-F10. A significantly higher 2-({sup 18}F)FDOPA uptake by B16-F1 than by B16-F10 and a reverse relationship for the uptake of ({sup 14}C) 2-deoxy-2-fluoro-D-glucose and ({sup 3}H)thymidine were observed 1 hr postinjection. F1-to-F10 ratios of both the 2-({sup 18}F)FDOPA uptake and the acid-insoluble radioactivity increased to about 5 at 6 hr, which paralleled the melanin content. FM3A mammary carcinoma showed a 2-({sup 18}F)FDOPA uptake similar to themore » B16-F10 but without the acid-insoluble radioactivity. With D,L-DOPA loading, a 55% decreased uptake by FM3A 1 hr postinjection was significantly greater than the 20% reduction in both melanomas. O-Methylated 2-({sup 18}F)FDOPA was a predominant acid-soluble metabolite in all tumors. Whole-body autoradiography discriminated the two melanomas clearly. 2-({sup 18}F)FDOPA may be a promising tracer for the selective imaging of melanogenesis.« less

[18F]MEL050 as a melanin-targeted PET tracer: Fully automated radiosynthesis and comparison to 18F-FDG for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases.

PubMed

Rizzo-Padoin, Nathalie; Chaussard, Michael; Vignal, Nicolas; Kotula, Ewa; Tsoupko-Sitnikov, Vadim; Vaz, Sofia; Hontonnou, Fortune; Liu, Wang-Qing; Poyet, Jean-Luc; Vidal, Michel; Merlet, Pascal; Hosten, Benoit; Sarda-Mantel, Laure

2016-12-01

Melanoma is a highly malignant cutaneous tumor of melanin-producing cells. MEL050 is a synthetic benzamide-derived molecule that specifically binds to melanin with high affinity. Our aim was to implement a fully automated radiosynthesis of [ 18 F]MEL050, using for the first time, the AllInOne™ synthesis module (Trasis), and to evaluate the potential of [ 18 F]MEL050 for the detection of pigmented melanoma in mice primary subcutaneous tumors and pulmonary metastases, and to compare it with that of [ 18 F]FDG. Automated radiosynthesis of [ 18 F]MEL050, including HPLC purification and formulation, were performed on an AllInOne™ synthesis module. [ 18 F]MEL050 was synthesized using a one-step bromine-for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumor) or intravenous (pulmonary metastases) injection of B16-F10-luc2 cells in NMRI mice. The maximum percentage of [ 18 F]MEL050 Injected Dose per g of lung tissue (%ID/g Max) was determined on PET images, compared to [ 18 F]FDG and correlated to in vivo bioluminescence imaging. The automated radiosynthesis of [ 18 F]MEL050 required an overall radiosynthesis time of 48min, with a yield of 13-18% (not-decay corrected) and radiochemical purity higher than 99%. [ 18 F]MEL050 PET/CT images were concordant with bioluminescence imaging, showing increased radiotracer uptake in all primary subcutaneous tumors and pulmonary metastases of mice. PET quantification of radiotracers uptake in tumors and muscles demonstrated similar tumor-to-background ratio (TBR) with [ 18 F]MEL050 and [ 18 F]FDG in subcutaneous tumors and higher TBR with [ 18 F]MEL050 than with [ 18 F]FDG in pulmonary metastases. We successfully implemented the radiosynthesis of [ 18 F]MEL050 using the AllInOne™ module, including HPLC purification and formulation. In vivo PET/CT validation of [ 18 F]MEL050 was obtained in mouse models of pigmented melanoma, where higher [ 18 F]MEL050 uptake was observed

Synthesis and preclinical characterization of [18F]FPBZA: a novel PET probe for melanoma.

PubMed

Wu, Shih-Yen; Huang, Shih-Pin; Lo, Yen-Chen; Liu, Ren-Shyan; Wang, Shyh-Jen; Lin, Wuu-Jyh; Shen, Chih-Chieh; Wang, Hsin-Ell

2014-01-01

Benzamide can specifically bind to melanoma cells. A 18F-labeled benzamide derivative, [18F]N-(2-diethylaminoethyl)-4-[2-(2-(2-fluoroethoxy) ethoxy)ethoxy]benzamide ([18F]FPBZA), was developed as a promising PET probe for primary and metastatic melanoma. [18F]FPBZA was synthesized via a one-step radiofluorination in this study. The specific uptake of [18F]FPBZA was studied in B16F0 melanoma cells, A375 amelanotic melanoma cells, and NB-DNJ-pretreated B16F0 melanoma cells. The biological characterization of [18F]FPBZA was performed on mice bearing B16F0 melanoma, A375 amelanotic melanoma, or inflammation lesion. [18F]FPBZA can be prepared efficiently with a yield of 40-50%. The uptake of [18F]FPBZA by B16F0 melanoma cells was significantly higher than those by A375 tumor cells and NB-DNJ-pretreated B16F0 melanoma cells. B16F0 melanoma displayed prominent uptake of [18F]FPBZA at 2 h (7.81±0.82%ID/g), compared with A375 tumor and inflammation lesion (3.00±0.71 and 1.67±0.56%ID/g, resp.). [18F]FPBZA microPET scan clearly delineated B16F0 melanoma but not A375 tumor and inflammation lesion. In mice bearing pulmonary metastases, the lung radioactivity reached 4.77±0.36%ID/g at 2 h (versus 1.16±0.23%ID/g in normal mice). Our results suggested that [18F]FPBZA PET would provide a promising and specific approach for the detection of primary and metastatic melanoma lesions.

Biocompatible inorganic nanoparticles for [18F]-fluoride binding with applications in PET imaging

PubMed Central

Jauregui-Osoro, Maite; Williamson, Peter A.; Glaria, Arnaud; Sunassee, Kavitha; Charoenphun, Putthiporn; Green, Mark A.; Mullen, Gregory E. D.; Blower, Philip J.

2014-01-01

A wide selection of insoluble nanoparticulate metal salts was screened for avid binding of [18F]-fluoride. Hydroxyapatite and aluminium hydroxide nanoparticles showed particularly avid and stable binding of [18F]-fluoride in various biological media. The in vivo behaviour of the [18F]-labelled hydroxyapatite and aluminium hydroxide particles was determined by PET-CT imaging in mice. [18F]-labelled hydroxyapatite was stable in circulation and when trapped in various tissues (lung embolisation, subcutaneous and intramuscular), but accumulation in liver via reticuloendothelial clearance was followed by gradual degradation and release of [18F]-fluoride (over a period of 4 h) which accumulated in bone. [18F]-labelled aluminium hydroxide was also cleared to liver and spleen but degraded slightly even without liver uptake (subcutanenous and intramuscular). Both materials have properties that are an attractive basis for the design of molecular targeted PET imaging agents labelled with 18F. PMID:21394352

Reduced dimethylaminoethanol in [(18)F]fluoromethylcholine: an important step towards enhanced tumour visualization.

PubMed

Slaets, Dominique; De Bruyne, Sylvie; Dumolyn, Caroline; Moerman, Lieselotte; Mertens, Koen; De Vos, Filip

2010-11-01

[(18)F]Fluoromethylcholine ([(18)F]FCho) is a radiotracer generally used for tumour visualization in patients. Due to high levels of dimethylaminoethanol (DMAE) remaining in [(18)F]FCho solutions synthesized by currently available methods, tumour visualization might be compromised. An improved purification method involving an optimized purification step for reducing the levels of DMAE was conceived. The physiological explanation for the interference of residual DMAE in [(18)F]FCho pharmacokinetics was further elaborated in a xenograft mouse model. The use of a series of polymer solid-phase extraction cartridges (Oasis HLB/WCX), instead of the commonly used combination of tC18 and Accell CM cartridges, reduced DMAE levels from 402.2±49.6 ppm to 3.0±0.5 ppm. Subsequent in vitro tests proved that (1) [(18)F]FCho uptake was reduced in the presence of DMAE at concentrations above 0.5 µM and (2) DMAE is a competitive inhibitor of [(18)F]FCho transport. In vivo experiments in xenograft mouse models corroborated reduced tumour uptake at DMAE plasma levels of about 2.5 µM as found in patients injected with contaminated [(18)F]FCho. Residual DMAE, even at levels below choline plasma concentrations found during fasting, compromises [(18)F]FCho uptake in vivo and care should be taken to avoid its interference in molecular imaging with [(18)F]FCho.

(18)F-FBPA as a tumor specific tracer of L-type amino acid transporter 1 (LAT1): PET evaluation in tumor and inflammation compared to (18)F-FDG and (11)C-methionine.

PubMed

Watabe, Tadashi; Hatazawa, Jun

2015-01-01

(18)F-FDG-PET is used worldwide for oncology patients. However, we sometimes encounter false positive cases of (18)F-FDG PET, such as moderate uptake in the inflammatory lesion, because (18)F-FDG accumulates not only in the cancer cells but also in the inflammatory cells (macrophage, granulation tissue, etc). To overcome this limitation of (18)F-FDG, we started to use (4-borono-2- [(18)F]fluoro-L-phenylalanine) (18)F-FBPA, an artificial amino acid tracer which is focusing attention as a tumor specific PET tracer. Physiological accumulation of (18)F-FBPA is limited in the kidney and urinary tract in humans, which enable preferable evaluation of uptake in the abdominal organs compared to (11)C-methionine ((11)C-MET). The purpose of this study was to evaluate (18)F-FBPA as a tumor specific tracer by in vitro cellular uptake analysis focusing on the selectivity of L-type amino acid transporter 1 (LAT1), which is specifically expressed in tumor cells, and in vivo PET analysis in rat xenograft and inflammation models compared to (18)F-FDG and (11)C-methionine. Uptake inhibition and efflux experiments were performed in HEK293-LAT1 and LAT2 cells using cold BPA, cold (18)F-FBPA, and hot (18)F-FBPA to evaluate LAT affinity and transport capacity. Position emission tomography studies were performed in rat xenograft model of C6 glioma 2 weeks after the implantation (n=9, body weight=197±10.5g) and subcutaneous inflammation model 4 days after the injection of turpentine oil (n=9, body weight=197±14.4g). Uptake on static PET images were compared among (18)F-FBPA at 60-70min post injection, (18)F-FDG at 60-70min, and (11)C-MET at 20-30min in the tumors and the inflammatory lesions by maximum standardized uptake value (SUVmax). Cellular uptake analysis showed no significant difference in inhibitory effect and efflux of LAT1 between cold (18)F-FBPA and cold BPA, suggesting the same affinity and transport capacity via LAT1. Uptake of (18)F-FBPA via LAT1 was superior to LAT2 by

18F-FDG PET/CT Imaging of Primary Gastric Lymphoma.

PubMed

Davis, Brady S; Thompson, Trevor A; Wolin, Ely A

2016-12-01

Primary gastric lymphoma (PGL) accounts for less than 4% of gastric neoplasms. 18 F-FDG PET with simultaneously acquired CT ( 18 F-FDG PET/CT) allows for staging and differentiation from other gastric cancers. Rapid diagnosis and staging are important because chemotherapeutic response is generally favorable. We describe a case of an 83-y-old woman with stage II 1 PGL. 18 F-FDG PET/CT can be helpful to differentiate various gastric masses and is an important factor in the staging of PGL. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Synthesis and Preclinical Characterization of [18F]FPBZA: A Novel PET Probe for Melanoma

PubMed Central

Huang, Shih-Pin; Lo, Yen-Chen; Liu, Ren-Shyan; Shen, Chih-Chieh

2014-01-01

Introduction. Benzamide can specifically bind to melanoma cells. A 18F-labeled benzamide derivative, [18F]N-(2-diethylaminoethyl)-4-[2-(2-(2-fluoroethoxy) ethoxy)ethoxy]benzamide ([18F]FPBZA), was developed as a promising PET probe for primary and metastatic melanoma. Methods. [18F]FPBZA was synthesized via a one-step radiofluorination in this study. The specific uptake of [18F]FPBZA was studied in B16F0 melanoma cells, A375 amelanotic melanoma cells, and NB-DNJ-pretreated B16F0 melanoma cells. The biological characterization of [18F]FPBZA was performed on mice bearing B16F0 melanoma, A375 amelanotic melanoma, or inflammation lesion. Results. [18F]FPBZA can be prepared efficiently with a yield of 40–50%. The uptake of [18F]FPBZA by B16F0 melanoma cells was significantly higher than those by A375 tumor cells and NB-DNJ-pretreated B16F0 melanoma cells. B16F0 melanoma displayed prominent uptake of [18F]FPBZA at 2 h (7.81 ± 0.82 %ID/g), compared with A375 tumor and inflammation lesion (3.00 ± 0.71 and 1.67 ± 0.56 %ID/g, resp.). [18F]FPBZA microPET scan clearly delineated B16F0 melanoma but not A375 tumor and inflammation lesion. In mice bearing pulmonary metastases, the lung radioactivity reached 4.77 ± 0.36 %ID/g at 2 h (versus 1.16 ± 0.23 %ID/g in normal mice). Conclusions. Our results suggested that [18F]FPBZA PET would provide a promising and specific approach for the detection of primary and metastatic melanoma lesions. PMID:25254219

Regional distribution and kinetics of [18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer.

PubMed

Sörensen, Jens; Owenius, Rikard; Lax, Michelle; Johansson, Silvia

2013-02-01

[(18)F]Fluciclovine (anti-[(18)F]FACBC) is a synthetic amino acid developed for PET assessment of the anabolic component of tumour metabolism in clinical routine. This phase 1 trial evaluated the safety, tracer stability and uptake kinetics of [(18)F]fluciclovine in patients. Six patients with biopsy-proven prostate cancer were investigated with 3-T MRI and PET/CT. All underwent dynamic [(18)F]fluciclovine PET/CT of the pelvic area for up to 120 min after injection of 418 ± 10 MBq of tracer with simultaneous blood sampling of radioactivity. The kinetics of uptake in tumours and normal tissues were evaluated using standardized uptake values (SUVs) and compartmental modelling. Tumour deposits as defined by MRI were clearly visualized by PET. Urine excretion was minimal and normal tissue background was low. Uptake of [(18)F]fluciclovine in tumour from the blood was rapid and the tumour-to-normal tissue contrast was highest between 1 and 15 min after injection with a 65 % reduction in mean tumour uptake at 90 min after injection. A one-compartment model fitted the tracer kinetics well. Early SUVs correlated well with both the influx rate constant (K (1)) and the volume of distribution of the tracer (V (T)). There were no signs of tracer metabolite formation. The product was well tolerated in all patients without significant adverse events. [(18)F]Fluciclovine shows high uptake in prostate cancer deposits and appears safe for use in humans. The production is robust and the formulation stable in vivo. An early imaging window seems to provide the best visual results. SUV measurements capture most of the kinetic information that can be obtained from more advanced models, potentially simplifying quantification in future studies.

Al18F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging.

PubMed

Cleeren, Frederik; Lecina, Joan; Ahamed, Muneer; Raes, Geert; Devoogdt, Nick; Caveliers, Vicky; McQuade, Paul; Rubins, Daniel J; Li, Wenping; Verbruggen, Alfons; Xavier, Catarina; Bormans, Guy

2017-01-01

Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The Al 18 F-labeling strategy involves chelation in aqueous medium of aluminum mono[ 18 F]fluoride ({Al 18 F} 2+ ) by a suitable chelator conjugated to a biomolecule. However, the need for elevated temperatures (100-120 °C) required for the chelation reaction limits its widespread use. Therefore, we designed a new restrained complexing agent (RESCA) for application of the AlF strategy at room temperature. Methods. The new chelator RESCA was conjugated to three relevant biologicals and the constructs were labeled with {Al 18 F} 2+ to evaluate the generic applicability of the one-step Al 18 F-RESCA-method. Results. We successfully labeled human serum albumin with excellent radiochemical yields in less than 30 minutes and confirmed in vivo stability of the Al 18 F-labeled protein in rats. In addition, we efficiently labeled nanobodies targeting the Kupffer cell marker CRIg, and performed µPET studies in healthy and CRIg deficient mice to demonstrate that the proposed radiolabeling method does not affect the functional integrity of the protein. Finally, an affibody targeting HER2 (PEP04314) was labeled site-specifically, and the distribution profile of (±)-[ 18 F]AlF(RESCA)-PEP04314 in a rhesus monkey was compared with that of [ 18 F]AlF(NOTA)-PEP04314 using whole-body PET/CT. Conclusion. This generic radiolabeling method has the potential to be a kit-based fluorine-18 labeling strategy, and could have a large impact on PET radiochemical space, potentially enabling the development of many new fluorine-18 labeled protein-based radiotracers.

Al18F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging

PubMed Central

Cleeren, Frederik; Lecina, Joan; Ahamed, Muneer; Raes, Geert; Devoogdt, Nick; Caveliers, Vicky; McQuade, Paul; Rubins, Daniel J; Li, Wenping; Verbruggen, Alfons; Xavier, Catarina; Bormans, Guy

2017-01-01

Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The Al18F-labeling strategy involves chelation in aqueous medium of aluminum mono[18F]fluoride ({Al18F}2+) by a suitable chelator conjugated to a biomolecule. However, the need for elevated temperatures (100-120 °C) required for the chelation reaction limits its widespread use. Therefore, we designed a new restrained complexing agent (RESCA) for application of the AlF strategy at room temperature. Methods. The new chelator RESCA was conjugated to three relevant biologicals and the constructs were labeled with {Al18F}2+ to evaluate the generic applicability of the one-step Al18F-RESCA-method. Results. We successfully labeled human serum albumin with excellent radiochemical yields in less than 30 minutes and confirmed in vivo stability of the Al18F-labeled protein in rats. In addition, we efficiently labeled nanobodies targeting the Kupffer cell marker CRIg, and performed µPET studies in healthy and CRIg deficient mice to demonstrate that the proposed radiolabeling method does not affect the functional integrity of the protein. Finally, an affibody targeting HER2 (PEP04314) was labeled site-specifically, and the distribution profile of (±)-[18F]AlF(RESCA)-PEP04314 in a rhesus monkey was compared with that of [18F]AlF(NOTA)-PEP04314 using whole-body PET/CT. Conclusion. This generic radiolabeling method has the potential to be a kit-based fluorine-18 labeling strategy, and could have a large impact on PET radiochemical space, potentially enabling the development of many new fluorine-18 labeled protein-based radiotracers. PMID:28824726

Synthesis of [18F]-labelled Maltose Derivatives as PET Tracers for Imaging Bacterial Infection

PubMed Central

Namavari, Mohammad; Gowrishankar, Gayatri; Hoehne, Aileen; Jouannot, Erwan; Gambhir, Sanjiv S

2015-01-01

Purpose To develop novel positron emission tomography (PET) agents for visualization and therapy monitoring of bacterial infections. Procedures It is known that maltose and maltodextrins are energy sources for bacteria. Hence, 18F-labelled maltose derivatives could be a valuable tool for imaging bacterial infections. We have developed methods to synthesize 4-O-(α-D-glucopyranosyl)-6-deoxy-6-[18F]fluoro-D-glucopyranoside (6-[18F]fluoromaltose) and 4-O-(α-D-glucopyranosyl)-1-deoxy-1-[18F]fluoro-D-glucopyranoside (1-[18F]fluoromaltose) as bacterial infection PET imaging agents. 6-[18F]fluoromaltose was prepared from precursor 1,2,3-tri-O-acetyl-4-O-(2′,3′,-di-O-acetyl-4′,6′-benzylidene-α-D-glucopyranosyl)-6-deoxy-6-nosyl-D-glucopranoside (5). The synthesis involved the radio-fluorination of 5 followed by acidic and basic hydrolysis to give 6-[18F]fluoromaltose. In an analogous procedure, 1-[18F]fluoromaltose was synthesized from 2,3, 6-tri-O-acetyl-4-O-(2′,3′,4′,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-deoxy-1-O-triflyl-D-glucopranoside (9). Stability of 6-[18F]fluoromaltose in phosphate-buffered saline (PBS) and human and mouse serum at 37 °C was determined. Escherichia coli uptake of 6-[18F]fluoromaltose was examined. Results A reliable synthesis of 1- and 6-[18F]fluoromaltose has been accomplished with 4–6 and 5–8 % radiochemical yields, respectively (decay-corrected with 95 % radiochemical purity). 6-[18F]fluoromaltose was sufficiently stable over the time span needed for PET studies (~96 % intact compound after 1-h and ~65 % after 2-h incubation in serum). Bacterial uptake experiments indicated that E. coli transports 6-[18F]fluoromaltose. Competition assays showed that the uptake of 6-[18F]fluoromaltose was completely blocked by co-incubation with 1 mM of the natural substrate maltose. Conclusion We have successfully synthesized 1- and 6-[18F]fluoromaltose via direct fluorination of appropriate protected maltose precursors. Bacterial uptake

Pleuroperitoneal Mesothelioma: A Rare Entity on 18F-FDG PET/CT

PubMed Central

Sahoo, Manas Kumar; Mukherjee, Anirban; Girish; Parida, Kumar; Agarwal, Krishan Kant; Bal, Chandrasekhar; Tripathi, Madhavi; Das, Chandan Jyoti; Shamim, Shamim Ahmed

2017-01-01

Pleuroperitoneal mesothelioma is an extremely rare entity. Only few cases are reported worldwide. We hereby represent a case of pleural mesothelioma referred for F-18-Fluorodeoxyglucose positron emission tomography/computed tomography for response evaluation. Diffuse F-18-Fluorodeoxyglucose avid peritoneal and omental thickening noted which subsequently turned out to be mesothelial involvement on peritoneal biopsy. This case demonstrates the role of F-18-Fluorodeoxyglucose positron emission tomography/computed tomography in detecting other sites of involvement in case of malignant mesothelioma. PMID:28242997

Optimization of 18 F-syntheses using 19 F-reagents at tracer-level concentrations and liquid chromatography/tandem mass spectrometry analysis: Improved synthesis of [18 F]MDL100907.

PubMed

Zhang, Xiang; Dunlow, Ryan; Blackman, Burchelle N; Swenson, Rolf E

2018-05-15

Traditional radiosynthetic optimization faces the challenges of high radiation exposure, cost, and inability to perform serial reactions due to tracer decay. To accelerate tracer development, we have developed a strategy to simulate radioactive 18 F-syntheses by using tracer-level (nanomolar) non-radioactive 19 F-reagents and LC-MS/MS analysis. The methodology was validated with fallypride synthesis under tracer-level 19 F-conditions, which showed reproducible and comparable results with radiosynthesis, and proved the feasibility of this process. Using this approach, the synthesis of [ 18 F]MDL100907 was optimized under 19 F-conditions with greatly improved yield. The best conditions were successfully transferred to radiosynthesis. A radiochemical yield of 19% to 22% was achieved with the radiochemical purity >99% and the molar activity 38.8 to 53.6 GBq/ μmol (n = 3). The tracer-level 19 F-approach provides a high-throughput and cost-effective process to optimize radiosynthesis with reduced radiation exposure. This new method allows medicinal and synthetic chemists to optimize radiolabeling conditions without the need to use radioactivity. Copyright © 2018 John Wiley & Sons, Ltd.

Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [(18)F]PBR102 and [ (18)F]PBR111 in a model of excitotoxin-induced neuroinflammation.

PubMed

Callaghan, P D; Wimberley, C A; Rahardjo, G L; Berghofer, P J; Pham, T Q; Jackson, T; Zahra, D; Bourdier, T; Wyatt, N; Greguric, I; Howell, N R; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Gregoire, M C; Katsifis, A

2015-01-01

The in vivo binding parameters of the novel imidazopyridine TSPO ligand [(18)F]PBR102 were assessed and compared with those of [(18)F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [(18)F]PBR102 or [(18)F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration-time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [(125)I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. The BPs of [(18)F]PBR102 [(18)F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [(11)C]PK11195. The presaturation study showed differences in the volume of distribution between the

Quantitative analysis of 18F-NaF dynamic PET/CT cannot differentiate malignant from benign lesions in multiple myeloma

PubMed Central

Sachpekidis, Christos; Hillengass, Jens; Goldschmidt, Hartmut; Anwar, Hoda; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2017-01-01

A renewed interest has been recently developed for the highly sensitive bone-seeking radiopharmaceutical 18F-NaF. Aim of the present study is to evaluate the potential utility of quantitative analysis of 18F-NaF dynamic PET/CT data in differentiating malignant from benign degenerative lesions in multiple myeloma (MM). 80 MM patients underwent whole-body PET/CT and dynamic PET/CT scanning of the pelvis with 18F-NaF. PET/CT data evaluation was based on visual (qualitative) assessment, semi-quantitative (SUV) calculations, and absolute quantitative estimations after application of a 2-tissue compartment model and a non-compartmental approach leading to the extraction of fractal dimension (FD). In total 263 MM lesions were demonstrated on 18F-NaF PET/CT. Semi-quantitative and quantitative evaluations were performed for 25 MM lesions as well as for 25 benign, degenerative and traumatic lesions. Mean SUVaverage for MM lesions was 11.9 and mean SUVmax was 23.2. Respectively, SUVaverage and SUVmax for degenerative lesions were 13.5 and 20.2. Kinetic analysis of 18F-NaF revealed the following mean values for MM lesions: K1 = 0.248 (1/min), k3 = 0.359 (1/min), influx (Ki) = 0.107 (1/min), FD = 1.382, while the respective values for degenerative lesions were: K1 = 0.169 (1/min), k3 = 0.422 (1/min), influx (Ki) = 0.095 (1/min), FD = 1. 411. No statistically significant differences between MM and benign degenerative disease regarding SUVaverage, SUVmax, K1, k3 and influx (Ki) were demonstrated. FD was significantly higher in degenerative than in malignant lesions. The present findings show that quantitative analysis of 18F-NaF PET data cannot differentiate malignant from benign degenerative lesions in MM patients, supporting previously published results, which reflect the limited role of 18F-NaF PET/CT in the diagnostic workup of MM. PMID:28913153

Quantitative analysis of 18F-NaF dynamic PET/CT cannot differentiate malignant from benign lesions in multiple myeloma.

PubMed

Sachpekidis, Christos; Hillengass, Jens; Goldschmidt, Hartmut; Anwar, Hoda; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

2017-01-01

A renewed interest has been recently developed for the highly sensitive bone-seeking radiopharmaceutical 18 F-NaF. Aim of the present study is to evaluate the potential utility of quantitative analysis of 18 F-NaF dynamic PET/CT data in differentiating malignant from benign degenerative lesions in multiple myeloma (MM). 80 MM patients underwent whole-body PET/CT and dynamic PET/CT scanning of the pelvis with 18 F-NaF. PET/CT data evaluation was based on visual (qualitative) assessment, semi-quantitative (SUV) calculations, and absolute quantitative estimations after application of a 2-tissue compartment model and a non-compartmental approach leading to the extraction of fractal dimension (FD). In total 263 MM lesions were demonstrated on 18 F-NaF PET/CT. Semi-quantitative and quantitative evaluations were performed for 25 MM lesions as well as for 25 benign, degenerative and traumatic lesions. Mean SUV average for MM lesions was 11.9 and mean SUV max was 23.2. Respectively, SUV average and SUV max for degenerative lesions were 13.5 and 20.2. Kinetic analysis of 18 F-NaF revealed the following mean values for MM lesions: K 1 = 0.248 (1/min), k 3 = 0.359 (1/min), influx (K i ) = 0.107 (1/min), FD = 1.382, while the respective values for degenerative lesions were: K 1 = 0.169 (1/min), k 3 = 0.422 (1/min), influx (K i ) = 0.095 (1/min), FD = 1. 411. No statistically significant differences between MM and benign degenerative disease regarding SUV average , SUV max , K 1 , k 3 and influx (K i ) were demonstrated. FD was significantly higher in degenerative than in malignant lesions. The present findings show that quantitative analysis of 18 F-NaF PET data cannot differentiate malignant from benign degenerative lesions in MM patients, supporting previously published results, which reflect the limited role of 18 F-NaF PET/CT in the diagnostic workup of MM.

Comparison study of [18F]FAl-NOTA-PRGD2, [18F]FPPRGD2, and [68Ga]Ga-NOTA-PRGD2 for PET imaging of U87MG tumors in mice.

PubMed

Lang, Lixin; Li, Weihua; Guo, Ning; Ma, Ying; Zhu, Lei; Kiesewetter, Dale O; Shen, Baozhong; Niu, Gang; Chen, Xiaoyuan

2011-12-21

[(18)F]FPPRGD2, an F-18 labeled dimeric cyclic RGDyK peptide, has favorable properties for PET imaging of angiogenesis by targeting the α(v)β(3) integrin receptor. This radiotracer has been approved by the FDA for use in clinical trials. However, the time-consuming multiple-step synthetic procedure required for its preparation may hinder the widespread usage of this tracer. The recent development of a method using an F-18 fluoride-aluminum complex to radiolabel peptides provides a strategy for simplifying the labeling procedure. On the other hand, the easy-to-prepare [(68)Ga]-labeled NOTA-RGD derivatives have also been reported to have promising properties for imaging α(v)β(3) integrin receptors. The purpose of this study was to prepare [(18)F]FPPRGD2 [corrected] , [(18)F]FAl-NOTA-PRGD2, and [(68)Ga]Ga-NOTA-PRGD2 and to compare their pharmacokinetics and tumor imaging properties using small animal PET. All three compounds showed rapid and high tracer uptake in U87MG tumors with high target-to-background ratios. The uptake in the liver, kidneys, and muscle were similar for all three tracers, and they all showed predominant renal clearance. In conclusion, [(18)F]FAl-NOTA-PRGD2 and [(68)Ga]Ga-NOTA-PRGD2 have imaging properties and pharmacokinetics comparable to those of [(18)F]FPPRGD2. Considering their ease of preparation and good imaging qualities, [(18)F]FAl-NOTA-PRGD2 and [(68)Ga]NOTA-PRGD2 are promising alternatives to [(18)F]FPPRGD2 for PET imaging of tumor α(v)β(3) integrin expression.

F-18 choline PET does not detect increased metabolism in F-18 fluoroethyltyrosine-negative low-grade gliomas.

PubMed

Roelcke, Ulrich; Bruehlmeier, Matthias; Hefti, Martin; Hundsberger, Thomas; Nitzsche, Egbert U

2012-01-01

Positron emission tomography (PET) with radiolabeled amino acids provides information on biopsy target and chemotherapy response in patients with low-grade gliomas (LGG). In this article, we addressed whether PET with F-18 choline (CHO) detects increased metabolism in F-18 fluoroethyltyrosine (FET)-negative LGG patients. Six LGG patients with nongadolinium-enhancing (magnetic resonance) FET-negative LGG were imaged with CHO PET. Regions of interest were positioned over tumor and contralateral brain. Uptake of FET and CHO was quantified as count ratio of tumor to contralateral brain. The mean FET uptake ratio for FET-negative LGG was 0.95 ± 0.03 (mean ± standard deviation). Five tumors did not show increased uptake ratios for CHO (0.96 ± 0.12). Slightly increased CHO uptake was found in 1 patient (1.24), which, however, was not associated with tumor visualization. Amino acid and choline uptake appear to behave similar in nongadolinium-enhancing LGG. For clinical purposes, CHO PET is not superior to FET PET.

Sodium 18F-Fluoride PET/CT of Bone, Joint and Other Disorders

PubMed Central

Jadvar, Hossein; Desai, Bhushan; Conti, Peter S.

2014-01-01

The use of 18F-sodium fluoride (18F-NaF) with positron emission tomography-computed tomography (PET/CT) is increasing. This resurgence of an old tracer has been fueled by several factors including superior diagnostic performance over standard 99mTc-based bone scintigraphy, growth in the availability of PET/CT imaging systems, increase in the number of regional commercial distribution centers for PET radiotracers, the recent concerns about potential chronic shortages with 99mTc based radiotracers, and the recent decision by the Centers for Medicare and Medicaid Services to reimburse for 18F-NaF PET/CT for evaluation of patients with known or suspected bone metastases through the National Oncologic PET Registry. The major goal of this article is to review the current evidence on the diagnostic utility of 18F-NaF in the imaging assessment of bone and joint in a variety of clinical conditions. PMID:25475379

18F-FEAnGA for PET of β-glucuronidase activity in neuroinflammation.

PubMed

Antunes, Inês F; Doorduin, Janine; Haisma, Hidde J; Elsinga, Philip H; van Waarde, Aren; Willemsen, Antoon T M; Dierckx, Rudi A; de Vries, Erik F J

2012-03-01

Activation of microglia is a hallmark of inflammatory, infectious, and degenerative diseases of the central nervous system. Several studies have indicated that there is an increase in release of β-glucuronidase by activated microglia into the extracellular space at the site of neuroinflammation. β-glucuronidase is involved in the hydrolysis of glycosaminoglycans on the cell surface and the degradation of the extracellular matrix. Therefore, β-glucuronidase might be a biomarker for ongoing neurodegeneration induced by neuroinflammation. In this study, we investigated whether the PET tracer (18)F-FEAnGA was able to detect β-glucuronidase release during neuroinflammation in a rat model of herpes encephalitis. Male Wistar rats were intranasally inoculated with herpes simplex virus 1 (HSV-1) or phosphate-buffered saline as a control. (11)C-(R)-PK11195 and (18)F-FEAnGA small-animal PET scans were acquired for 60 min. Logan graphical analysis was used to calculate (18)F-FEAnGA distribution volumes (DV(Logan)) in various brain areas. After administration of (18)F-FEAnGA, the area under the activity concentration-versus-time curve of the whole brain was 2 times higher in HSV-1-infected rats than in control rats. In addition, the DV(Logan) of (18)F-FEAnGA was most increased in the frontopolar cortex, frontal cortex, bulbus olfactorius, cerebral cortex, cerebellum, and brainstem of HSV-1-infected rats, when compared with control rats. The conversion of (18)F-FEAnGA to 4-hydroxy-3-nitrobenzyl alcohol was found to be 1.6 times higher in HSV-1-infected rats than in control rats and correlated with the DV(Logan) of (18)F-FEAnGA in the same areas of the brain. Furthermore, the DV(Logan) of (18)F-FEAnGA also correlated with β-glucuronidase activity in the same brain regions. In addition, DV(Logan) of (18)F-FEAnGA showed a tendency to correlate with (11)C-(R)-PK11195 uptake (marker for activated microglia) in the same brain regions. Despite relatively low brain uptake, (18)F

Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography

PubMed Central

Weinstein, Edward A.; Ordonez, Alvaro A.; DeMarco, Vincent P.; Murawski, Allison M.; Pokkali, Supriya; MacDonald, Elizabeth M.; Klunk, Mariah; Mease, Ronnie C.; Pomper, Martin G.; Jain, Sanjay K.

2015-01-01

The Enterobacteriaceae are a family of rod-shaped Gram-negative bacteria that normally inhabit the gastrointestinal tract and are the most common cause of Gram-negative bacterial infections in humans. In addition to causing serious multidrug-resistant, hospital-acquired infections, a number of Enterobacteriaceae species are also recognized as biothreat pathogens. As a consequence, new tools are urgently needed to specifically identify and localize infections due to Enterobacteriaceae and to monitor antimicrobial efficacy. In this report, we used commercially available 2-[18F]-fluorodeoxyglucose (18F-FDG) to produce 2-[18F]-fluorodeoxysorbitol (18F-FDS), a radioactive probe for Enterobacteriaceae, in 30 min. 18F-FDS selectively accumulated in Enterobacteriaceae, but not in Gram-positive bacteria or healthy mammalian or cancer cells in vitro. In a murine myositis model, 18F-FDS positron emission tomography (PET) rapidly differentiated true infection from sterile inflammation with a limit of detection of 6.2 ± 0.2 log10 colony-forming units (CFU) for Escherichia coli. Our findings were extended to models of mixed Gram-positive and Gram-negative thigh co-infections, brain infection, Klebsiella pneumonia, and mice undergoing immunosuppressive chemotherapy. This technique rapidly and specifically localized infections due to Enterobacteriaceae, providing a three-dimensional holistic view within the animal. Last, 18F-FDS PET monitored the efficacy of antimicrobial treatment, demonstrating a PET signal proportionate to the bacterial burden. Therapeutic failures associated with multidrug-resistant, extended-spectrum β-lactamase (ESBL)–producing E. coli infections were detected in real time. Together, these data show that 18F-FDS is a candidate imaging probe for translation to human clinical cases of known or suspected infections owing to Enterobacteriaceae. PMID:25338757

A quantitative analysis of the F18 flight control system

NASA Technical Reports Server (NTRS)

Doyle, Stacy A.; Dugan, Joanne B.; Patterson-Hine, Ann

1993-01-01

This paper presents an informal quantitative analysis of the F18 flight control system (FCS). The analysis technique combines a coverage model with a fault tree model. To demonstrate the method's extensive capabilities, we replace the fault tree with a digraph model of the F18 FCS, the only model available to us. The substitution shows that while digraphs have primarily been used for qualitative analysis, they can also be used for quantitative analysis. Based on our assumptions and the particular failure rates assigned to the F18 FCS components, we show that coverage does have a significant effect on the system's reliability and thus it is important to include coverage in the reliability analysis.

Synthesis and characterization of (18)F-labeled active site inhibited factor VII (ASIS).

PubMed

Erlandsson, Maria; Nielsen, Carsten H; Jeppesen, Troels E; Kristensen, Jesper B; Petersen, Lars C; Madsen, Jacob; Kjaer, Andreas

2015-05-15

Activated factor VII blocked in the active site with Phe-Phe-Arg-chloromethyl ketone (active site inhibited factor VII (ASIS)) is a 50-kDa protein that binds with high affinity to its receptor, tissue factor (TF). TF is a transmembrane glycoprotein that plays an important role in, for example, thrombosis, metastasis, tumor growth, and tumor angiogenesis. The aim of this study was to develop an (18)F-labeled ASIS derivative to assess TF expression in tumors. Active site inhibited factor VII was labeled using N-succinimidyl-4-[(18)F]fluorobenzoate, and the [(18)F]ASIS was purified on a PD-10 desalting column. The radiochemical yield was 25 ± 6%, the radiochemical purity was >97%, and the pseudospecific radioactivity was 35 ± 9 GBq/µmol. The binding efficacy was evaluated in pull-down experiments, which monitored the binding of unlabeled ASIS and [(18)F]ASIS to TF and to a specific anti-factor VII antibody (F1A2-mAb). No significant difference in binding efficacy between [(18)F]ASIS and ASIS could be detected. Furthermore, [(18)F]ASIS was relatively stable in vitro and in vivo in mice. In conclusion, [(18)F]ASIS has for the first time been successfully synthesized as a possible positron emission tomography tracer to image TF expression levels. In vivo positron emission tomography studies to evaluate the full potential of [(18)F]ASIS are in progress. Copyright © 2015 John Wiley & Sons, Ltd.

Synthesis, radiolabeling, and biological evaluation of ( R)- and ( S)-2-amino-5-[ 18F]fluoro-2-methylpentanoic acid (( R)-, ( S)-[ 18F]FAMPe) as potential positron emission tomography tracers for brain tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bouhlel, Ahlem; Zhou, Dong; Li, Aixiao

In this paper, a novel 18F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[ 18F]fluoro-2-methylpentanoic acid ([ 18F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [ 18F]FAMPe were obtained in good radiochemical yield (24–52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that ( S)-[ 18F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and smallmore » animal PET/CT studies in the mouse DBT model of glioblastoma showed that both ( R)- and ( S)-[ 18F]FAMPe have good tumor imaging properties with the ( S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Finally, comparison of the SUVs showed that ( S)-[ 18F]FAMPe had higher tumor to brain ratios compared to ( S)-[ 18F]FET, a well-established system L substrate.« less

Synthesis, radiolabeling, and biological evaluation of ( R)- and ( S)-2-amino-5-[ 18F]fluoro-2-methylpentanoic acid (( R)-, ( S)-[ 18F]FAMPe) as potential positron emission tomography tracers for brain tumors

DOE PAGES

Bouhlel, Ahlem; Zhou, Dong; Li, Aixiao; ...

2015-04-06

In this paper, a novel 18F-labeled α,α-disubstituted amino acid-based tracer, 2-amino-5-[ 18F]fluoro-2-methylpentanoic acid ([ 18F]FAMPe), has been developed for brain tumor imaging with a longer alkyl side chain than previously reported compounds to increase brain availability via system L amino acid transport. Both enantiomers of [ 18F]FAMPe were obtained in good radiochemical yield (24–52% n = 8) and high radiochemical purity (>99%). In vitro uptake assays in mouse DBT gliomas cells revealed that ( S)-[ 18F]FAMPe enters cells partly via sodium-independent system L transporters and also via other nonsystem A transport systems including transporters that recognize glutamine. Biodistribution and smallmore » animal PET/CT studies in the mouse DBT model of glioblastoma showed that both ( R)- and ( S)-[ 18F]FAMPe have good tumor imaging properties with the ( S)-enantiomer providing higher tumor uptake and tumor to brain ratios. Finally, comparison of the SUVs showed that ( S)-[ 18F]FAMPe had higher tumor to brain ratios compared to ( S)-[ 18F]FET, a well-established system L substrate.« less

Binding of /sup 18/F by cell membranes and cell walls of Streptococcus mutans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yotis, W.W.; Zeb, M.; McNulty, J.

1983-07-01

The binding of /sup 18/F to isolated cell membranes and cell walls of Streptococcus mutans GS-5 or other bacteria was assayed. The attachment of /sup 18/F to these cell envelopes proceeded slowly and reached equilibrium within 60 min. /sup 18/F binding was stimulated by Ca/sup 2 +/ (1 mM). The binding of /sup 18/F to cellular components was dependent upon the pH, as well as the amount of /sup 18/F and dose of the binder employed. The binding of /sup 18/F by cell walls prepared from fluoride-sensitive and fluoride-resistant cells of S. salivarius and S. mutans did not differ significantly.more » The pretreatment of cell walls or cell membranes for 60 min at 30 degrees C with 1 mg of RNase, DNase, or trypsin per ml did not influence the binding of /sup 18/F by the walls and membranes of S. mutans GS-5. However, prior exposure of cell membranes to sodium dodecyl sulfate caused a significant reduction in the number of /sup 18/F atoms bound by the membranes. In saturated assay systems, cell membranes of S. mutans GS-5 bound 10(15) to 10(16) atoms of /sup 18/F per mg (dry weight), whereas cell walls from S. mutans GS-5, FA-1, and HS-6 or Actinomyces viscosus T14V and T14AV bound 10(12) to 10(13) atoms of /sup 18/F per mg (dry weight). /sup 18/F in this quantity (10(12) to 10(13) atoms) cannot be detected with the fluoride electrode. The data provide, for the first time, a demonstration of /sup 18/F binding by cell membranes and walls of oral flora.« less

F18 Life Support: APECS and EDOX Cockpit Integration

NASA Technical Reports Server (NTRS)

Herrick, Paul

1998-01-01

Two systems are currently being integrated into the F18 Hornet support aircraft at NASA Dryden Flight Research Center (DFRC). The first system is the Aircrew Personal Environmental Control System (APECS). The system is designed to increase aircrew performance by combating heat stress in the cockpit. The second system is the Extended Duration Oxygen System (EDOX). This system will provide additional redundancy and oxygen system duration to the F18 without extensive modification to the current system.

F-18 HARV research pilot Dana Purifoy

NASA Technical Reports Server (NTRS)

1996-01-01

Dana D. Purifoy is an aerospace research pilot at NASA's Dryden Flight Research Center, Edwards, California. He joined NASA in August 1994. Purifoy is a former Air Force test pilot who served as a project pilot in the joint NASA/Air Force X-29 Forward Swept Wing research program conducted at Dryden from 1984 to 1991. His most recent assignment in the Air Force was flying U-2 aircraft as a test pilot at Air Force Plant 42, Palmdale, CA. In addition to flying the X-29 at Dryden as an Air Force pilot, Purifoy also served as project pilot and joint test force director with the AFTI F-16 (Advanced Fighter Technology Integration/F-16) program, also located at Dryden. Before his assignments as project pilot on the X-29 and AFTI/F-16 aircraft, Purifoy was chief of the Academics Systems Branch at the Air Force Test Pilot School at Edwards. Prior to becoming a test pilot, he flew F-111 and F-16 aircraft in Great Britain and Germany. He has accumulated 3800 hours of flying time in his career. The final flight for the F-18 High Alpha Research Vehicle (HARV) took place at NASA Dryden on May 29, 1996. The highly modified F-18 airplane flew 383 flights over a nine year period and demonstrated concepts that greatly increase fighter maneuverability. Among concepts proven in the aircraft is the use of paddles to direct jet engine exhaust in cases of extreme altitudes where conventional control surfaces lose effectiveness. Another concept, developed by NASA Langley Research Center, is a deployable wing-like surface installed on the nose of the aircraft for increased right and left (yaw) control on nose-high flight angles.

A novel approach to breast cancer diagnosis via PET imaging of microcalcifications using 18F-NaF

PubMed Central

Wilson, George H.; Gore, John C.; Yankeelov, Thomas E.; Barnes, Stephanie; Peterson, Todd E.; True, Jarrod M.; Shokouhi, Sepideh; McIntyre, J. Oliver.; Sanders, Melinda; Abramson, Vandana; Ngyuen, The-Quyen; Mahadevan-Jansen, Anita; Tantawy, Mohammed N.

2015-01-01

Rationale Current radiological methods for diagnosing breast cancer detect specific morphological features of solid tumors and/or any associated calcium deposits. These deposits originate from an early molecular microcalcification process which consists of two types: type 1 is calcium oxylate (CO) and type II is carbonated calcium hydroxyapetite (HAP). Type I microcalcifications are mainly associated with benign tumors while type II have been shown to be produced, internally, by malignant cells. No current non-invasive in vivo techniques are available for detecting intratumoral microcalcifications. Such a technique would have a significant impact on breast cancer diagnosis and prognosis in preclinical and clinical settings. 18F-NaF PET has been solely used for bone imaging by targeting the bone HAP. In this work, we provide preliminary evidence that 18F-NaF PET imaging can be used to detect breast cancer by targeting the HAP lattice within the tumor microenvironment with high specificity and soft-tissue contrast-to-background ratio, while delineating tumors from inflammation. METHODS Mice were injected with approximately 106 MDA-MB-231 cells subcutaneously and imaged with 18F-NaF PET/CT in a 120 min dynamic sequence when the tumors reached a size of ~250 mm3. Regions-of-interest (ROIs) were drawn around the tumor, muscle, and bone. The concentration of the radiotracer within those ROIs were compared to one another. For comparison to inflammation, rats with inflammatory paws were subjected to 18F-NaF PET imaging. RESULTS Tumor uptake of 18F− was significantly higher (p<0.05) than muscle uptake where the tumor-to-muscle ratio was ~3.5. The presence of type II microcalcification in the MDA-MB-231 cell line was confirmed histologically using alizarin red S and von Kossa staining as well as Raman microspectroscopy. No uptake of 18F− was observed in the rat inflamed tissue. Lack of HAP in the inflamed tissue was verified histologically. CONCLUSIONS This study

Advances in PET myocardial perfusion imaging: F-18 labeled tracers.

PubMed

Rischpler, Christoph; Park, Min-Jae; Fung, George S K; Javadi, Mehrbod; Tsui, Benjamin M W; Higuchi, Takahiro

2012-01-01

Coronary artery disease and its related cardiac disorders represent the most common cause of death in the USA and Western world. Despite advancements in treatment and accompanying improvements in outcome with current diagnostic and therapeutic modalities, it is the correct assignment of these diagnostic techniques and treatment options which are crucial. From a diagnostic standpoint, SPECT myocardial perfusion imaging (MPI) using traditional radiotracers like thallium-201 chloride, Tc-99m sestamibi or Tc-99m tetrofosmin is the most utilized imaging technique. However, PET MPI using N-13 ammonia, rubidium-82 chloride or O-15 water is increasing in availability and usage as a result of the growing number of medical centers with new-generation PET/CT systems taking advantage of the superior imaging properties of PET over SPECT. The routine clinical use of PET MPI is still limited, in part because of the short half-life of conventional PET MPI tracers. The disadvantages of these conventional PET tracers include expensive onsite production and inconvenient on-scanner tracer administration making them unsuitable for physical exercise stress imaging. Recently, two F-18 labeled radiotracers with longer radioactive half-lives than conventional PET imaging agents have been introduced. These are flurpiridaz F 18 (formerly known as F-18 BMS747158-02) and F-18 fluorobenzyltriphenylphosphonium. These longer half-life F-18 labeled perfusion tracers can overcome the production and protocol limitations of currently used radiotracers for PET MPI.

[18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging.

PubMed

Lemoine, Laëtitia; Verdurand, Mathieu; Vacher, Bernard; Blanc, Elodie; Le Bars, Didier; Newman-Tancredi, Adrian; Zimmer, Luc

2010-03-01

The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors. Since all clinical PET 5-HT(1A) radiopharmaceuticals are antagonists, it is of great interest to develop a( 18)F labelled agonist. F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT(1A) receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT(1A) receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [(18)F]MPPF, a validated 5-HT(1A) antagonist radiopharmaceutical. The chemical and radiochemical purities of [(18)F]F15599 were >98%. In vitro [(18)F]F15599 binding was consistent with the known 5-HT(1A) receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [(18)F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [(18)F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT(1A) antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain

Stability analysis of an F/A-18 E/F cable mount m odel

NASA Technical Reports Server (NTRS)

Thompson, Nancy; Farmer, Moses

1994-01-01

A full-span F/A-18 E/F cable mounted wind tunnel model is part of a flutter clearance program at the NASA Langley Transonic Dynamics Tunnel. Parametric analysis of this model using GRUMCBL software was conducted to assess stability for wind tunnel tests. Two configurations of the F/A-18 E/F were examined. The parameters examined were pulley-cable friction, mach number, dynamic pressure, cable geometry, center of gravity location, cable tension, snubbing the model, drag, and test medium. For the nominal cable geometry (Cable Geometry 1), Configuration One was unstable for cases with higher pulley-cable friction coefficients. A new cable geometry (Cable Geometry 3) was determined in which Configuration One was stable for all cases evaluated. Configuration Two with the nominal center of gravity position was found to be unstable for cases with higher pulley-cable friction coefficients; however, the model was stable when the center of gravity moved forward 1/2. The model was tested using the cable mount system during the initial wind tunnel entry and was stable as predicted.

Biodistribution and predictive value of 18F-fluorocyclophosphamide in mice bearing human breast cancer xenografts.

PubMed

Kesner, Amanda L; Hsueh, Wei-Ann; Htet, Nwe Linn; Pio, Betty S; Czernin, Johannes; Pegram, Mark D; Phelps, Michael E; Silverman, Daniel H S

2007-12-01

In mice bearing human breast cancer xenografts, we examined the biodistribution of (18)F-fluorocyclophosphamide ((18)F-F-CP) to evaluate its potential as a noninvasive prognostic tool for predicting the resistance of tumors to cyclophosphamide therapy. (18)F-F-CP was synthesized as we recently described, and PET data were acquired after administration of (18)F-F-CP in mice bearing human breast cancer xenografts (MCF-7 cells). Tracer biodistribution in reconstructed images was quantified by region-of-interest analysis. Distribution was also assessed by harvesting dissected organs, tumors, and blood, determining (18)F content in each tissue with a gamma-well counter. The mice were subsequently treated with cyclophosphamide, and tumor size was monitored for at least 3 wk after chemotherapy administration. The distribution of harvested activity correlated strongly with distribution observed in PET images. Target organs were related to routes of metabolism and excretion. (18)F-F-CP uptake was highest in kidneys, lowest in brain, and intermediate in tumors, as determined by both image-based and tissue-based measurements. (18)F-F-CP uptake was not inhibited by coadministration of an approximately x700 concentration of unlabeled cyclophosphamide. PET measures of (18)F-F-CP uptake in tumor predicted the magnitude of the response to subsequent administration of cyclophosphamide. Noninvasive assessment of (18)F-F-CP uptake using PET may potentially be helpful for predicting the response of breast tumors to cyclophosphamide before therapy begins.

[(18)F]Florbetaben: a review in β-amyloid PET imaging in cognitive impairment.

PubMed

Syed, Yahiya Y; Deeks, Emma

2015-07-01

Intravenous (18)F-labelled florbetaben ([(18)F]florbetaben) [Neuraceq™] is a polyethylene glycol stilbene derivative that is approved in the USA, EU and South Korea for positron emission tomography (PET) imaging of the brain. It is used to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer's disease and other causes of cognitive impairment. In vitro, [(18)F]florbetaben has high affinity and selectivity for β-amyloid. It has a short PET scan time (15-20 min). Visual assessment of regional and whole brain [(18)F]florbetaben PET images detected brain β-amyloid with high sensitivity and specificity, with good inter-reader agreement, in a phase III study in patients with various levels of cognitive function when compared with postmortem histopathological assessment. The whole brain visual assessment displayed high positive and negative predictive values, enabling amyloid pathology to be reliably detected or excluded. Quantitative PET analyses were generally consistent with the visual assessments. [(18)F]florbetaben was generally well tolerated in clinical trials. All adverse reactions in [(18)F]florbetaben recipients were mild to moderate in severity and the most common were injection-site-related (erythema, irritation and pain). There were no serious adverse reactions related to [(18)F]florbetaben. In summary, [(18)F]florbetaben is a highly accurate β-amyloid PET tracer that has the potential to support the clinical diagnosis of Alzheimer's disease and other causes of cognitive decline.

Synthesis and preclinical characterization of 1-(6'-deoxy-6'-[18F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-6'-[18F]FAZAL) as a positron emission tomography radiotracer to assess tumor hypoxia.

PubMed

Wanek, Thomas; Kreis, Katharina; Križková, Petra; Schweifer, Anna; Denk, Christoph; Stanek, Johann; Mairinger, Severin; Filip, Thomas; Sauberer, Michael; Edelhofer, Patricia; Traxl, Alexander; Muchitsch, Viktoria E; Mereiter, Kurt; Hammerschmidt, Friedrich; Cass, Carol E; Damaraju, Vijaya L; Langer, Oliver; Kuntner, Claudia

2016-11-01

Positron emission tomography (PET) using fluorine-18 ( 18 F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[ 18 F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[ 18 F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [ 18 F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [ 18 F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10). Both radiolabeling precursor β-6 and unlabeled reference compound β-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of β-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[ 18 F]1 in tumor cell lines. In biodistribution studies in healthy mice β-[ 18 F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of β-[ 18 F]1. In ex vivo autoradiography experiments β-[ 18 F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[ 18 F]1 shows potential as PET hypoxia radiotracer which merits further investigation. Copyright © 2016 Elsevier Ltd. All rights reserved.

The influence of interpreters' professional background and experience on the interpretation of multimodality imaging of pulmonary lesions using 18F-3'-deoxy-fluorothymidine and 18F-fluorodeoxyglucose PET/CT.

PubMed

Xu, Bai-xuan; Liu, Chang-bin; Wang, Rui-min; Shao, Ming-zhe; Fu, Li-ping; Li, Yun-gang; Tian, Jia-he

2013-01-01

Based on the results of a recently accomplished multicenter clinical trial for the incremental value of a dual-tracer (18F-FDG and 18F-FLT), dual-modality (PET and CT) imaging in the differential diagnosis of pulmonary lesions, we investigate some issues that might affect the image interpretation and result reporting. The images were read in two separate sessions. Firstly the images were read and reported by physician(s) of the imaging center on completion of each PET/CT scanning. By the end of MCCT, all images collected during the trial were re-read by a collective of readers in an isolated, blinded, and independent way. One hundred sixty two patients successfully passed the data verification and entered into the final analysis. The primary reporting result showed adding 18F-FDG image information did not change the clinical performance much in sensitivity, specifity and accuracy, but the ratio between SUVFLT and SUVFDG did help the differentiation efficacy among the three subgroups of patients. The collective reviewing result showed the diagnostic achievement varied with reading strategies. ANOVA indicated significant differences among (18)F-FDG, (18)F-FLT in SUV (F = 14.239, p = 0.004). CT had almost the same diagnostic performance as 18F-FLT. When the 18F-FDG, 18F-FLT and CT images read in pair, both diagnostic sensitivity and specificity improved. The best diagnostic figures were obtained in full-modality strategy, when dual-tracer PET worked in combination with CT. With certain experience and training both radiologists and nuclear physicians are qualified to read and to achieve the similar diagnostic accuracy in PET/CT study. Making full use of modality combination and selecting right criteria seems more practical than professional back ground and personal experience in the new hybrid imaging technology, at least when novel tracer or application is concerned.

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

PubMed Central

Kettenbach, Kathrin; Reffert, Laura M.; Schieferstein, Hanno; Pektor, Stefanie; Eckert, Raphael; Miederer, Matthias; Rösch, Frank

2018-01-01

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging. PMID:29562610

[18F]-NaF PET/CT imaging in cardiac amyloidosis.

PubMed

Van Der Gucht, Axel; Galat, Arnault; Rosso, Jean; Guellich, Aziz; Garot, Jérôme; Bodez, Diane; Plante-Bordeneuve, Violaine; Hittinger, Luc; Dubois-Randé, Jean-Luc; Evangelista, Eva; Sasanelli, Myriam; Chalaye, Julia; Meignan, Michel; Itti, Emmanuel; Damy, Thibaud

2016-08-01

Cardiac amyloidosis (CA) is recognized as a common cause of restrictive cardiomyopathy and heart failure due to the deposition of insoluble proteins in the myocardial interstitium. We emphasize the role of [18F]-sodium fluoride (NaF) PET/CT as a potential noninvasive tool to identify and differentiate the transthyretin-related cardiac amyloidosis from the light-chain cardiac amyloidosis. We report cases of a 73-year-old man and a 75-year-old woman followed in our center for congestive heart failure with marked alteration of the left ventricular ejection fraction due to familial transthyretin Val122Ile cardiac amyloidosis and light-chain cardiac amyloidosis, respectively, confirmed on endomyocardial biopsy.

(18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial.

PubMed

Nanni, Cristina; Zanoni, Lucia; Pultrone, Cristian; Schiavina, Riccardo; Brunocilla, Eugenio; Lodi, Filippo; Malizia, Claudio; Ferrari, Matteo; Rigatti, Patrizio; Fonti, Cristina; Martorana, Giuseppe; Fanti, Stefano

2016-08-01

To compare the accuracy of (18)F-FACBC and (11)C-choline PET/CT in patients radically treated for prostate cancer presenting with biochemical relapse. This prospective study enrolled 100 consecutive patients radically treated for prostate cancer and presenting with rising PSA. Of these 100 patients, 89 were included in the analysis. All had biochemical relapse after radical prostatectomy (at least 3 months previously), had (11)C-choline and (18)F-FACBC PET/CT performed within 1 week and were off hormonal therapy at the time of the scans. The two tracers were compared directly in terms of overall positivity/negativity on both a per-patient basis and a per-site basis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for both the tracers; follow-up at 1 year (including correlative imaging, PSA trend and pathology when available) was considered as the standard of reference. In 51 patients the results were negative and in 25 patients positive with both the tracers, in eight patients the results were positive with (18)F-FACBC but negative with (11)C-choline, and in five patients the results were positive with (11)C-choline but negative with (18)F-FACBC. Overall in 49 patients the results were false-negative (FN), in two true-negative, in 24 true-positive (TP) and in none false-positive (FP) with both tracers. In terms of discordances between the tracers: (1) in one patient, the result was FN with (11)C-choline but FP with (18)F-FACBC (lymph node), (2) in seven, FN with (11)C-choline but TP with (18)F-FACBC (lymph node in five, bone in one, local relapse in one), (3) in one, FP with (11)C-choline (lymph node) but TP with (18)F-FACBC (local relapse), (4) in two, FP with (11)C-choline (lymph nodes in one, local relapse in one) but FN with (18)F-FACBC, and (5) in three, TP with (11)C-choline (lymph nodes in two, bone in one) but FN with (18)F-FACBC. With (11)C-choline and (18)F-FACBC, sensitivities

Alanine and glycine conjugates of (2S,4R)-4-[18F]fluoroglutamine for tumor imaging.

PubMed

Zha, Zhihao; Ploessl, Karl; Lieberman, Brian P; Wang, Limin; Kung, Hank F

2018-05-01

Glutamine is an essential source of energy, metabolic substrates, and building block for supporting tumor proliferation. Previously, (2S,4R)-4-[ 18 F]fluoroglutamine (4F-Gln) was reported as a glutamine-related metabolic imaging agent. To improve the in vivo kinetics of this radiotracer, two new dipeptides, [ 18 F]Gly-(2S,4R)4-fluoroglutamine (Gly-4F-Gln) and [ 18 F]Ala-(2S,4R)4-fluoroglutamine (Ala-4F-Gln) were investigated. Radiolabeling was performed via 2-steps 18 F-fluorination. Cell uptake studies of Gly-4F-Gln and Ala-4F-Gln were investigated in 9 L cell lines. In vitro and in vivo metabolism studies were carried out in Fisher 344 rats. Biodistribution and microPET imaging studies were performed in 9 L tumor-bearing rats. In vitro incubation of these [ 18 F]dipeptides in rat and human blood showed a rapid conversion to (2S,4R)-4-[ 18 F]fluoroglutamine (t 1/2  = 2.3 and 0.2 min for [ 18 F]Gly-4F-Gln and [ 18 F]Ala-4F-Gln, respectively for human blood). Biodistribution and PET imaging in Fisher 344 rats bearing 9 L tumor xenografts showed that these dipeptides rapidly localized in the tumors, comparable to that of (2S,4R)-4-[ 18 F]fluoroglutamine (4F-Gln). The results support that these dipeptides, [ 18 F]Gly-4F-Gln and [ 18 F]Ala-4F-Gln, are prodrugs, which hydrolyze in the blood after an iv injection. They appear to be selectively taken up and trapped by tumor tissue in vivo. The dipeptide, [ 18 F]Ala-4F-Gln, may be suitable as a PET tracer for imaging glutaminolysis in tumors. Copyright © 2018 Elsevier Inc. All rights reserved.

Disseminated Multi-system Sarcoidosis Mimicking Metastases on 18F-FDG PET/CT.

PubMed

Makis, William; Palayew, Mark; Rush, Christopher; Probst, Stephan

2018-06-07

A 60-year-old female with no significant medical history presented with hematuria. A computed tomography (CT) scan revealed extensive lymphadenopathy with hypodensities in the liver and spleen, and she was referred for an 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/CT (PET/CT) study to assess for malignancy of unknown primary. PET/CT revealed extensive 18 F-FDG avid lymphadenopathy as well as innumerable intensely 18 F-FDG avid lung, liver and splenic nodules, highly concerning for malignancy. A PET-guided bone marrow biopsy of the posterior superior iliac spine revealed several non-necrotizing, well-formed granulomas, consistent with sarcoidosis. The patient was managed conservatively and remained clinically well over the subsequent 9 years of follow-up.

Quantification of 18F-Fluoride Kinetics: Evaluation of Simplified Methods.

PubMed

Raijmakers, Pieter; Temmerman, Olivier P P; Saridin, Carrol P; Heyligers, Ide C; Becking, Alfred G; van Lingen, Arthur; Lammertsma, Adriaan A

2014-07-01

(18)F-fluoride PET is a promising noninvasive method for measuring bone metabolism and bone blood flow. The purpose of this study was to assess the performance of various clinically useful simplified methods by comparing them with full kinetic analysis. In addition, the validity of deriving bone blood flow from K1 of (18)F-fluoride was investigated using (15)O-H2O as a reference. Twenty-two adults (mean age ± SD, 44.8 ± 25.2 y), including 16 patients scheduled for bone surgery and 6 healthy volunteers, were studied. All patients underwent dynamic (15)O-H2O and (18)F-fluoride scans before surgery. Ten of these patients had serial PET measurements before and at 2 time points after local bone surgery. During all PET scans, arterial blood was monitored continuously. (18)F-fluoride data were analyzed using nonlinear regression (NLR) and several simplified methods (Patlak and standardized uptake value [SUV]). SUV was evaluated for different time intervals after injection and after normalizing to body weight, lean body mass, and body surface area, and simplified measurements were compared with NLR results. In addition, changes in SUV and Patlak-derived fluoride influx rate (Ki) after surgery were compared with corresponding changes in NLR-derived Ki. Finally, (18)F-fluoride K1 was compared with bone blood flow derived from (15)O-H2O data, using the standard single-tissue-compartment model. K1 of (18)F-fluoride correlated with measured blood flow, but the correlation coefficient was relatively low (r = 0.35, P < 0.001). NLR resulted in a mean Ki of 0.0160 ± 0.0122, whereas Patlak analysis, for the interval 10-60 min after injection, resulted in an almost-identical mean Ki of 0.0161 ± 0.0117. The Patlak-derived Ki, for 10-60 min after injection, showed a high correlation with the NLR-derived Ki (r = 0.976). The highest correlation between Ki and lean body mass-normalized SUV was found for the interval 50-60 min (r = 0.958). Finally, changes in SUV correlated

[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

PubMed

Kim, Woosuk; Le, Thuc M; Wei, Liu; Poddar, Soumya; Bazzy, Jimmy; Wang, Xuemeng; Uong, Nhu T; Abt, Evan R; Capri, Joseph R; Austin, Wayne R; Van Valkenburgh, Juno S; Steele, Dalton; Gipson, Raymond M; Slavik, Roger; Cabebe, Anthony E; Taechariyakul, Thotsophon; Yaghoubi, Shahriar S; Lee, Jason T; Sadeghi, Saman; Lavie, Arnon; Faull, Kym F; Witte, Owen N; Donahue, Timothy R; Phelps, Michael E; Herschman, Harvey R; Herrmann, Ken; Czernin, Johannes; Radu, Caius G

2016-04-12

Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.

[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity

PubMed Central

Kim, Woosuk; Le, Thuc M.; Wei, Liu; Poddar, Soumya; Bazzy, Jimmy; Wang, Xuemeng; Uong, Nhu T.; Abt, Evan R.; Capri, Joseph R.; Austin, Wayne R.; Van Valkenburgh, Juno S.; Steele, Dalton; Gipson, Raymond M.; Slavik, Roger; Cabebe, Anthony E.; Taechariyakul, Thotsophon; Yaghoubi, Shahriar S.; Lee, Jason T.; Sadeghi, Saman; Lavie, Arnon; Faull, Kym F.; Witte, Owen N.; Donahue, Timothy R.; Phelps, Michael E.; Herschman, Harvey R.; Herrmann, Ken; Czernin, Johannes; Radu, Caius G.

2016-01-01

Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds—[18F]Clofarabine; 2-chloro-2′-deoxy-2′-[18F]fluoro-9-β-d-arabinofuranosyl-adenine ([18F]CFA) and 2′-deoxy-2′-[18F]fluoro-9-β-d-arabinofuranosyl-guanine ([18F]F-AraG)—for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [18F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [18F]F-AraG is a better substrate for dGK than for dCK. [18F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [18F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [18F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [18F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [18F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [18F]CFA PET as a new cancer biomarker for treatment stratification and monitoring. PMID:27035974

New Dioxaborolane Chemistry Enables [(18)F]-Positron-Emitting, Fluorescent [(18)F]-Multimodality Biomolecule Generation from the Solid Phase.

PubMed

Rodriguez, Erik A; Wang, Ye; Crisp, Jessica L; Vera, David R; Tsien, Roger Y; Ting, Richard

2016-05-18

New protecting group chemistry is used to greatly simplify imaging probe production. Temperature and organic solvent-sensitive biomolecules are covalently attached to a biotin-bearing dioxaborolane, which facilitates antibody immobilization on a streptavidin-agarose solid-phase support. Treatment with aqueous fluoride triggers fluoride-labeled antibody release from the solid phase, separated from unlabeled antibody, and creates [(18)F]-trifluoroborate-antibody for positron emission tomography and near-infrared fluorescent (PET/NIRF) multimodality imaging. This dioxaborolane-fluoride reaction is bioorthogonal, does not inhibit antigen binding, and increases [(18)F]-specific activity relative to solution-based radiosyntheses. Two applications are investigated: an anti-epithelial cell adhesion molecule (EpCAM) monoclonal antibody (mAb) that labels prostate tumors and Cetuximab, an anti-epidermal growth factor receptor (EGFR) mAb (FDA approved) that labels lung adenocarcinoma tumors. Colocalized, tumor-specific NIRF and PET imaging confirm utility of the new technology. The described chemistry should allow labeling of many commercial systems, diabodies, nanoparticles, and small molecules for dual modality imaging of many diseases.

18F-FDG avidity of pheochromocytomas and paragangliomas: a new molecular imaging signature?

PubMed

Taïeb, David; Sebag, Frederic; Barlier, Anne; Tessonnier, Laurent; Palazzo, Fausto F; Morange, Isabelle; Niccoli-Sire, Patricia; Fakhry, Nicolas; De Micco, Catherine; Cammilleri, Serge; Enjalbert, Alain; Henry, Jean-François; Mundler, Olivier

2009-05-01

Our objective was to evaluate (18)F-FDG PET uptake in patients with nonmetastatic and metastatic chromaffin-derived tumors. Twenty-eight consecutive unrelated patients with chromaffin tumors, including 9 patients with genetically determined disease, were studied. A combination of preoperative imaging work-up, surgical findings, and pathologic analyses was used to classify the patients into 2 groups: those with nonmetastatic disease (presumed benign, n = 18) and those with metastatic tumors (n = 10). (18)F-FDG PET was performed in all cases. Visual and quantitative analyses were individually graded for each tumor. Somatic mutations of the succinate dehydrogenase subunits B and D and Von-Hippel Lindau genes were also evaluated in 6 benign sporadic tumor samples. All but 2 patients showed significantly increased (18)F-FDG uptake on visual analysis. The maximum standardized uptake value (SUVmax) ranged from 1.9 to 42 (mean +/- SD, 8.2 +/- 9.7; median, 4.6) in nonmetastatic tumors and 2.3 to 29.3 (mean +/- SD, 9.7 +/- 8.4; median, 7.4) in metastatic tumors. No statistical difference was observed between the groups (P = 0.44), but succinate dehydrogenase-related tumors were notable in being the most (18)F-FDG-avid tumors (SUVmax, 42, 29.3, 21, 17, and 5.3). Succinate dehydrogenase and Von-Hippel Lindau-related tumors had a significantly higher SUVmax than did neurofibromatosis type 1 and multiple endocrine neoplasia type 2A syndrome-related tumors (P = 0.02). (18)F-FDG PET was superior to (131)I-metaiodobenzylguanidine in all metastatic patients but one. By contrast, (18)F-FDG PET underestimated the extent of the disease, compared with 6-(18)F-fluorodopa PET, in 5 patients with metastatic pheochromocytoma. However, succinate dehydrogenase mutations (germline and somatic) and functional dedifferentiation do not adequately explain (18)F-FDG uptake since most tumors were highly avid for (18)F-FDG. (18)F-FDG PET positivity is almost a constant feature of pheochromocytomas

Site specific measurements of bone formation using [18F] sodium fluoride PET/CT

PubMed Central

Puri, Tanuj; Siddique, Musib; Frost, Michelle L.; Moore, Amelia E. B.; Fogelman, Ignac

2018-01-01

Dynamic positron emission tomography (PET) imaging with fluorine-18 labelled sodium fluoride ([18F]NaF) allows the quantitative assessment of regional bone formation by measuring the plasma clearance of fluoride to bone at any site in the skeleton. Today, hybrid PET and computed tomography (CT) dual-modality systems (PET/CT) are widely available, and [18F]NaF PET/CT offers a convenient non-invasive method of studying bone formation at the important osteoporotic fracture sites at the hip and spine, as well as sites of pure cortical or trabecular bone. The technique complements conventional measurements of bone turnover using biochemical markers or bone biopsy as a tool to investigate new therapies for osteoporosis, and has a potential role as an early biomarker of treatment efficacy in clinical trials. This article reviews methods of acquiring and analyzing dynamic [18F]NaF PET/CT scan data, and outlines a simplified approach combining venous blood sampling with a series of short (3- to 5-minute) static PET/CT scans acquired at different bed positions to estimate [18F]NaF plasma clearance at multiple sites in the skeleton with just a single injection of tracer. PMID:29541623

Site specific measurements of bone formation using [18F] sodium fluoride PET/CT.

PubMed

Blake, Glen M; Puri, Tanuj; Siddique, Musib; Frost, Michelle L; Moore, Amelia E B; Fogelman, Ignac

2018-02-01

Dynamic positron emission tomography (PET) imaging with fluorine-18 labelled sodium fluoride ([ 18 F]NaF) allows the quantitative assessment of regional bone formation by measuring the plasma clearance of fluoride to bone at any site in the skeleton. Today, hybrid PET and computed tomography (CT) dual-modality systems (PET/CT) are widely available, and [ 18 F]NaF PET/CT offers a convenient non-invasive method of studying bone formation at the important osteoporotic fracture sites at the hip and spine, as well as sites of pure cortical or trabecular bone. The technique complements conventional measurements of bone turnover using biochemical markers or bone biopsy as a tool to investigate new therapies for osteoporosis, and has a potential role as an early biomarker of treatment efficacy in clinical trials. This article reviews methods of acquiring and analyzing dynamic [ 18 F]NaF PET/CT scan data, and outlines a simplified approach combining venous blood sampling with a series of short (3- to 5-minute) static PET/CT scans acquired at different bed positions to estimate [ 18 F]NaF plasma clearance at multiple sites in the skeleton with just a single injection of tracer.

No-carrier-added [.sup.18 F]-N-fluoroalkylspiroperidols

DOEpatents

Shiue, Chyng-Yann; Wolf, Alfred P.; Bai, Lan-Qin; Teng, Ren-Tui

1989-01-01

There is disclosed radioligands labeled with the position emitting radionuclide [.sup.18 F] suitable for dynamic study in living humans with position emission transaxial tomography. These new [.sup.18 F]-N-fluoroalkylspiroperidols, wherein the alkyl group contains from 2-6 carbon atoms, exhibit extremely high affinity for the dopamine receptors and provide enhanced uptake and retention in the brain concomitant with reduced radiation burden. These characteristics all combine to make these new radioligands useful for mapping dopamine receptors in normal and disease states in the living brain. Additionally, a new synthetic procedure for these radioligands as well as a new procedure for preparing the radiolabeled alkyl halide alkylating reagents are also disclosed.

18F-FLT PET/CT in the Evaluation of Pheochromocytomas and Paragangliomas: A Pilot Study.

PubMed

Blanchet, Elise M; Taieb, David; Millo, Corina; Martucci, Victoria; Chen, Clara C; Merino, Maria; Herscovitch, Peter; Pacak, Karel

2015-12-01

(18)F-FDG PET/CT has been proven to be a highly sensitive method for pheochromocytomas/paragangliomas (PHEOs/PGLs) associated with succinate dehydrogenase (SDH) mutations. This finding has been attributed to altered tumor cell metabolism resulting from these mutations and does not provide additional prognostic information to genotype. Therefore, identification of new biomarkers for aggressiveness is needed. A high Ki-67 index was proposed to be an additional prognostic factor. This pilot study aimed to evaluate 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT, a PET proliferation tracer, as a potential imaging agent in a series of 12 PHEO/PGL patients with different genetic backgrounds, to compare (18)F-FLT uptake with (18)F-FDG PET/CT, and to evaluate classic factors of aggressiveness. Twelve patients (7 metastatic and 5 nonmetastatic) were prospectively evaluated with (18)F-FDG and (18)F-FLT and followed for at least 2 y after the initial imaging work-up. Uptake was assessed at a lesion level, visually and quantitatively by maximum standardized uptake values (SUVmax) for both tracers. (18)F-FLT uptake was compared with risk factors known to be linked with a poor prognosis in PGLs (SDHB-mutated status, lesion size, dopaminergic phenotype) and with (18)F-FDG uptake. In 12 patients, 77 lesions were assessed. All lesions had low (18)F-FLT uptake (median SUVmax, 2.25; range, 0.7-4.5). There was no apparent superiority of (18)F-FLT uptake in progressive lesions, and most of the lesions showed a mismatch, with high (18)F-FDG uptake (median SUVmax, 10.8; range, 1.1-79.0) contrasting with low (18)F-FLT uptake. This study suggests that PHEOs/PGLs-even those that progress-do not exhibit intense (18)F-FLT uptake. It provides the first in vivo demonstration that proliferation may not be a major determinant of (18)F-FDG uptake in these tumors. These findings provide new insight into the biologic behavior of PGL and suggest that antiproliferative agents may be suboptimal

HPLC and TLC methods for analysis of [18F]FDG and its metabolites from biological samples.

PubMed

Rokka, Johanna; Grönroos, Tove J; Viljanen, Tapio; Solin, Olof; Haaparanta-Solin, Merja

2017-03-24

The most used positron emission tomography (PET) tracer, 2-[ 18 F]fluoro-2-deoxy-d-glucose ([ 18 F]FDG), is a glucose analogue that is used to measure tissue glucose consumption. Traditionally, the Sokoloff model is the basis for [ 18 F]FDG modeling. According to this model, [ 18 F]FDG is expected to be trapped in a cell in the form of [ 18 F]FDG-6-phosphate ([ 18 F]FDG-6-P). However, several studies have shown that in tissues, [ 18 F]FDG metabolism goes beyond [ 18 F]FDG-6-P. Our aim was to develop radioHPLC and radioTLC methods for analysis of [ 18 F]FDG metabolites from tissue samples. The radioHPLC method uses a sensitive on-line scintillation detector to detect radioactivity, and the radioTLC method employs digital autoradiography to detect the radioactivity distribution on a TLC plate. The HPLC and TLC methods were developed using enzymatically in vitro-produced metabolites of [ 18 F]FDG as reference standards. For this purpose, three [ 18 F]FDG metabolites were synthesized: [ 18 F]FDG-6-P, [ 18 F]FD-PGL, and [ 18 F]FDG-1,6-P2. The two methods were evaluated by analyzing the [ 18 F]FDG metabolic profile from rodent ex vivo tissue homogenates. The HPLC method with an on-line scintillation detector had a wide linearity in a range of 5Bq-5kBq (LOD 46Bq, LOQ 139Bq) and a good resolution (Rs ≥1.9), and separated [ 18 F]FDG and its metabolites clearly. The TLC method combined with digital autoradiography had a high sensitivity in a wide range of radioactivity (0.1Bq-2kBq, LOD 0.24Bq, LOQ 0.31Bq), and multiple samples could be analyzed simultaneously. As our test and the method validation with ex vivo samples showed, both methods are useful, and at best they complement each other in analysis of [ 18 F]FDG and its radioactive metabolites from biological samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Utility of 18F-fluorodeoxy glucose and 18F-sodium fluoride positron emission tomography/computed tomography in the diagnosis of medication-related osteonecrosis of the jaw: A preclinical study in a rat model.

PubMed

Kim, Yemi; Lee, Ho-Young; Yoon, Hai-Jeon; Kim, Bom Sahn

2016-04-01

The aim of this study was to determine the clinical utility of positron emission tomography/computed tomography (PET/CT) using 18F-FDG and 18F-NaF for the diagnosis of osteonecrosis of the jaw (ONJ), by observing characteristics in rat models treated with zoledronic acid (ZA) and/or dexamethasone (DX) followed by tooth extraction. A total of 48 rats were divided randomly into four groups: Group 1, rats treated with ZA and DX; Group 2, rats treated with ZA; Group 3, rats treated with DX; and Group 4, rats treated with vehicle as normal controls. They underwent examinations with both 18F-FDG and 18F-NaF PET/CT at 4 weeks prior to tooth extraction (baseline) and 4 weeks after tooth extraction. Rats were then sacrificed to evaluate the histological incidence and characteristics of ONJ. Histological and radiological characteristics of all groups were compared to assess the effects of medication and tooth extraction. Baseline PET/CT studies using 18F-FDG and 18F-NaF showed no difference in uptake among the groups. However, 18F-FDG PET/CT performed at 4 weeks after tooth extraction showed increased glucose metabolism at the extraction site in both the ZA/DX and the ZA-only groups compared with that in the vehicle-treated group, in accordance with the higher incidence of histological ONJ (p < 0.05, respectively). 18F-NaF PET/CT performed at 4 weeks after tooth extraction showed decreased bone uptake in the extraction site in the ZA/DX, ZA, and DX groups versus the vehicle group (all p < 0.05), but this was not correlated with the incidence of histological ONJ. The incidence of ONJ was highest in the ZA/DX group (66.7%), followed by the ZA group, both of which were significantly higher than in the DX and vehicle groups (both p < 0.05). 18F-FDG PET/CT as an inflammatory marker appeared to be a more appropriate imaging modality than 18F-NaF PET/CT in diagnosing ONJ in a rat model including a ZA/DX group. However, the decreased bone remodeling tendency highlighted by 18F-NaF

F-18 sodium fluoride PET/CT does not effectively image myocardial inflammation due to suspected cardiac sarcoidosis.

PubMed

Weinberg, Richard L; Morgenstern, Rachelle; DeLuca, Albert; Chen, Jennifer; Bokhari, Sabahat

2017-12-01

Sarcoidosis is an inflammatory disorder of unknown etiology that can involve the heart. While effective in imaging cardiac sarcoidosis, F-18 fluorodeoxyglucose (FDG) PET/CT often shows non-specific myocardial uptake. F-18 sodium fluoride (NaF) has been used to image inflammation in coronary artery plaques and has low background myocardial uptake. Here, we evaluated whether F-18 NaF can image myocardial inflammation due to clinically suspected cardiac sarcoidosis. We performed a single institution pilot study testing if F-18 NaF PET/CT can detect myocardial inflammation in patients with suspected cardiac sarcoidosis. Patients underwent cardiac PET/CT with F-18 FDG as part of their routine care and subsequently received an F-18 NaF PET/CT scan. Three patients underwent F-18 FDG and F-18 NaF imaging. In all patients, there was F-18 FDG uptake consistent with cardiac sarcoidosis. The F-18 NaF PET/CT scans showed no myocardial uptake. In this small preliminary study, PET/CT scan using F-18 NaF does not appear to detect myocardial inflammation caused by suspected cardiac sarcoidosis.

The F-18 simulator at NASA's Dryden Flight Research Center, Edwards, California

NASA Image and Video Library

2004-10-04

The F-18 simulator at NASA's Dryden Flight Research Center, Edwards, California. Simulators offer a safe and economical alternative to actual flights to gather data, as well as being excellent facilities for pilot practice and training. The F-18 Hornet is used primarily as a safety chase and mission support aircraft at NASA's Dryden Flight Research Center, Edwards, California. As support aircraft, the F-18's are used for safety chase, pilot proficiency, aerial photography and other mission support functions.

[F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging.

PubMed

Marquié, Marta; Siao Tick Chong, Michael; Antón-Fernández, Alejandro; Verwer, Eline E; Sáez-Calveras, Nil; Meltzer, Avery C; Ramanan, Prianca; Amaral, Ana C; Gonzalez, Jose; Normandin, Marc D; Frosch, Matthew P; Gómez-Isla, Teresa

2017-10-01

[F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer's disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n = 6), intermediate Braak (III-IV, n = 7) and high Braak (V-VI, n = 9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging-pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.

Preclinical evaluation of the anti-tumor effects of the natural isoflavone genistein in two xenograft mouse models monitored by [18F]FDG, [18F]FLT, and [64Cu]NODAGA-cetuximab small animal PET.

PubMed

Honndorf, Valerie S; Wiehr, Stefan; Rolle, Anna-Maria; Schmitt, Julia; Kreft, Luisa; Quintanilla-Martinez, Letitia; Kohlhofer, Ursula; Reischl, Gerald; Maurer, Andreas; Boldt, Karsten; Schwarz, Michael; Schmidt, Holger; Pichler, Bernd J

2016-05-10

The natural phytoestrogen genistein is known as protein kinase inhibitor and tumor suppressor in various types of cancers. We studied its antitumor effect in two different xenograft models using positron emission tomography (PET) in vivo combined with ex vivo histology and nuclear magnetic resonance (NMR) metabolic fingerprinting. A431 and Colo205 tumor-bearing mice were treated with vehicle or genistein (500 mg/kg/d) over a period of 12 days. Imaging was performed with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and 3'-deoxy-3'-[18F]fluorothymidine ([18F] FLT). In a second study A431 tumor-bearing mice were treated with vehicle, genistein (500 mg/kg/d), cetuximab (1 mg/3d) or a combination of the compounds and imaged using [18F]FDG, [18F]FLT and [64Cu]NODAGA-cetuximab. Data were compared to histology and principal components analysis (PCA) of NMR fingerprinting data. Genistein reduced tumor growth significantly in both xenografts. [18F] FLT uptake was consistent in both models and corresponded to histological findings and also PCA whereas [18F]FDG and [64Cu]NODAGA-cetuximab were not suitable for therapy monitoring. As mono-therapy the natural isoflavone genistein has a powerful therapeutic effect in vivo on A431 and Colo205 tumors. [18F]FLT has superior consistency compared to the other tested tracers in therapy monitoring, while the treatment effect could be shown on the molecular level by histology and metabolic fingerprinting.

Comparison of Two Site-Specifically 18F-Labeled Affibodies for PET Imaging of EGFR Positive Tumors

DOE PAGES

Su, Xinhui; Cheng, Kai; Jeon, Jongho; ...

2014-06-27

The epidermal growth factor receptor (EGFR) serves as an attractive target for cancer molecular imaging and therapy. Our previous positron emission tomography (PET) studies showed that the EGFR-targeting affibody molecules 64Cu-DOTA-Z EGFR:1907 and 18F-FBEM-Z EGFR:1907 can discriminate between high and low EGFR-expression tumors and have the potential for patient selection for EGFR-targeted therapy. Compared with 64Cu, 18F may improve imaging of EGFR-expression and is more suitable for clinical application, but the labeling reaction of 18F-FBEM-Z EGFR:1907 requires a long synthesis time. The aim of the present study is to develop a new generation of 18F labeled affibody probes (Al 18F-NOTA-Zmore » EGFR:1907 and 18F-CBT-Z EGFR:1907) and to determine whether they are suitable agents for imaging of EGFR expression. The first approach consisted of conjugating Z EGFR:1907 with NOTA and radiolabeling with Al 18F to produce Al 18F-NOTA-Z EGFR:1907. In a second approach the prosthetic group 18F-labeled-2-cyanobenzothiazole ( 18F-CBT) was conjugated to Cys-Z EGFR:1907 to produce 18F-CBT-Z EGFR:1907. Binding affinity and specificity of Al 18F-NOTA-Z EGFR:1907 and 18F-CBT-Z EGFR:1907 to EGFR were evaluated using A431 cells. Biodistribution and PET studies were conducted on mice bearing A431 xenografts after injection of Al 18F-NOTA-Z EGFR:1907 or 18F-CBT-Z EGFR:1907 with or without coinjection of unlabeled affibody proteins. The radiosyntheses of Al 18F-NOTA-Z EGFR:1907 and 18F-CBT-Z EGFR:1907 were completed successfully within 40 and 120 min with a decay-corrected yield of 15% and 41% using a 2-step, 1-pot reaction and 2-step, 2-pot reaction, respectively. Both probes bound to EGFR with low nanomolar affinity in A431 cells. Although 18F-CBT-Z EGFR:1907 showed instability in vivo, biodistribution studies revealed rapid and high tumor accumulation and quick clearance from normal tissues except the bones. In contrast, Al 18F-NOTA-Z EGFR:1907 demonstrated high in vitro and in

Comparison of Two Site-Specifically 18F-Labeled Affibodies for PET Imaging of EGFR Positive Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Xinhui; Cheng, Kai; Jeon, Jongho

The epidermal growth factor receptor (EGFR) serves as an attractive target for cancer molecular imaging and therapy. Our previous positron emission tomography (PET) studies showed that the EGFR-targeting affibody molecules 64Cu-DOTA-Z EGFR:1907 and 18F-FBEM-Z EGFR:1907 can discriminate between high and low EGFR-expression tumors and have the potential for patient selection for EGFR-targeted therapy. Compared with 64Cu, 18F may improve imaging of EGFR-expression and is more suitable for clinical application, but the labeling reaction of 18F-FBEM-Z EGFR:1907 requires a long synthesis time. The aim of the present study is to develop a new generation of 18F labeled affibody probes (Al 18F-NOTA-Zmore » EGFR:1907 and 18F-CBT-Z EGFR:1907) and to determine whether they are suitable agents for imaging of EGFR expression. The first approach consisted of conjugating Z EGFR:1907 with NOTA and radiolabeling with Al 18F to produce Al 18F-NOTA-Z EGFR:1907. In a second approach the prosthetic group 18F-labeled-2-cyanobenzothiazole ( 18F-CBT) was conjugated to Cys-Z EGFR:1907 to produce 18F-CBT-Z EGFR:1907. Binding affinity and specificity of Al 18F-NOTA-Z EGFR:1907 and 18F-CBT-Z EGFR:1907 to EGFR were evaluated using A431 cells. Biodistribution and PET studies were conducted on mice bearing A431 xenografts after injection of Al 18F-NOTA-Z EGFR:1907 or 18F-CBT-Z EGFR:1907 with or without coinjection of unlabeled affibody proteins. The radiosyntheses of Al 18F-NOTA-Z EGFR:1907 and 18F-CBT-Z EGFR:1907 were completed successfully within 40 and 120 min with a decay-corrected yield of 15% and 41% using a 2-step, 1-pot reaction and 2-step, 2-pot reaction, respectively. Both probes bound to EGFR with low nanomolar affinity in A431 cells. Although 18F-CBT-Z EGFR:1907 showed instability in vivo, biodistribution studies revealed rapid and high tumor accumulation and quick clearance from normal tissues except the bones. In contrast, Al 18F-NOTA-Z EGFR:1907 demonstrated high in vitro and in

Does Delayed-Time-Point Imaging Improve 18F-FDG-PET in Patients With MALT Lymphoma?

PubMed Central

Mayerhoefer, Marius E.; Giraudo, Chiara; Senn, Daniela; Hartenbach, Markus; Weber, Michael; Rausch, Ivo; Kiesewetter, Barbara; Herold, Christian J.; Hacker, Marcus; Pones, Matthias; Simonitsch-Klupp, Ingrid; Müllauer, Leonhard; Dolak, Werner; Lukas, Julius; Raderer, Markus

2016-01-01

Purpose To determine whether in patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue lymphoma (MALT), delayed–time-point 2-18F-fluoro-2-deoxy-d-glucose-positron emission tomography (18F-FDG-PET) performs better than standard–time-point 18F-FDG-PET. Materials and Methods Patients with untreated histologically verified MALT lymphoma, who were undergoing pretherapeutic 18F-FDG-PET/computed tomography (CT) and consecutive 18F-FDG-PET/magnetic resonance imaging (MRI), using a single 18F-FDG injection, in the course of a larger-scale prospective trial, were included. Region-based sensitivity and specificity, and patient-based sensitivity of the respective 18F-FDG-PET scans at time points 1 (45–60 minutes after tracer injection, TP1) and 2 (100–150 minutes after tracer injection, TP2), relative to the reference standard, were calculated. Lesion-to-liver and lesion-to-blood SUVmax (maximum standardized uptake values) ratios were also assessed. Results 18F-FDG-PET at TP1 was true positive in 15 o f 23 involved regions, and 18F-FDG-PET at TP2 was true-positive in 20 of 23 involved regions; no false-positive regions were noted. Accordingly, region-based sensitivities and specificities were 65.2% (confidence interval [CI], 45.73%–84.67%) and 100% (CI, 100%-100%) for 18F-FDG-PET at TP1; and 87.0% (CI, 73.26%–100%) and 100% (CI, 100%-100%) for 18F-FDG-PET at TP2, respectively. FDG-PET at TP1 detected lymphoma in at least one nodal or extranodal region in 7 of 13 patients, and 18F-FDG-PET at TP2 in 10 of 13 patients; accordingly, patient-based sensitivity was 53.8% (CI, 26.7%–80.9%) for 18F-FDG-PET at TP1, and 76.9% (CI, 54.0%–99.8%) for 18F-FDG-PET at TP2. Lesion-to-liver and lesion-to-blood maximum standardized uptake value ratios were significantly lower at TP1 (ratios, 1.05 ± 0.40 and 1.52 ± 0.62) than at TP2 (ratios, 1.67 ± 0.74 and 2.56 ± 1.10; P = 0.003 and P = 0.001). Conclusions Delayed–time-point imaging

Validation of a [Al18F]PSMA-11 preparation for clinical applications.

PubMed

Al-Momani, Ehab; Israel, Ina; Samnick, Samuel

2017-12-01

Imaging prostate-specific membrane antigen (PSMA) using positron emission tomography (PET) has been presented so far as the most sensitive and specific with regard to prostate cancer detection, in particular in high-risk prostate cancer patients. Currently, it mainly features Gallium-68 ( 68 Ga) labeled PSMA ligands, notably [ 68 Ga]Glu-urea-Lys(Ahx)-HBED-CC ([ 68 Ga]-PSMA-11) and [ 68 Ga]DOTAGA-FFK (Sub-KuE termed ([ 68 Ga]PSMA-I&T). However, 68 Ga has several shortcomings as radionuclide including a short half-life and non-ideal energies. This has motivated consideration of 18 F-labeled analogues for PET imaging of prostate cancer. Here, we describe a simple synthesis and validation of a fluorine-18 labeled Glu-urea-Lys(Ahx)-HBED-CC ([Al 18 F]PSMA-11) for nuclear medicine applications. An efficient method for preparation of [Al 18 F]PSMA-11 was developed and validated (according to Pharm Eur) for routinely clinical applications. [Al 18 F]PSMA-11 was reproducibly obtained in radiochemical yields of 84 ± 6% (n = 15) and > 98% radiochemical purity using an improved one-step radiofluorination in aqueous solution. The total (production/preparation) time, including purification, pharmacological formulation of the isolated product and the quality control of the injectable solution was less than 60min. The [Al 18 F]PSMA-11 was stable over 4h in 1% EtOH/saline selected as injection solution. The solution was sterile, non-pyrogenic and ready for clinical applications after sterile filtration through a 0.22µm membrane filter under sterile conditions. In addition, [Al 18 F]PSMA-11 exhibited higher uptake and retention in PMSA-expressing LNCap prostate cells as compared to its clinically established 68 Ga-labeled analogues [ 68 Ga]PSMA-11 and [ 68 Ga]PSMA-I&T as well as to [ 68 Ga]NOTA-Bn-PSMA. The simple and fast preparation of [Al 18 F]PSMA-11 combined with its favorable pharmacological properties warrant its translation to a clinical setting. The facile and high

Normal bone and soft tissue distribution of fluorine-18-sodium fluoride and artifacts on 18F-NaF PET/CT bone scan: a pictorial review.

PubMed

Sarikaya, Ismet; Elgazzar, Abdelhamid H; Sarikaya, Ali; Alfeeli, Mahmoud

2017-10-01

Fluorine-18-sodium fluoride (F-NaF) PET/CT is a relatively new and high-resolution bone imaging modality. Since the use of F-NaF PET/CT has been increasing, it is important to accurately assess the images and be aware of normal distribution and major artifacts. In this pictorial review article, we will describe the normal uptake patterns of F-NaF in the bone tissues, particularly in complex structures, as well as its physiologic soft tissue distribution and certain artifacts seen on F-NaF PET/CT images.

Distinct [18F]THK5351 binding patterns in primary progressive aphasia variants.

PubMed

Schaeverbeke, Jolien; Evenepoel, Charlotte; Declercq, Lieven; Gabel, Silvy; Meersmans, Karen; Bruffaerts, Rose; Adamczuk, Kate; Dries, Eva; Van Bouwel, Karen; Sieben, Anne; Pijnenburg, Yolande; Peeters, Ronald; Bormans, Guy; Van Laere, Koen; Koole, Michel; Dupont, Patrick; Vandenberghe, Rik

2018-06-26

To assess the binding of the PET tracer [ 18 F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology. The study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [ 18 F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [ 18 F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction. Patients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [ 18 F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [ 18 F]THK5351 scans without partial volume correction revealed similar results. [ 18 F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [ 18 F]THK5351 binding correlates with the severity of clinical

Automated production of [18 F]FTHA according to GMP.

PubMed

Savisto, Nina; Viljanen, Tapio; Kokkomäki, Esa; Bergman, Jörgen; Solin, Olof

2018-02-01

14-(R,S)-[ 18 F]fluoro-6-thia-heptadecanoic acid is a tracer for fatty acid imaging by positron emission tomography. High demand for this tracer required us to replace semiautomatic synthesis with a fully automated procedure. An automated synthesis device was constructed in-house for multistep nucleophilic 18 F-fluorination and a control system was developed. The synthesis device was combined with a sterile filtration unit and both were qualified. 14-(R,S)-[ 18 F]fluoro-6-thia-heptadecanoic acid was produced according to good manufacturing practice guidelines set by the European Union. The synthesis includes an initial nucleophilic labelling reaction, deprotection, preparative HPLC separation, purification of the final product, and formulation for injection. The duration and temperature of the reaction and hydrolysis were optimized, and the radiochemical stability of the formulated product was determined. The rotary evaporator used to evaporate the solvent after HPLC purification was replaced with solid phase extraction purification. We also replaced the human serum albumin used in the earlier procedure with a phosphate buffer-ascorbic acid mixture in the final formulation solution. From 2011 to 2016, we performed 219 synthesis procedures, 94% of which were successful. The radiochemical yield of 14-(R,S)-[ 18 F]fluoro-6-thia-heptadecanoic acid, decay-corrected to the end of bombardment, was 13% ± 6.3%. The total amount of formulated end product was 1.7 ± 0.8 GBq at end of synthesis. Copyright © 2017 John Wiley & Sons, Ltd.

Design of CGMP Production of 18F- and 68Ga-Radiopharmaceuticals

PubMed Central

Chu, Pei-Chun; Chao, Hao-Yu; Shieh, Wei-Chen; Chen, Chuck C.

2014-01-01

Objective. Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals. Methods. The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for 68Ga-DOTATATE and 18F-FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of 68Ga-DOTATATE and 18F-FDG were established. Results. CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of 68Ga-DOTATATE and 18F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free. Conclusion. CGMP compliance of radiopharmaceuticals has been reviewed. 68Ga-DOTATATE and 18F-FDG were synthesized with high radiochemical yield under CGMP process. PMID:25276810

Single-Cell Imaging Using Radioluminescence Microscopy Reveals Unexpected Binding Target for [18F]HFB.

PubMed

Kiru, Louise; Kim, Tae Jin; Shen, Bin; Chin, Frederick T; Pratx, Guillem

2018-06-01

Cell-based therapies are showing great promise for a variety of diseases, but remain hindered by the limited information available regarding the biological fate, migration routes and differentiation patterns of infused cells in trials. Previous studies have demonstrated the feasibility of using positron emission tomography (PET) to track single cells utilising an approach known as positron emission particle tracking (PEPT). The radiolabel hexadecyl-4-[ 18 F]fluorobenzoate ([ 18 F]HFB) was identified as a promising candidate for PEPT, due to its efficient and long-lasting labelling capabilities. The purpose of this work was to characterise the labelling efficiency of [ 18 F]HFB in vitro at the single-cell level prior to in vivo studies. The binding efficiency of [ 18 F]HFB to MDA-MB-231 and Jurkat cells was verified in vitro using bulk gamma counting. The measurements were subsequently repeated in single cells using a new method known as radioluminescence microscopy (RLM) and binding of the radiolabel to the single cells was correlated with various fluorescent dyes. Similar to previous reports, bulk cell labelling was significantly higher with [ 18 F]HFB (18.75 ± 2.47 dpm/cell, n = 6) than 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) (7.59 ± 0.73 dpm/cell, n = 7; p ≤ 0.01). However, single-cell imaging using RLM revealed that [ 18 F]HFB accumulation in live cells (8.35 ± 1.48 cpm/cell, n = 9) was not significantly higher than background levels (4.83 ± 0.52 cpm/cell, n = 12; p > 0.05) and was 1.7-fold lower than [ 18 F]FDG uptake in the same cell line (14.09 ± 1.90 cpm/cell, n = 13; p < 0.01). Instead, [ 18 F]HFB was found to bind significantly to fragmented membranes associated with dead cell nuclei, suggesting an alternative binding target for [ 18 F]HFB. This study demonstrates that bulk analysis alone does not always accurately portray the labelling efficiency, therefore highlighting the need for more routine screening of

Dryden/Edwards 1994 Thrust-Vectoring Aircraft Fleet - F-18 HARV, X-31, F-16 MATV

NASA Technical Reports Server (NTRS)

1994-01-01

The three thrust-vectoring aircraft at Edwards, California, each capable of flying at extreme angles of attack, cruise over the California desert in formation during flight in March 1994. They are, from left, NASA's F-18 High Alpha Research Vehicle (HARV), flown by the NASA Dryden Flight Research Center; the X-31, flown by the X-31 International Test Organization (ITO) at Dryden; and the Air Force F-16 Multi-Axis Thrust Vectoring (MATV) aircraft. All three aircraft were flown in different programs and were developed independently. The NASA F-18 HARV was a testbed to produce aerodynamic data at high angles of attack to validate computer codes and wind tunnel research. The X-31 was used to study thrust vectoring to enhance close-in air combat maneuvering, while the F-16 MATV was a demonstration of how thrust vectoring could be applied to operational aircraft.

Decomposed Fragment Identification in C_8F_18 RF Plasma for a-C:F Film Production

NASA Astrophysics Data System (ADS)

Sakai, Yosuke; Tazawa, Shota; Bratescu, Maria; Suda, Yoshiyuki; Sugawara, Hirotake

2004-09-01

Amorphous fluorocarbon polymer (a-C:F) film shows excellent insulation properties such as low dielectric constant (<2.5), high dielectric strength (>2 MV/cm), low surface energy, and chemical inertness. Therefore, we have studied this film for a purpose of an additional insulator to enhance the breakdown voltage in an alternative to a SF6 gas insulation system. The films are prepared using a C_8F_18 vapor RF plasma. When per-fluorocarbon, such as C_8F_18 as source gases, then the deposition rate becomes roughly two orders of magnitude higher than that obtained from conventional low molecular-weight source monomers (CF_4, C_2F_6, C_3F_6, and C_4F_8) [1]. The breakdown voltage (V_s) of N_2, Ar and He gases between the a-C:F film coated Al sphere-sphere electrodes for a gas pressure (p) times gap length (d), pd=0.1-100 Torr¥cm, was studied as well. Then, Vs between the a-C:F film coated electrodes was a several times higher than that between the Al electrodes in the present pd range[2]. In this work, the decomposed species of C_8F_18 in the plasma were identified using emission spectra from the plasma and Quadra-pole mass spectrograph, and the reason why the high deposition rate was obtained was discussed. The physical and chemical properties of a-C:F film was analyzed. [1] C.P.Lungu, et.al., Jpn. J. Appl. Phys. 38 (12B) L1544 - L1546 (1999) [2] C.Biloiu, et.al., Jpn. J. Appl. Phys. 42 (2B) L 201- L203 (2003) Work supported by Grant-in-Aid for Scientific Research (B), JSPS.

[18F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and μ-Opioid Receptor

PubMed Central

2017-01-01

18F-Labeled building blocks from the type of [18F]fluorophenylazocarboxylic-tert-butyl esters offer a rapid, mild, and reliable method for the 18F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds 3d and 3e with single-digit and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the μ-opioid receptor, but enhanced selectivity for the μ-subtype in comparison to the lead compound AH-7921. A “minimalist procedure” without the use of a cryptand and base for the preparation of 4-[18F]fluorophenylazocarboxylic-tert-butyl ester [18F]2a was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives ([18F]2b–f). With the substituted [18F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by 18F-fluoroarylation, namely the methoxy azocarboxamide [18F]3d as the D3 receptor radioligand and [18F]4a as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [18F]fluorophenylazocarboxylic-tert-butyl esters, the method of 18F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of 18F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography . PMID:29479577

Continuous-Flow Synthesis of N-Succinimidyl 4-[18F]fluorobenzoate Using a Single Microfluidic Chip

PubMed Central

Kimura, Hiroyuki; Tomatsu, Kenji; Saiki, Hidekazu; Arimitsu, Kenji; Ono, Masahiro; Kawashima, Hidekazu; Iwata, Ren; Nakanishi, Hiroaki; Ozeki, Eiichi; Kuge, Yuji; Saji, Hideo

2016-01-01

In the field of positron emission tomography (PET) radiochemistry, compact microreactors provide reliable and reproducible synthesis methods that reduce the use of expensive precursors for radiolabeling and make effective use of the limited space in a hot cell. To develop more compact microreactors for radiosynthesis of 18F-labeled compounds required for the multistep procedure, we attempted radiosynthesis of N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) via a three-step procedure using a microreactor. We examined individual steps for [18F]SFB using a batch reactor and microreactor and developed a new continuous-flow synthetic method with a single microfluidic chip to achieve rapid and efficient radiosynthesis of [18F]SFB. In the synthesis of [18F]SFB using this continuous-flow method, the three-step reaction was successfully completed within 6.5 min and the radiochemical yield was 64 ± 2% (n = 5). In addition, it was shown that the quality of [18F]SFB synthesized on this method was equal to that synthesized by conventional methods using a batch reactor in the radiolabeling of bovine serum albumin with [18F]SFB. PMID:27410684

Comparison of 18F-Labeled Fluoroalkylphosphonium Cations with 13N-NH3 for PET Myocardial Perfusion Imaging.

PubMed

Kim, Dong-Yeon; Kim, Hyeon Sik; Reder, Sybille; Zheng, Jin Hai; Herz, Michael; Higuchi, Takahiro; Pyo, A Young; Bom, Hee-Seung; Schwaiger, Markus; Min, Jung-Joon

2015-10-01

Despite substantial advances in the diagnosis of cardiovascular disease, there is a need for 18F-labeled myocardial perfusion agents for the diagnosis of ischemic heart disease because current PET tracers for myocardial perfusion imaging have a short half-life that limits their widespread clinical use in PET. Thus, 18F-labeled fluoroalkylphosphonium derivatives (18F-FATPs), including (5-18F-fluoropentyl)triphenylphosphonium cation (18F-FPTP), (6-18F-fluorohexyl)triphenylphosphonium cation (18F-FHTP), and (2-(2-18F-fluoroethoxy)ethyl)triphenylphosphonium cation (18F-FETP), were synthesized. The myocardial extraction and image quality of the 18F-FATPs were compared with those of 13N-NH3 in rat models. The first-pass extraction fraction (EF) values of the 18F-FATPs (18F-FPTP, 18F-FHTP, 18F-FETP) and 13N-NH3 were measured in isolated rat hearts perfused with the Langendorff method (flow velocities, 0.5, 4.0, 8.0, and 16.0 mL/min). Normal and myocardial infarction rats were imaged with small-animal PET after intravenous injection of 37 MBq of 18F-FATPs and 13N-NH3. To determine pharmacokinetics, a region of interest was drawn around the heart, and time-activity curves of the 18F-FATPs and 13N-NH3 were generated to obtain the counts per pixel per second. Defect size was analyzed on the basis of polar map images of 18F-FATPs and 13N-NH3. The EF values of 18F-FATPs and 13N-NH3 were comparable at low flow velocity (0.5 mL/min), whereas at higher flows EF values of 18F-FATPs were significantly higher than those of 13N-NH3 (4.0, 8.0, and 16.0 mL/min, P<0.05). Myocardium-to-liver ratios of 18F-FPTP, 18F-FHTP, 18F-FETP, and 13N-NH3 were 2.10±0.30, 4.36±0.20, 3.88±1.03, and 0.70±0.09, respectively, 10 min after injection, whereas myocardium-to-lung ratios were 5.00±0.25, 4.33±0.20, 7.98±1.23, and 2.26±0.14, respectively. Although 18F-FATPs and 13N-NH3 sharply delineated myocardial perfusion defects, defect size on the 13N-NH3 images was significantly smaller than on the

Aerodynamics of powered missile separation from F/A-18 aircraft

NASA Technical Reports Server (NTRS)

Ahmad, J. U.; Shanks, S. P.; Buning, P. G.

1993-01-01

A 3D dynamic 'chimera' algorithm that solves the thin-layer Navier-Stokes equations over multiple moving bodies was modified to numerically simulate the aerodynamics, missile dynamics, and missile plume interactions of a missile separating from a generic wing and from an F/A-18 aircraft in transonic flow. The missile is mounted below the wing for missile separation from the wing and on the F/A-18 fuselage at the engine inlet side for missile separation from aircraft. Static and powered missile separation cases are considered to examine the influence of the missile and plume on the wing and F/A-18 fuselage and engine inlet. The aircraft and missile are at two degrees angle of attack, Reynolds number of 10 million, freestream Mach number of 1.05 and plume Mach number of 3.0. The computational results show the details of the flow field.

.sup.18 F-4-Fluoroantipyrine

DOEpatents

Shiue, Chyng-Yann; Wolf, Alfred P.

1984-03-13

The novel radioactive compound .sup.18 F-4-fluoroantipyrine having high specific activity which can be used in nuclear medicine in diagnostic applications, prepared by the direct fluorination of antipyrine in acetic acid with radioactive fluorine at room temperature and purifying said radioactive compound by means of gel chromatography with ethyl acetate as eluent is disclosed. The non-radioactive 4-fluoroantipyrine can also be prepared by the direct fluorination of antipyrine in acetic acid with molecular fluorine at room temperature and purified by means of gel chromotography with ethyl acetate eluent.

[Is 3'-deoxy-3'- [18F] fluorothymidine ([18F]-FLT) the next tracer for routine clinical PET after R [18F]-FDG?].

PubMed

Couturier, Olivier; Leost, Françoise; Campone, Mario; Carlier, Thomas; Chatal, Jean-François; Hustinx, Roland

2005-09-01

Positron emission tomography (PET) with [18F]-FDG is now firmly established as a clinical tool in oncology. Its applications are however limited in some indications, due to the lack of specificity of its uptake mechanism for tumors, or the low avidity of some cancer types such as prostate. Alternative tracers are thus being developed, in order to fill up this void. Proliferation as a biological target is particularly attractive in cancer imaging. From that perspective, fluorothymidine ([18F]-FLT or FLT) has generated a strong interest among the scientific community, especially since the radiosynthesis process has been improved and simplified, thus making possible to envision a routine use for the tracer. This article aims at summarizing the status of the current scientific data regarding FLT. The uptake mechanism of FLT is well known, relying on the thymidine kinase 1 (TK1) enzymatic activity, and thus on DNA synthesis. Preclinical studies have shown a clear relationship between tracer accumulation and level of tumor proliferation, even though DNA salvage pathwayss intervene in the process and may complicate the interpretation of the results. Several clinical studies suggest a good specificity for tumor, albeit with a lower sensitivity than with FDG. In all likelihood however, the future of FLT lies in the evaluation of antitumor response and possibly the pretherapeutic prognostic characterization, rather than in the diagnosis and staging of malignancies. Although the scientific data regarding this issue remain limited, initial results are encouraging. Further significant work remains to be done in order to fully assess the clinical performances of the tracer, on the one hand, and to determine its place relative to FDG and other emerging tracers, on the other hand. Until these studies are completed, FLT should be considered as a promising tracer, but remaining at an experimental stage of its development.

New Dioxaborolane Chemistry Enables [18F]-Positron-Emitting, Fluorescent [18F]-Multimodality Biomolecule Generation from the Solid Phase

PubMed Central

Crisp, Jessica L.; Vera, David R.; Tsien, Roger Y.; Ting, Richard

2016-01-01

New protecting group chemistry is used to greatly simplify imaging probe production. Temperature and organic solvent-sensitive biomolecules are covalently attached to a biotin-bearing dioxaborolane, which facilitates antibody immobilization on a streptavidin-agarose solid-phase support. Treatment with aqueous fluoride triggers fluoride-labeled antibody release from the solid phase, separated from unlabeled antibody, and creates [18F]-trifluoroborate-antibody for positron emission tomography and near-infrared fluorescent (PET/NIRF) multimodality imaging. This dioxaborolane-fluoride reaction is bioorthogonal, does not inhibit antigen binding, and increases [18F]-specific activity relative to solution-based radiosyntheses. Two applications are investigated: an anti-epithelial cell adhesion molecule (EpCAM) monoclonal antibody (mAb) that labels prostate tumors and Cetuximab, an anti-epidermal growth factor receptor (EGFR) mAb (FDA approved) that labels lung adenocarcinoma tumors. Colocalized, tumor-specific NIRF and PET imaging confirm utility of the new technology. The described chemistry should allow labeling of many commercial systems, diabodies, nanoparticles, and small molecules for dual modality imaging of many diseases. PMID:27064381

Feasibility of assessing [(18)F]FDG lung metabolism with late dynamic PET imaging.

PubMed

Laffon, Eric; de Clermont, Henri; Vernejoux, Jean-Marc; Jougon, Jacques; Marthan, Roger

2011-04-01

The aim of this work was to non-invasively establish the feasibility of assessing 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) lung metabolism with the use of a late dynamic positron emission tomograpy (PET) acquisition, i.e., beyond 2 h after injection. The present method has been probed in 11 patients without any respiratory disease, under fasting conditions, by assessing mean values of (18)F-FDG lung metabolism. A kinetic model analysis has been implemented on a simple calculation sheet. An arbitrary (population based) input function has been used in each individual, which was obtained from literature data. In the healthy lung, no (18)F-FDG release was found, and the mean values (±SD) of the (18)F-FDG uptake rate constant and of the fraction of the free tracer in blood and interstitial volume were: K = 0.0016 min(-1) (±0.0005), and F = 0.18 (±0.10), respectively. These results were in very close agreement with literature data that were obtained by both three-compartment model analysis and Patlak graphical analysis (gold standards), and that used an invasive blood sampling. Furthermore, K and the standard uptake value index have been compared. We conclude that assessing lung metabolism of (18)F-FDG in humans with the use of late dynamic PET imaging is feasible. The arbitrary input function of this non-invasive feasibility study could be replaced in further experiments by an input function obtained by arterial sampling. It is suggested that this method may prove useful to quantify (18)F-FDG lung metabolism under pathological conditions.

Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain.

PubMed

Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Therriault, Joseph; Kang, Min Su; Shin, Monica; Guiot, Marie-Christine; Guo, Qi; Harada, Ryuichi; Comley, Robert A; Massarweh, Gassan; Soucy, Jean-Paul; Okamura, Nobuyuki; Gauthier, Serge; Rosa-Neto, Pedro

2017-03-31

18 F-THK5351 is a quinoline-derived tau imaging agent with high affinity to paired helical filaments (PHF). However, high levels of 18 F-THK5351 retention in brain regions thought to contain negligible concentrations of PHF raise questions about the interpretation of the positron emission tomography (PET) signals, particularly given previously described interactions between quinolone derivatives and monoamine oxidase B (MAO-B). Here, we tested the effects of MAO-B inhibition on 18 F-THK5351 brain uptake using PET and autoradiography. Eight participants (five mild cognitive impairment, two Alzheimer's disease, and one progressive supranuclear palsy) had baseline 18 F-AZD4694 and 18 F-THK5351 scans in order to quantify brain amyloid and PHF load, respectively. A second 18 F-THK5351 scan was conducted 1 week later, 1 h after a 10-mg oral dose of selegiline. Three out of eight patients also had a third 18 F-THK5351 scan 9-28 days after the selegiline administration. The primary outcome measure was standardized uptake value (SUV), calculated using tissue radioactivity concentration from 50 to 70 min after 18 F-THK5351 injection, normalizing for body weight and injected radioactivity. The SUV ratio (SUVR) was determined using the cerebellar cortex as the reference region. 18 F-THK5351 competition autoradiography studies in postmortem tissue were conducted using 150 and 500 nM selegiline. At baseline, 18 F-THK5351 SUVs were highest in the basal ganglia (0.64 ± 0.11) and thalamus (0.62 ± 0.14). In the post-selegiline scans, the regional SUVs were reduced on average by 36.7% to 51.8%, with the greatest reduction noted in the thalamus (51.8%) and basal ganglia (51.4%). MAO-B inhibition also reduced 18 F-THK5351 SUVs in the cerebellar cortex (41.6%). The SUVs remained reduced in the three patients imaged at 9-28 days. Tissue autoradiography confirmed the effects of MAO-B inhibition on 18 F-THK5351 uptake. These results indicate that the interpretation of 18 F

Preclinical characterization of 18F-MAA, a novel PET surrogate of 99mTc-MAA.

PubMed

Wu, Shih-Yen; Kuo, Jia-Wei; Chang, Tien-Kuei; Liu, Ren-Shen; Lee, Rheun-Chuan; Wang, Shyh-Jen; Lin, Wuu-Jyh; Wang, Hsin-Ell

2012-10-01

(99m)Tc-labeled macroaggregated albumin ((99m)Tc-MAA) scintigraphy scan is routinely performed for lung perfusion imaging and for the assessment of in vivo distribution of (90)Y-labeled SIR-Spheres prior to selective internal radiation treatment for hepatocellular carcinoma. Positron emission tomography (PET) imaging is superior to gamma scintigraphy in terms of sensitivity, spatial resolution and accuracy of quantification. This study reported that (18)F-labeled macroaggregated albumin ((18)F-MAA) is an ideal PET imaging surrogate for (99m)Tc-MAA. (18)F-MAA was prepared from the commercial MAA kit via a one-step conjugation with N-succinimidyl 4-(18)F-fluorobenzoate ((18)F-SFB). The biodistribution study and microPET/microSPECT imaging were conducted in normal SD rats after intravenous injection of (18)F-MAA/(99m)Tc-MAA. A comparison study of these two radiotracers was performed after co-injection via the intrahepatic arterial in a N1S1 hepatoma-bearing SD rat model. The optimal condition for (18)F-MAA preparation is coupling MAA (0.5mg) with (18)F-SFB at 45°C for 5 min in a phosphate buffer of pH 8.5. (18)F-MAA was prepared in 60 min with high radiochemical yield (30%-35%) and high radiochemical purity (>95%). The in vivo distribution of (18)F-MAA after intravenous injection meets the specifications of MAA depicted in European Pharmacopeia. Our study demonstrated excellent correlation between (18)F-MAA and (99m)Tc-MAA in the regional distribution of tumor, liver and lungs (R(2)=0.965, 0.886 and 0.991, respectively), and also in the tumor-to-liver and tumor-to-lungs ratio (R(2)=0.965 and 0.987, respectively) in a N1S1 hepatoma-bearing SD rat model. The organ uptakes derived from animal PET/CT and SPECT/CT imaging after administration of these two tracers were in accordance with those obtained in the distribution studies. Starting from commercial MAA kit, an efficient preparation of (18)F-MAA was successfully established. Highly correlated, almost parallel

Prospective trial evaluating the sensitivity and specificity of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) PET and MRI in patients with recurrent gliomas.

PubMed

Youland, Ryan S; Pafundi, Deanna H; Brinkmann, Debra H; Lowe, Val J; Morris, Jonathan M; Kemp, Bradley J; Hunt, Christopher H; Giannini, Caterina; Parney, Ian F; Laack, Nadia N

2018-05-01

Treatment-related changes can be difficult to differentiate from progressive glioma using MRI with contrast (CE). The purpose of this study is to compare the sensitivity and specificity of 18F-DOPA-PET and MRI in patients with recurrent glioma. Thirteen patients with MRI findings suspicious for recurrent glioma were prospectively enrolled and underwent 18F-DOPA-PET and MRI for neurosurgical planning. Stereotactic biopsies were obtained from regions of concordant and discordant PET and MRI CE, all within regions of T2/FLAIR signal hyperintensity. The sensitivity and specificity of 18F-DOPA-PET and CE were calculated based on histopathologic analysis. Receiver operating characteristic curve analysis revealed optimal tumor to normal (T/N) and SUVmax thresholds. In the 37 specimens obtained, 51% exhibited MRI contrast enhancement (M+) and 78% demonstrated 18F-DOPA-PET avidity (P+). Imaging characteristics included M-P- in 16%, M-P+ in 32%, M+P+ in 46% and M+P- in 5%. Histopathologic review of biopsies revealed grade II components in 16%, grade III in 43%, grade IV in 30% and no tumor in 11%. MRI CE sensitivity for recurrent tumor was 52% and specificity was 50%. PET sensitivity for tumor was 82% and specificity was 50%. A T/N threshold > 2.0 altered sensitivity to 76% and specificity to 100% and SUVmax > 1.36 improved sensitivity and specificity to 94 and 75%, respectively. 18F-DOPA-PET can provide increased sensitivity and specificity compared with MRI CE for visualizing the spatial distribution of recurrent gliomas. Future studies will incorporate 18F-DOPA-PET into re-irradiation target volume delineation for RT planning.

Fully automated SPE-based synthesis and purification of 2-[18F]fluoroethyl-choline for human use.

PubMed

Schmaljohann, Jörn; Schirrmacher, Esther; Wängler, Björn; Wängler, Carmen; Schirrmacher, Ralf; Guhlke, Stefan

2011-02-01

2-[(18)F]Fluoroethyl-choline ([(18)F]FECH) is a promising tracer for the detection of prostate cancer as well as brain tumors with positron emission tomography (PET). [(18)F]FECH is actively transported into mammalian cells, becomes phosphorylated by choline kinase and gets incorporated into the cell membrane after being metabolized to phosphatidylcholine. So far, its synthesis is a two-step procedure involving at least one HPLC purification step. To allow a wider dissemination of this tracer, finding a purification method avoiding HPLC is highly desirable and would result in easier accessibility and more reliable production of [(18)F]FECH. [(18)F]FECH was synthesized by reaction of 2-bromo-1-[(18)F]fluoroethane ([(18)F]BFE) with dimethylaminoethanol (DMAE) in DMSO. We applied a novel and very reliable work-up procedure for the synthesis of [(18)F]BFE. Based on a combination of three different solid-phase cartridges, the purification of [(18)F]BFE from its precursor 2-bromoethyl-4-nitrobenzenesulfonate (BENos) could be achieved without using HPLC. Following the subsequent reaction of the purified [(18)F]BFE with DMAE, the final product [(18)F]FECH was obtained as a sterile solution by passing the crude reaction mixture through a combination of two CM plus cartridges and a sterile filter. The fully automated synthesis was performed using as well a Raytest SynChrom module (Raytest, Germany) or a Scintomics HotboxIII module (Scintomics, Germany). The radiotracer [(18)F]FECH can be synthesized in reliable radiochemical yields (RCY) of 37±5% (Synchrom module) and 33±5% (Hotbox III unit) in less than 1 h using these two fully automated commercially available synthesis units without HPLC involvement for purification. Detailed quality control of the final injectable [(18)F]FECH solution proved the high radiochemical purity and the absence of Kryptofix2.2.2, DMAE and DMSO used in the course of synthesis. Sterility and bacterial endotoxin testing following standard

TANK 18-F AND 19-F TANK FILL GROUT SCALE UP TEST SUMMARY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stefanko, D.; Langton, C.

2012-01-03

High-level waste (HLW) tanks 18-F and 19-F have been isolated from FTF facilities. To complete operational closure the tanks will be filled with grout for the purpose of: (1) physically stabilizing the tanks, (2) limiting/eliminating vertical pathways to residual waste, (3) entombing waste removal equipment, (4) discouraging future intrusion, and (5) providing an alkaline, chemical reducing environment within the closure boundary to control speciation and solubility of select radionuclides. This report documents the results of a four cubic yard bulk fill scale up test on the grout formulation recommended for filling Tanks 18-F and 19-F. Details of the scale upmore » test are provided in a Test Plan. The work was authorized under a Technical Task Request (TTR), HLE-TTR-2011-008, and was performed according to Task Technical and Quality Assurance Plan (TTQAP), SRNL-RP-2011-00587. The bulk fill scale up test described in this report was intended to demonstrate proportioning, mixing, and transportation, of material produced in a full scale ready mix concrete batch plant. In addition, the material produced for the scale up test was characterized with respect to fresh properties, thermal properties, and compressive strength as a function of curing time.« less

18F-FDG PET/CT in breast cancer: Evidence-based recommendations in initial staging.

PubMed

Caresia Aroztegui, Ana Paula; García Vicente, Ana María; Alvarez Ruiz, Soledad; Delgado Bolton, Roberto Carlos; Orcajo Rincon, Javier; Garcia Garzon, Jose Ramon; de Arcocha Torres, Maria; Garcia-Velloso, Maria Jose

2017-10-01

Current guidelines do not systematically recommend 18F-FDG PET/CT for breast cancer staging; and the recommendations and level of evidence supporting its use in different groups of patients vary among guidelines. This review summarizes the evidence about the role of 18F-FDG PET/CT in breast cancer staging and the therapeutic and prognostic impact accumulated in the last decade. Other related aspects, such as the association of metabolic information with biology and prognosis are considered and evidence-based recommendations for the use of 18F-FDG PET/CT in breast cancer staging are offered. We systematically searched MEDLINE for articles reporting studies with at least 30 patients related to clinical questions following the Problem/Population, Intervention, Comparison, and Outcome framework. We critically reviewed the selected articles and elaborated evidence tables structuring the summarized information into methodology, results, and limitations. The level of evidence and the grades of recommendation for the use of 18F-FDG PET/CT in different contexts are summarized. Level III evidence supports the use of 18F-FDG PET/CT for initial staging in patients with recently diagnosed breast cancer; the diagnostic and therapeutic impact of the 18F-FDG PET/CT findings is sufficient for a weak recommendation in this population. In patients with locally advanced breast cancer, level II evidence supports the use of 18F-FDG PET/CT for initial staging; the diagnostic and therapeutic impact of the 18F-FDG PET/CT findings is sufficient for a strong recommendation in this population. In patients with recently diagnosed breast cancer, the metabolic information from baseline 18F-FDG PET/CT is associated with tumor biology and has prognostic implications, supported by level II evidence. In conclusion, 18F-FDG PET/CT is not recommended for staging all patients with early breast cancer, although evidence of improved regional and systemic staging supports its use in locally advanced

Clinical utility of (18)F-fluoride PET/CT in benign and malignant bone diseases.

PubMed

Li, Yuxin; Schiepers, Christiaan; Lake, Ralph; Dadparvar, Simin; Berenji, Gholam R

2012-01-01

(18)F labeled sodium fluoride is a positron-emitting, bone seeking agent with more favorable skeletal kinetics than conventional phosphate and diphosphonate compounds. With the expanding clinical usage of PET/CT, there is renewed interest in using (18)F-fluoride PET/CT for imaging bone diseases. Growing evidence indicates that (18)F fluoride PET/CT offers increased sensitivity, specificity, and diagnostic accuracy in evaluating metastatic bone disease compared to (99m)Tc based bone scintigraphy. National Oncologic PET Registry (NOPR) has expanded coverage for (18)F sodium fluoride PET scans since February 2011 for the evaluation of osseous metastatic disease. In this article, we reviewed the pharmacological characteristics of sodium fluoride, as well as the clinical utility of PET/CT using (18)F-fluoride in both benign and malignant bone disorders. Published by Elsevier Inc.

No-carrier-added (/sup 18/F)-N-methylspiroperidol

DOEpatents

Shiue, C.Y.; Fowler, J.S.; Wolf, A.P.

1985-10-04

The present invention is directed to the synthesis of a radioligand, labeled with a positron emitting radionuclide which is suitable for dynamic studies in humans using positron emission transaxial tomography. No-carrier-added (NCA) (/sup 18/F)-N-methylspiroperiodl is prepared from four different sustrates: p-nitrobenzonitrile, cyclopropyl p-nitrophenyl ketone, p-cyclopropanoyl-N,N,N-trimethylanilinium iodide and p-cyclopropanoyl-N,N,N-trimethylanilinium perchlorate. The process for the production of NCA (/sup 18/F)-N-methylspiroperidol is a nucleophilic aromatic substitution reaction. Furthermore, the compound of this invention is shown to be effective as a new drug of choice for in vivo examination of dopamine binding sites in a human brain. In particular, this drug is primarily useful in the noninvasive technique of positron emission transaxial tomography (PETT).

[18F-Fluorocholine PET-CT for localization of parathyroid adenomas].

PubMed

Kluijfhout, Wouter P; Vriens, Menno R; Borel Rinkes, Inne H M; Valk, Gerlof D; de Klerk, John M H; de Keizer, Bart

2015-01-01

18F-fluorocholine PET-CT is a new imaging modality for the localization of pathological parathyroid glands in patients with primary hyperparathyroidism. The PET-CT is a combination scan that uses both the physiological information from the PET and the anatomical information from the CT. Uptake of the radio-isotope 18F-fluorocholine is increased in pathological parathyroid glands. 18F-fluorocholine PET-CT helps clinicians to localize the pathological parathyroid glands where conventional modalities fail to do so. This enables surgeons to carry out targeted minimal invasive surgery. It may also prevent the patient having to undergo a more extensive exploration, with its associated risks, and alleviate the necessity of taking medications with side effects. Although the literature on this subject is still scarce, preliminary results are promising. As any hospital with a PET-CT can perform the scan, we expect that its use in patients with hyperparathyroidism will increase over the next few years.

The Role of 18F-FDG PET/CT Integrated Imaging in Distinguishing Malignant from Benign Pleural Effusion.

PubMed

Sun, Yajuan; Yu, Hongjuan; Ma, Jingquan; Lu, Peiou

2016-01-01

The aim of our study was to evaluate the role of 18F-FDG PET/CT integrated imaging in differentiating malignant from benign pleural effusion. A total of 176 patients with pleural effusion who underwent 18F-FDG PET/CT examination to differentiate malignancy from benignancy were retrospectively researched. The images of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging were visually analyzed. The suspected malignant effusion was characterized by the presence of nodular or irregular pleural thickening on CT imaging. Whereas on PET imaging, pleural 18F-FDG uptake higher than mediastinal activity was interpreted as malignant effusion. Images of 18F-FDG PET/CT integrated imaging were interpreted by combining the morphologic feature of pleura on CT imaging with the degree and form of pleural 18F-FDG uptake on PET imaging. One hundred and eight patients had malignant effusion, including 86 with pleural metastasis and 22 with pleural mesothelioma, whereas 68 patients had benign effusion. The sensitivities of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging in detecting malignant effusion were 75.0%, 91.7% and 93.5%, respectively, which were 69.8%, 91.9% and 93.0% in distinguishing metastatic effusion. The sensitivity of 18F-FDG PET/CT integrated imaging in detecting malignant effusion was higher than that of CT imaging (p = 0.000). For metastatic effusion, 18F-FDG PET imaging had higher sensitivity (p = 0.000) and better diagnostic consistency with 18F-FDG PET/CT integrated imaging compared with CT imaging (Kappa = 0.917 and Kappa = 0.295, respectively). The specificities of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging were 94.1%, 63.2% and 92.6% in detecting benign effusion. The specificities of CT imaging and 18F-FDG PET/CT integrated imaging were higher than that of 18F-FDG PET imaging (p = 0.000 and p = 0.000, respectively), and CT imaging had better diagnostic consistency with 18F-FDG PET/CT integrated

The Role of 18F-FDG PET/CT Integrated Imaging in Distinguishing Malignant from Benign Pleural Effusion

PubMed Central

Sun, Yajuan; Yu, Hongjuan; Ma, Jingquan

2016-01-01

Objective The aim of our study was to evaluate the role of 18F-FDG PET/CT integrated imaging in differentiating malignant from benign pleural effusion. Methods A total of 176 patients with pleural effusion who underwent 18F-FDG PET/CT examination to differentiate malignancy from benignancy were retrospectively researched. The images of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging were visually analyzed. The suspected malignant effusion was characterized by the presence of nodular or irregular pleural thickening on CT imaging. Whereas on PET imaging, pleural 18F-FDG uptake higher than mediastinal activity was interpreted as malignant effusion. Images of 18F-FDG PET/CT integrated imaging were interpreted by combining the morphologic feature of pleura on CT imaging with the degree and form of pleural 18F-FDG uptake on PET imaging. Results One hundred and eight patients had malignant effusion, including 86 with pleural metastasis and 22 with pleural mesothelioma, whereas 68 patients had benign effusion. The sensitivities of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging in detecting malignant effusion were 75.0%, 91.7% and 93.5%, respectively, which were 69.8%, 91.9% and 93.0% in distinguishing metastatic effusion. The sensitivity of 18F-FDG PET/CT integrated imaging in detecting malignant effusion was higher than that of CT imaging (p = 0.000). For metastatic effusion, 18F-FDG PET imaging had higher sensitivity (p = 0.000) and better diagnostic consistency with 18F-FDG PET/CT integrated imaging compared with CT imaging (Kappa = 0.917 and Kappa = 0.295, respectively). The specificities of CT imaging, 18F-FDG PET imaging and 18F-FDG PET/CT integrated imaging were 94.1%, 63.2% and 92.6% in detecting benign effusion. The specificities of CT imaging and 18F-FDG PET/CT integrated imaging were higher than that of 18F-FDG PET imaging (p = 0.000 and p = 0.000, respectively), and CT imaging had better diagnostic consistency with

In vivo evaluation of 18F-MNI698: an 18F-labeled radiotracer for imaging of serotonin 4 receptors in brain.

PubMed

Tavares, Adriana Alexandre S; Caillé, Fabien; Barret, Olivier; Papin, Caroline; Lee, Hsiaoju; Morley, Thomas J; Fowles, Krista; Holden, Daniel; Seibyl, John P; Alagille, David; Tamagnan, Gilles D

2014-05-01

Serotonin 4 receptors (5-hydroxytryptamine receptor 4 [5HT4R]) hold promise as a novel therapeutic approach to multiple brain disorders, including Alzheimer and Huntington disease. In vivo imaging of these receptors with selective 5HT4R radiotracers and PET would be valuable to investigate alterations in 5HT4R in different brain disorders and to assist drug discovery. In this study, (18)F-MNI698 was evaluated as a potential PET radiotracer for imaging of 5HT4R in the brain. Eighteen PET studies were performed in 3 adult rhesus monkeys. The radiotracer was administered as a bolus intravenous injection or bolus plus constant infusion (time that would be required to inject the bolus at the infusion rate = 60 min), and arterial blood was collected for data quantification. Kinetic models were used to estimate distribution volumes and binding potentials, for which the cerebellum was used as a reference region. (18)F-MNI698 test-retest variability and upper mass dose limits were determined. Preblocking studies using several doses of SB204070, a selective 5HT4R antagonist, were performed. (18)F-MNI698 avidly entered the monkey brain (peak percentage injected dose of ∼ 6.6%), and its brain distribution was consistent with known 5HT4R densities. At 120 min after bolus injection and after the start of radiotracer infusion, only less than 5% and approximately 10% parent compound was present in blood, respectively. Measured binding potentials were underestimated by 22%-36% when noninvasive methods were used for data quantification in comparison with invasive methods. A good agreement was found between test-retest measurements. The radiotracer upper mass dose limit (<5% occupancy) was determined to be 13.1 μg per 70 kg of body weight. SB204070 blocked the radiotracer binding in a dose-dependent manner. Data indicate that (18)F-MNI698 is a promising PET radiotracer for imaging of 5HT4R in the brain, and human studies are warranted based on these study results.

Facile purification and click labeling with 2-[ 18F]fluoroethyl azide using solid phase extraction cartridges

DOE PAGES

Zhou, Dong; Chu, Wenhua; Peng, Xin; ...

2014-11-04

In this paper, a facile method was developed to purify 2-[ 18F]fluoroethyl azide ([ 18F]FEA) using a C18 cartridge and an Oasis® HLB cartridge in series, in which [18F]FEA was exclusively trapped on the HLB cartridge. [ 18F]FEA can be eluted for reactions in solution; alternatively click labeling can be carried out on the HLB cartridge itself by loading an alkyne substrate and copper (I) catalyst dissolved in DMF onto the cartridge. Finally, this solid phase extraction methodology for purification and click labeling with [ 18F]FEA, either in solution or on the cartridge, is safe, simple, reproducible in high yield,more » and compatible with automated synthesis of 18F-labeled PET tracers.« less

Development of [18F]afatinib as new TKI-PET tracer for EGFR positive tumors.

PubMed

Slobbe, Paul; Windhorst, Albert D; Stigter-van Walsum, Marijke; Schuit, Robert C; Smit, Egbert F; Niessen, Heiko G; Solca, Flavio; Stehle, Gerd; van Dongen, Guus A M S; Poot, Alex J

2014-10-01

Afatinib is an irreversible ErbB family blocker that was approved for the treatment of EGFR mutated non-small cell lung cancer in 2013. Positron emission tomography (PET) with fluorine-18 labeled afatinib provides a means to obtain improved understanding of afatinib tumor disposition in vivo. PET imaging with [(18)F]afatinib may also provide a method to select treatment responsive patients. The aim of this study was to label afatinib with fluorine-18 and evaluate its potential as TKI-PET tracer in tumor bearing mice. A radiochemically novel coupling, using peptide coupling reagent BOP, was explored and optimized to synthesize [(18)F]afatinib, followed by a metabolite analysis and biodistribution studies in two clinically relevant lung cancer cell lines, xenografted in nude mice. A reliable [(18)F]afatinib radiosynthesis was developed and the tracer could be produced in yields of 17.0 ± 2.5% calculated from [(18)F]F(-) and >98% purity. The identity of the product was confirmed by co-injection on HPLC with non-labeled afatinib. Metabolite analysis revealed a moderate rate of metabolism, with >80% intact tracer in plasma at 45 min p.i. Biodistribution studies revealed rapid tumor accumulation and good retention for a period of at least 2 hours, while background tissues showed rapid clearance of the tracer. We have developed a method to synthesize [(18)F]afatinib and related fluorine-18 labeled 4-anilinoquinazolines. [(18)F]Afatinib showed good stability in vivo, justifying further evaluation as a TKI-PET tracer. Copyright © 2014 Elsevier Inc. All rights reserved.

Defining optimal tracer activities in pediatric oncologic whole-body 18F-FDG-PET/MRI.

PubMed

Gatidis, Sergios; Schmidt, Holger; la Fougère, Christian; Nikolaou, Konstantin; Schwenzer, Nina F; Schäfer, Jürgen F

2016-12-01

To explore the feasibility of reducing administered tracer activities and to assess optimal activities for combined 18 F-FDG-PET/MRI in pediatric oncology. 30 18 F-FDG-PET/MRI examinations were performed on 24 patients with known or suspected solid tumors (10 girls, 14 boys, age 12 ± 5.6 [1-18] years; PET scan duration: 4 min per bed position). Low-activity PET images were retrospectively simulated from the originally acquired data sets using randomized undersampling of list mode data. PET data of different simulated administered activities (0.25-2.5 MBq/kg body weight) were reconstructed with or without point spread function (PSF) modeling. Mean and maximum standardized uptake values (SUV mean and SUV max ) as well as SUV variation (SUV var ) were measured in physiologic organs and focal FDG-avid lesions. Detectability of organ structures and of focal 18 F-FDG-avid lesions as well as the occurrence of false-positive PET lesions were assessed at different simulated tracer activities. Subjective image quality steadily declined with decreasing tracer activities. Compared to the originally acquired data sets, mean relative deviations of SUV mean and SUV max were below 5 % at 18 F-FDG activities of 1.5 MBq/kg or higher. Over 95 % of anatomic structures and all pathologic focal lesions were detectable at 1.5 MBq/kg 18 F-FDG. Detectability of anatomic structures and focal lesions was significantly improved using PSF. No false-positive focal lesions were observed at tracer activities of 1 MBq/kg 18 F-FDG or higher. Administration of 18 F-FDG activities of 1.5 MBq/kg is, thus, feasible without obvious diagnostic shortcomings, which is equivalent to a dose reduction of more than 50 % compared to current recommendations. Significant reduction in administered 18 F-FDG tracer activities is feasible in pediatric oncologic PET/MRI. Appropriate activities of 18 F-FDG or other tracers for specific clinical questions have to be further established in selected patient

18F-Fluorodeoxyglucose Positron Emission Tomography/CT Scanning in Diagnosing Vascular Prosthetic Graft Infection

PubMed Central

Saleem, Ben R.; Pol, Robert A.; Slart, Riemer H. J. A.; Reijnen, Michel M. P. J.; Zeebregts, Clark J.

2014-01-01

Vascular prosthetic graft infection (VPGI) is a severe complication after vascular surgery. CT-scan is considered the diagnostic tool of choice in advanced VPGI. The incidence of a false-negative result using CT is relatively high, especially in the presence of low-grade infections. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scanning has been suggested as an alternative for the diagnosis and assessment of infectious processes. Hybrid 18F-FDG PET/CT has established the role of 18F-FDG PET for the assessment of suspected VPGI, providing accurate anatomic localization of the site of infection. However, there are no clear guidelines for the interpretation of the uptake patterns of 18F-FDG as clinical tool for VPGI. Based on the available literature it is suggested that a linear, diffuse, and homogeneous uptake should not be regarded as an infection whereas focal or heterogeneous uptake with a projection over the vessel on CT is highly suggestive of infection. Nevertheless, 18F-FDG PET and 18F-FDG PET/CT can play an important role in the detection of VPGI and monitoring response to treatment. However an accurate uptake and pattern recognition is warranted and cut-off uptake values and patterns need to be standardized before considering the technique to be the new standard. PMID:25210712

Recoil /sup 18/F chemistry. XI. High pressure investigation of 1,1-difluoroethane

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manning, R.G.; Root, J.W.

1980-06-15

Nuclear recoil /sup 18/F reactions in CH/sub 3/CHF/sub 2/ have been investigated throughout the effective pressure range 0.3--190 atm. The principal reaction channel is F-to-HF abstraction for which the combined yield from quasithermal and energetic processes in the presence of 5 mole% H/sub 2/S additive is 83.4% +- 0.2%. A reaction mechanism is proposed that involves the organic product forming channels F-for-F, F-for-..cap alpha..H, F-for-..beta..H, F-for-CH/sub 3/ and F-for-CHF/sub 2/. The results are compared with those reported for the /sup 18/F+CH/sub 3/CF/sub 3/ system.

Initial in vivo PET imaging of 5-HT1A receptors with 3-[18F]mefway

PubMed Central

Wooten, Dustin W; Hillmer, Ansel T; Murali, Dhanabalan; Barnhart, Todd E; Thio, Joanne P; Bajwa, Alisha K; Bonab, Ali A; Normandin, Marc D; Schneider, Mary L; Mukherjee, Jogeshwar; Christian, Bradley T

2014-01-01

4-trans-[18F]Mefway is a PET radiotracer with high affinity for 5-HT1A receptors. Our preliminary work indicated the positional isomer, 3-[18F]mefway, would be suitable for PET imaging of 5-HT1A receptors. We now compare the in vivo behaviour of 3-mefway with 4-mefway to evaluate 3-[18F]mefway as a potential 5-HT1A PET radiotracer. Two male rhesus macaques were given bolus injections of both 3- and 4-trans-[18F]mefway in separate experiments. 90 minute dynamic PET scans were acquired. TACs were extracted in the mesial temporal lobe (MTL) and caudal anterior cingulate gyrus (cACg). The cerebellum (CB) was used as a reference region. In vivo behavior of the radiotracers in the CB was compared based upon the ratio of normalized PET uptake for 3- and 4-trans-[18F]mefway. Specific binding was compared by examining MTL/CB and cACg/CB ratios. The subject-averaged ratio of 3-[18F]mefway to 4-trans-[18F]mefway in the cerebellum was 0.96 for 60-90 minutes. MTL/CB reached plateaus of ~2.7 and ~6 by 40 minutes and 90 minutes for 3- and 4-trans-[18F]mefway, respectively. cACg/CB reached plateaus of ~2.5 and ~6 by 40 minutes and 70 minutes for 3- and 4-trans-[18F]mefway, respectively. The short pseudoequilibration times and sufficient uptake of 3-[18F]mefway may be useful in studies requiring short scan times. Furthermore, the similar nondisplaceable clearance in the CB to 4-trans-[18F]mefway suggests the lower BPND of 3-[18F]mefway is due to a lower affinity. The lower affinity of 3-[18F]mefway may make it useful for measuring changes in endogenous 5-HT levels, however, this remains to be ascertained. PMID:25143866

18F-Positron Emitting/Trimethine Cyanine-Fluorescent Contrast for Image-Guided Prostate Cancer Management.

PubMed

Kommidi, Harikrishna; Guo, Hua; Nurili, Fuad; Vedvyas, Yogindra; Jin, Moonsoo M; McClure, Timothy D; Ehdaie, Behfar; Sayman, Haluk B; Akin, Oguz; Aras, Omer; Ting, Richard

2018-05-10

[ 18/19 F]-4, an anionic GCPII/PSMA inhibitor for image-guided intervention in prostate cancer, is described. [ 19 F]-4 is radiolabeled with a radiochemical yield that is ≥27% and a molar activity of 190 ± 50 mCi/μmol in a <1 h, one-step, aqueous isotopic exchange reaction. [ 19 F]-4 allows PSMA expression to be imaged by fluorescence (FL) and [ 18 F]-PET. PC3-PIP (PSMA-positive, EC 50 = 6.74 ± 1.33 nM) cancers are specifically delineated in mice that bear 3 million (18 mg) PC3-PIP and PC3 (control, PSMA-negative) cells. Colocalization of [ 18/19 F]-4 PET, fluorescence, scintillated biodistribution, and PSMA expression are observed.

Synthesis and evaluation of novel 18 F-labeled quinazoline derivatives with low lipophilicity for tumor PET imaging.

PubMed

Chong, Yan; Chang, Jin; Zhao, Wenwen; He, Yong; Li, Yuqiao; Zhang, Huabei; Qi, Chuanmin

2018-02-01

Four novel 18 F-labeled quinazoline derivatives with low lipophilicity, [ 18 F]4-(2-fluoroethoxy)-6,7-dimethoxyquinazoline ([ 18 F]I), [ 18 F]4-(3-((4-(2-fluoroethoxy)-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine ([ 18 F]II), [ 18 F]4-(2-fluoroethoxy)-7-methoxy-6-(2-methoxyethoxy)quinazoline ([ 18 F]III), and [ 18 F]4-(2-fluoroethoxy)-6,7-bis(2-methoxyethoxy)quinazoline ([ 18 F]IV), were synthesized via a 2-step radiosynthesis procedure with an overall radiochemical yield of 10% to 38% (without decay correction) and radiochemical purities of >98%. The lipophilicity and stability of labeled compounds were tested in vitro. The log P values of the 4 radiotracers ranged from 0.52 to 1.07. We then performed ELISA to measure their affinities to EGFR-TK; ELISA assay results indicated that each inhibitor was specifically bounded to EGFR-TK in a dose-dependent manner. The EGFR-TK autophosphorylation IC 50 values of [ 18 F]I, [ 18 F]II, [ 18 F]III, and [ 18 F]IV were 7.732, 0.4698, 0.1174, and 0.1176 μM, respectively. All labeled compounds were evaluated via cellular uptake and blocking studies in HepG2 cell lines in vitro. Cellular uptake and blocking experiment results indicated that [ 18 F]I and [ 18 F]III had excellent cellular uptake at 120-minute postinjection in HepG2 carcinoma cells (51.80 ± 3.42%ID/mg protein and 27.31 ± 1.94%ID/mg protein, respectively). Additionally, biodistribution experiments in S180 tumor-bearing mice in vivo indicated that [ 18 F]I had a very fast clearance in blood and a relatively high uptake ratio of tumor to blood (4.76) and tumor to muscle (1.82) at 60-minute postinjection. [ 18 F]III had a quick clearance in plasma, and its highest uptake ratio of tumor to muscle was 2.55 at 15-minute postinjection. These experimental results and experiences were valuable for the further exploration of novel radiotracers of quinazoline derivatives. Copyright © 2017 John Wiley & Sons, Ltd.

Evaluation of an [(18)F]AlF-NOTA Analog of Exendin-4 for Imaging of GLP-1 Receptor in Insulinoma.

PubMed

Kiesewetter, Dale O; Guo, Ning; Guo, Jinxia; Gao, Haokao; Zhu, Lei; Ma, Ying; Niu, Gang; Chen, Xiaoyuan

2012-01-01

The GLP-1 receptor plays an important role in glucose homeostasis and thus is a very important target for diabetes therapy. The receptor is also overexpressed in insulinoma, a tumor of pancreatic beta-cells. We previously evaluated two fluorine-18-labeled analogs of exendin-4 prepared by conjugation with [(18)F]FBEM (N-[2-(4-[(18)F]fluorobenzamide)ethyl]maleimide). Both compounds demonstrated good tumor uptake, but the synthesis of the radiotracers was time consuming. To overcome this challenge, we developed a NOTA analog and performed radiolabeling using aluminum [(18)F]fluoride complexation. Cys(40)-exendin-4 was conjugated with NOTA mono N-ethylmaleimide. [(18)F]AlF conjugation was conducted and the radiolabeled product purified by preparative HPLC. Dynamic and static PET imaging scans were conducted on nude mice with established INS-1 xenografts. Uptake of tumor and other major organs in static images was quantitated (%ID/g) and comparison with blocking studies was made. PET quantification was also compared with ex vivo biodistribution results. The radiosynthesis provided [(18)F]AlF-NOTA-MAL-cys(40)-exendin-4 in 23.6 ± 2.4 % radiochemical yield (uncorrected, n = 3) after HPLC; the process required about 55 min. The specific activity at time of injection ranged from 19.6 to 31.4 GBq (0.53-0.85 Ci)/µmol. Tumor uptake had reached its maximum (16.09 ± 1.18% ID/g, n = 4) by 5 min and remained nearly constant for the duration of the study. Kidney uptake continued to increase throughout the entire one hour time course. Pre-injection of exendin-4 caused a marked reduction in tissue uptake with the major exception of liver and kidneys, in which uptake was not affected. HPLC analysis of the radioactive components in extracts of the tumor and plasma showed primarily parent compound at 60 min post-injection, whereas extracts of kidney and urine contained exclusively one polar radioactive component. The radiotracer is prepared in a simple one-step procedure and obtained

18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

PubMed

Passamonti, Luca; Vázquez Rodríguez, Patricia; Hong, Young T; Allinson, Kieren S J; Williamson, David; Borchert, Robin J; Sami, Saber; Cope, Thomas E; Bevan-Jones, W Richard; Jones, P Simon; Arnold, Robert; Surendranathan, Ajenthan; Mak, Elijah; Su, Li; Fryer, Tim D; Aigbirhio, Franklin I; O'Brien, John T; Rowe, James B

2017-03-01

The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum