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Multiple tools are now available to determine the requirement for a biopsy to diagnose prostate cancer, and PET/CT with radiolabeled prostate-specific membrane antigen (PSMA)-targeting radiotracers has been recommended for detecting primary prostate cancer. Particularly, the radiotracer 18 F-PSMA-1007 was found to be more favorable for primary tumors compared with other PSMA-targeting radiotracers because of its low clearance via the urinary tract and better image resolution. Thus, we performed a systematic review and meta-analysis to more accurately evaluate the detection performance of 18 F-PSMA-1007 PET/CT in primary prostate cancer patients.An update on the databases of PubMed/MEDLINE, EMBASE, and Cochrane Library for comprehensive literature search was performed on September 30, 2021. The pooling detection rate was calculated on a per-patient basis. The pooling median of the SUV max was analyzed from the included studies. Furthermore, the positive predictive value of 18 F-PSMA-1007 PET/CT with pathologic lesions was analyzed using the criterion standard.Twelve studies (540 patients total) were included in the meta-analysis. The overall pooling detection rate of 18 F-PSMA-1007 per patient was 94%, and the pooling median of SUV max located at the intraprostate tumor was 16 (range, 3.7-77.7). The positive predictive value of 18 F-PSMA-1007 per lesion with histopathological validation was 0.90, detecting regional lymph node metastasis was 0.94, and detecting localized prostatic tumors was 0.84.In the current meta-analysis, we revealed the excellent performance of 18 F-PSMA-1007 to detect localized prostatic tumor lesions and regional lymph node metastasis. Moreover, the uptake of localized tumors in primary prostate cancer was nearly liver uptake and may be considered a suspicious malignancy if it was equal to or greater than the liver uptake.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals and also a contribution in relation to MRI-agents is included. Conclusion: Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

18F-FDG is the dominant radiotracer in oncology; however, it has limitations. Novel labeled fibroblast activation protein (FAP) radiotracers have been developed and published in several studies. Thus, this meta-analysis aimed to compare the detection rates (DRs) of FDG and FAP, based on previous studies from a systematic review.PubMed/MEDLINE and Cochrane library databases were used to perform a comprehensive and systematic search and are updated to April 30, 2022. The DR, relative risk, and the SUVmax were calculated between the FAP and FDG tracers. Finally, the sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve of FAP and FDG were analyzed using gold and reference standards.Thirty studies (1170 patients) were included in the meta-analysis. The relative risks of FAP DR for the primary tumor, recurrent tumor, lymph node metastasis, and distant metastasis were FDG 1.06- to 3.00-fold per patient and per lesion. For the primary tumor, FAP uptake was most intense in pancreatic cancer, followed by head and neck, cervical, colorectal, lung, gastric, and hepatocellular carcinoma, and was higher than FDG except for urological system cancer. The sensitivity (0.84-0.98), diagnostic odds ratio (19.36-358.47), and summary receiver operating characteristic curve (0.94-0.99) of FAP based on patient and lesion were better for primary tumors, LN metastasis, and distant metastasis than FDG.Fibroblast activation protein is an extremely potential radiotracer to replace most of the use of FDG in oncology. It is noteworthy that the FAP tracers for primary tumors had low specificity despite excellent sensitivity and had lower uptake than FDG in urological system cancer. In addition, the difference in detection between FAP and FDG for LN metastasis could not be certain in sarcoma.

The performance of FASTlab synthesizers and three-year operational experience at four hospitals in Taiwan were analyzed and summarized. [18F]FDG was daily produced with about 80% (EOB) of RCY and USP-compliant specification at four centers in Taiwan. The easiness to operate the cassette and high RCY of produced [18F]FDG are the main advantages for clinical use at the PET center of hospitals, but some underlying defects of the synthesizer or cassettes should be paid attention to and proactively scrutinized, such as cassette leakage and low tC18 trapping yield.

[Using this automated synthesis method, the RCY of the [Using the improved semipreparative HPLC purification, [

Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Main Body This selection of highlights provides commentary on 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first-in-human application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted. Hot topics cover the entire scope of EJNMMI Radiopharmacy and Chemistry, demonstrating the progress in the research field, and include new PET-labelling methods for 11C and 18F, the importance of choosing the proper chelator for a given radioactive metal ion, implications of total body PET on use of radiopharmaceuticals, legislation issues and radionuclide therapy including the emerging role of 161Tb.

One of the hallmarks of cancer is increased cell proliferation. Measurements of cell proliferation by estimation of DNA synthesis with several radiolabeled nucleosides have been tested to assess tumor growth. Deoxycytidine can be phosphorylated by deoxycytidine kinase (dCK) and is incorporated into DNA. This study evaluated a radiofluorinated deoxycytidine analog, 5-[18F]fluoro-2′-deoxycytidine ([18F]FdCyd), as a proliferation probe and compared it with 5-[18F]fluoro-2′-deoxyuridine ([18F]FdUrd), 3′-deoxy-3'-[18F]fluorothymidine ([18F]FLT), and [18F]fluorodeoxyglucose ([18F]FDG) in a tumor-bearing mouse model. [18F]FdCyd was synthesized from two precursors by direct electrophilic substitution. The serum stability and partition coefficient of [18F]FdCyd were evaluated in vitro. Positron emission topography (PET) imaging of Lewis lung carcinoma (LLC)-bearing mice with [18F]FdCyd, [18F]FdUrd, [18F]FLT, and [18F]FDG were evaluated. [18F]FdCyd was stable in mouse serum and normal saline for up to 4 h. With all radiotracers except [18F]FLT, PET can clearly delineate the tumor lesion. [18F]FdCyd and [18F]FdUrd showed high accumulation in the liver and kidney. The SUV and tumor-to-muscle (T/M) ratios derived from PET imaging of the radiotracers were [18F]FDG > [18F]FdCyd > [18F]FdUrd > [18F]FLT. Selective retention in tumors with a favorable tumor/muscle ratio makes [18F]FdCyd a protential candidate for further investigation as a proliferation imaging agent.

(4S)-4-(3-18F-Fluoropropyl)-l-glutamate (FSPG) positron emission tomography (PET) reflects system xC− transporter (xCT) expression. FSPG PET has been used to detect brain, lung, breast and liver cancer with only modest success. There is no report on the use of FSPG PET in pancreatic ductal adenocarcinoma (PDAC), presumably because of normal xCT expression in the pancreas. Nonetheless, the tissue-specific expression of xCT in the pancreas suggests that FSPG PET may be ideal for identifying metastasized PDAC. The performance of FSPG in detecting PDAC metastases was compared with that of 18F-fluorodeoxyglucose (FDG) in small-animal PET studies in seven PDAC tumour-bearing mice and in prospective PET/computed tomography (CT) studies in 23 patients with tissue-confirmed PDAC of stage III or stage IV. All PET/CT results were correlated with the results of histopathology or contrast-enhanced CT (ceCT) performed 3 and 6 months later. In the rodent model, FSPG PET consistently found more PDAC metastases earlier than FDG PET. FSPG PET showed a trend for a higher sensitivity, specificity and diagnostic accuracy than FDG PET in detecting PDAC metastases in a patient-based analysis: 95.0%, 100.0% and 95.7%, and 90.0%, 66.7% and 90.0%, respectively. In a lesion-based analysis, FSPG PET identified significantly more PDAC metastases, especially in the liver, than FDG PET (109 vs. 95; P = 0.0001, 95% CI 4.9–14.6). The tumour-to-background ratios for FSPG and FDG uptake on positive scans were similar (FSPG 4.2 ± 4.3, FDG 3.6 ± 3.0; P = 0.44, 95% CI −1.11 to 0.48), despite a lower tumour maximum standardized uptake value in FSPG-avid lesions (FSPG 4.2 + 2.3, FDG 7.7 + 5.7; P = 0.002, 95% CI 0.70–4.10). Because of the lower physiological activity of FSPG in the liver, FSPG PET images of the liver are more easy to interpret than FDG PET images, and therefore the use of FSPG improves the detection of liver metastasis. FSPG PET is superior to FDG PET in detecting metastasized PDAC, especially in the liver.

Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. Results This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals and also a contribution in relation to MRI-agents is included. Conclusion Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

Additional file 1. Table 1: List of reagents used in the automated procedure.

(4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is a positron emission tomography (PET) imaging agent for measuring the system xC− transporter activity. It has been used for the detection of various cancers and metastasis in clinical trials. [18F]FSPG is also a promising diagnostic tool for evaluation of multiple sclerosis, drug resistance in chemotherapy, inflammatory brain diseases, and infectious lesions. Due to the very short half-life (110 min) of 18F nuclide, [18F]FSPG needs to be produced on a daily basis; therefore, fast and efficient synthesis and analytical methods for quality control must be established to assure the quality and safety of [18F]FSPG for clinical use. To manufacture cGMP-compliant [18F]FSPG, all four nonradioactive stereoisomers of FSPG were prepared as reference standards for analysis. (2S,4S)-1 and (2R,4R)-1 were synthesized starting from protected L- and D-glutamate derivatives in three steps, whereas (2S,4R)-1 and (2R,4S)-1 were prepared in three steps from protected (S)- and (R)-pyroglutamates. A chiral HPLC method for simultaneous determination of four FSPG stereoisomers was developed by using a 3-cm Chirex 3126 column and a MeCN/CuSO4(aq) mobile phase. In this method, (2R,4S)-1, (2S,4S)-1, (2R,4R)-1, and (2S,4R)-1 were eluted in sequence with sufficient resolution in less than 25 min without derivatization. Scale-up synthesis of intermediates for the production of [18F]FSPG in high optical purity was achieved via stereo-selective synthesis or resolution by recrystallization. The enantiomeric excess of intermediates was determined by HPLC using a Chiralcel OD column and monitored at 220 nm. The nonradioactive precursor with >98% ee can be readily distributed to other facilities for the production of [18F]FSPG. Based on the above accomplishments, cGMP-compliant [18F]FSPG met the acceptance criteria in specifications and was successfully manufactured for human use. It has been routinely prepared and used in several pancreatic ductal adenocarcinoma metastasis-related clinical trials.

Introduction [ 18 F]Fluoromethylcholine ([ 18 F]FCH) is a potent tumors imaging agent. In order to fulfill the demand of pre-clinical and clinical studies, we have developed an automated high yield one-pot synthesis of this potent tumors imaging agent. Methods [ 18 F]FCH was synthesized using a modified TRACERlab Fx FN module. Briefly, dibromomethane (10% in CH 3 CN) was fluorinated with K[ 18 F]/K 2.2.2 in a glassy carbon reaction vessel at 120° C for about 5 min to generate [ 18 F]fluorobromomethane ([ 18 F]FBM). The resulting [ 18 F]FBM was then bubbling (He, 700 mL/min) through four Sep-Pak® Silica Plus Long cartridges to react with dimethylaminoethanol (10% DMAE in 0.3 mL DMSO) which was pre-loaded on Sep-Pak® C 18 Plus Short cartridge. The [ 18 F]FCH was purified by solid-phase extraction (SPE) using one Sep-Pak® C 18 Plus Short and one Sep-Pak® CM Plus Short in series. The quality of [ 18 F]FCH synthesized by this method was verified by HPLC and TLC as compared to authentic sample. Results Using this improved one-pot method, the RCY of [ 18 F]FCH was 18.8 ± 2.1% (EOB, n = 27) in a synthesis time of 49 ± 5 min from EOB. The radiochemical purity of [ 18 F]FCH was greater than 90% and the residual DMAE concentration in the final product was less than 10 ppm. Conclusions This optimized method could fulfill the demand of [ 18 F]FCH for both pre-clinical and clinical studies, especially for nearby study sites without a cyclotron.

Automated three-step two-pot production of no-carrier-added (NCA) [

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/μmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 μSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) μSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.

Performing quantitative small-animal PET with an arterial input function has been considered technically challenging. Here, we introduce a catheterization procedure that keeps a rat physiologically stable for 1.5 mo. We demonstrated the feasibility of quantitative small-animal 18F-FDG PET in rats by performing it repeatedly to monitor the time course of variations in the cerebral metabolic rate of glucose (CMRglc). Methods: Aseptic surgery was performed on 2 rats. Each rat underwent catheterization of the right femoral artery and left femoral vein. The catheters were sealed with microinjection ports and then implanted subcutaneously. Over the next 3 wk, each rat underwent 18F-FDG quantitative small-animal PET 6 times. The CMRglc of each brain region was calculated using a 3-compartment model and an operational equation that included a k*4. Results: On 6 mornings, we completed 12 18F-FDG quantitative small-animal PET studies on 2 rats. The rats grew steadily before and after the 6 quantitative small-animal PET studies. The CMRglc of the conscious brain (e.g., right parietal region, 99.6 ± 10.2 μmol/100 g/min; n = 6) was comparable to that for 14C-deoxyglucose autoradiographic methods. Conclusion: Maintaining good blood patency in catheterized rats is not difficult. Longitudinal quantitative small-animal PET imaging with an arterial input function can be performed routinely.

Automated three-step two-pot production of no-carrier-added (NCA) [18F]FDOPA was first implemented in the iPHASE FlexLab module. Decay-corrected radiochemical yield (RCY) of [18F]FDOPA synthesized by this method was 10~14% (n = 7) with a synthesis time of ~110 min [18F]FDOPA was obtained in > 95% of radiochemical purity with a molar activity of ~431 GBq/μmol. With the method successfully implementing on the commercial FlexLab module and its built-in step-by-step activity monitoring, further processes optimization would be achieved.

A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4′-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (Ki = 0.11–1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [18F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [18F]7a exhibited the highest uptake in the midbrain, whereas [18F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [18F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [18F]7a is a promising lead for the further development of novel [18F]-labeled PET imaging agents for SERT binding sites in the brain.

One of the hallmarks of cancer is increased cell proliferation. Measurements of cell proliferation by estimation of DNA synthesis with several radiolabeled nucleosides have been tested to assess tumor growth. Deoxycytidine can be phosphorylated by deoxycytidine kinase (dCK) and is incorporated into DNA. This study evaluated a radiofluorinated deoxycytidine analog, 5-[

(4S)-4-(3-The performance of FSPG in detecting PDAC metastases was compared with that ofIn the rodent model, FSPG PET consistently found more PDAC metastases earlier than FDG PET. FSPG PET showed a trend for a higher sensitivity, specificity and diagnostic accuracy than FDG PET in detecting PDAC metastases in a patient-based analysis: 95.0%, 100.0% and 95.7%, and 90.0%, 66.7% and 90.0%, respectively. In a lesion-based analysis, FSPG PET identified significantly more PDAC metastases, especially in the liver, than FDG PET (109 vs. 95; P = 0.0001, 95% CI 4.9-14.6). The tumour-to-background ratios for FSPG and FDG uptake on positive scans were similar (FSPG 4.2 ± 4.3, FDG 3.6 ± 3.0; P = 0.44, 95% CI -1.11 to 0.48), despite a lower tumour maximum standardized uptake value in FSPG-avid lesions (FSPG 4.2 + 2.3, FDG 7.7 + 5.7; P = 0.002, 95% CI 0.70-4.10). Because of the lower physiological activity of FSPG in the liver, FSPG PET images of the liver are more easy to interpret than FDG PET images, and therefore the use of FSPG improves the detection of liver metastasis.FSPG PET is superior to FDG PET in detecting metastasized PDAC, especially in the liver.

PET imaging with (18)F-FDOPA has been successfully applied in the diagnosis and surveillance of neuroblastoma (NB) by targeting the overexpression of aromatic L-amino acid decarboxylase. This study aims to assess the impact of residual (18)F-fluoride on (18)F-FDOPA PET in NB and to implement a method to maintain low (18)F-fluoride content in future studies.Automatic synthesis of (18)F-FDOPA was based on the electrophilic method using TRACERlab FXFE module. Radio-TLC was employed to determine residual (18)F-fluoride levels. We analyzed the impact of residual (18)F-fluoride on the images of 35 patients undergoing (18)F-FDOPA PET at initial diagnosis and/or follow-ups of NB.In 35 batches of (18)F-FDOPA products from 9/28/2010 to 07/27/2011, the mean residual (18)F-fluoride level was 4.4 % (range 0.2-19.1 %). Residual (18)F-fluoride level ≥4.0 % was associated with dense uptake in the growth plates, skull, and pelvis on PET scans, which may interfere with the interpretation of (18)F-FDOPA imaging in NB. By applying stringent restraints in (18)F-FDOPA production, including regular renewal of reagents, exclusive use of NH4OH, and timely replacement of HPLC column, the incidence of (18)F-FDOPA batches with residual (18)F-fluoride level ≥4.0 % was reduced from 33 to 4 % (P 0.0001) during 7/30/2011-4/29/2013.By monitoring residual (18)F-fluoride levels and keeping stringent restraint procedures, low (18)F-fluoride content was achieved in most batches of (18)F-FDOPA, which diminished false-positive skeletal uptake. An appropriate upper limit of (18)F-fluoride level is suggested to be included in the criteria of routine quality control of (18)F-FDOPA productions.

[[Using this improved one-pot method, the RCY of [This optimized method could fulfill the demand of [

The GE FASTlab radiosynthesis module is routinely used for the production of [(18)F]FDG, utilizing the commercially available phosphate cassettes. Because of the observation of a white precipitate in the product vial before the product expiry time, we re-examined the quality of the produced [(18)F]FDG solution.Phosphate buffered [(18)F]FDG solution was synthesized on the FASTlab and analyzed at both National Taiwan University Hospital (NTUH) of Taiwan and Royal Brisbane and Women's Hospital (RBWH) of Australia. In addition to the standard product quality control (QC), the concentration of aluminum (Al(3+)) as probable cause of the precipitations in the [(18)F]FDG solution was analyzed by inductively coupled plasma mass spectrometry (ICP-MS at RBWH) and inductively coupled plasma optical emission spectrometry (ICP-OES at NTUH), and using three semi-quantitative methods at NTUH, Advantec(®) Alumi Check Test Strip, Quantofix(®) Aluminum Test Strip and MColortest™ Aluminum Test kit.The precipitates were observed in the [(18)F]FDG solution within 24 (NTUH) and 6 (RBWH) hours after the end of synthesis in 38-100 % of the batches, dependent on the batch of the FASTlab cassettes. Addition of metal-free HCl(aq) to aliquots of [(18)F]FDG containing precipitate, followed by ICP-MS analysis revealed Al(3+) concentrations of 70-80 ppm. Al(3+) concentrations of 10-12 ppm were detected in [(18)F]FDG batches that did not show any precipitation. In contrast, less than 5 ppm of the residual Al(3+) was detected by semi-quantitative methods in all batches.The US (USP), British (BP), European (EP) and Japanese (JP) pharmacopeias demand that [(18)F]FDG for injection should be clear and particulate free within the given shelf-life/expiration time. To avoid Al-phosphate precipitation within the product expiry time, FASTlab citrate cassettes, rather than phosphate cassettes, should be used for [(18)F]FDG production. Although testing for Al(3+) is not listed in the [(18)F]FDG monographs of the USP, BP and EP, residual Al(3+) levels should be considered in the interests of patient safety.

The aim of this study was to assess the feasibility of using 4-[(18)F]-ADAM as a brain SERT imaging agent in humans.Enrolled in the study were 19 healthy Taiwanese subjects (11 men, 8 women; age 33 ± 9 years). The PET data were semiquantitatively analyzed and expressed as specific uptake ratios (SUR) and distribution volume ratios (DVR) using the software package PMOD. The SUR and DVR of 4-[(18)F]-ADAM in the raphe nucleus (RN), midbrain (MB), thalamus (TH), striatum (STR) and prefrontal cortex (PFC) were determined using the cerebellum (CB) as the reference region.4-[(18)F]-ADAM bound to known SERT-rich regions in human brain. The order of the regional brain uptake was MB (RN)THSTRPFCCB. The DVR (n = 4, t* = 60 min) in the RN, TH, STR and PFC were 3.00 ± 0.50, 2.25 ± 0.45, 2.05 ± 0.31 and 1.40 ± 0.13, respectively. The optimal time for imaging brain SERT with 4-[(18)F]-ADAM was 120-140 min after injection. At the optimal imaging time, the SURs (n = 15) in the MB, TH, STR, and PFC were 2.25 ± 0.20, 2.28 ± 0.20, 2.12 ± 0.18 and 1.47 ± 0.14, respectively. There were no significant differences in SERT availability between men and women (p 0.05).The results of this study showed that 4-[(18)F]-ADAM was safe for human studies and its distribution in human brain appeared to correlate well with the known distribution of SERT in the human brain. In addition, it had high specific binding and a reasonable optimal time for imaging brain SERT in humans. Thus, 4-[(18)F]-ADAM may be feasible for assessing the status of brain SERT in humans.

4-[18F]F-ADAM (1a), 2-[18F]F-ADAM (2a), N-Desmethyl-4-[18F]F-ADAM (3a) and [18F]F-AFM (4a ) were synthesized in 1.7, 3.9, 2.9 and 0.6% yield (EOS), respectively, in a synthesis time of ∼120 min from EOB. PET studies in rats showed that the maximum specific uptake ratios of 1a, 2a, 3a and 4a in midbrain were 3.86, 0.73, 0.35 and 2.23, respectively. Thus, in terms of radiochemical yield, specific binding and in vivo stability, 4-[18F]F-ADAM may be the most appropriate SERT imaging agent for human studies.

3, 4-Methylenedioxymethamphetamine (MDMA, "ecstasy") has toxic effects on serotonergic neurons in the brain. Our aim was to determine whether N,N-dimethyl-2-(2-amino-4-[(18)F]-fluorophenylthio) benzylamine (4-[(18)F]-ADAM; a serotonin transporter imaging agent) and micropositron emission tomography (micro-PET) can be used to examine in vivo the effect of fluoxetine on MDMA-induced loss of serotonin transporters in rat brain. Male Sprague-Dawley rats were injected with fluoxetine [1 dose, 5 mg/kg, subcutaneously (s.c.)] followed by MDMA (twice a day for 4 consecutive days, 10 mg/kg, s.c.). Micro-PET with 4-[(18)F]-ADAM was performed on days 4, 10, 17, 24, and 31. In addition, the time course of occupancy by fluoxetine at 4-[(18)F]-ADAM sites was measured. Specific 4-[(18)F]-ADAM uptake ratios (SURs) were calculated from the micro-PET imaging data for various brain regions. Immunohistochemistry was performed 7 days after the last micro-PET scan. From day 4 to day 31, SURs were markedly decreased (by approximately 55-75% compared to control values) in all brain regions in MDMA-treated rats. The effect of MDMA was markedly attenuated (approximately 30-50%) by fluoxetine. The fluoxetine-induced decrease in uptake in different brain regions was 40-75% at 90-min postinjection, and this decrease returned to baseline values in most brain regions by day 31. The distribution and intensity of serotonin transporter (SERT) immunostaining in the brain paralleled the PET imaging results, suggesting that a single dose of fluoxetine provides long-lasting protection against MDMA-induced loss of SERT and that such neuroprotection is detectable in vivo by 4-[(18)F]-ADAM micro-PET.

4-[(18)F]-ADAM is a potent serotonin transport imaging agent. We studied its toxicity in rats and radiation dosimetry in monkeys before human studies are undertaken.Single and multiple-dosage toxicity studies were conducted in Sprague-Dawley rats. Male and female rats were injected intravenously with 4-F-ADAM as a single dose of 1,023.7 microg/kg (1,000 times the human dose) or as five consecutive daily doses of 102.37 microg/kg (100 times the human dose). PET/CT scans were performed in seven Formosa Rock monkeys (four males and three females) using a Siemens Biograph scanner. After injection of 4-[(18)F]-ADAM (182+/-8 MBq), a low dose CT scan and a series of eight whole-body PET scans were performed. Whole-body images were acquired in 3-D mode. Time-activity data of source organs were used to calculate the residence times and estimate the absorbed radiation dose using OLINDA/EXM software.In the rats neither the single dose nor the five daily doses of 4-F-ADAM produced overt adverse effects clinically. In the monkeys the radiation doses received by most organs ranged between 7.1 and 35.7 microGy/MBq, and the urinary bladder was considered to be the critical organ. The effective doses extrapolated to male and female adult humans were 17.4 and 21.8 microSv/MBq, respectively.Toxicity studies in Sprague-Dawley rats and radiation dosimetry studies in Formosa Rock monkeys suggested that 4-[(18)F]-ADAM is safe for use in human PET imaging studies.

An improved synthesis of N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM, 2) as a potent serotonin transporter (SERT) imaging agent is described. Molecular orbital (MO) calculation predicts that N,N-dimethyl-2-(2-nitro-4-trimethylammoniumtrifluoromethanesulfonylphenylthio)benzamide (8) is probably a better precursor than N,N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine (1) for preparing 2. Radioligand 2 was synthesized by the reaction of either precursor 1 or precursor 8 with K[(18)F]/K(2.2.2) at 120 degrees C followed by reduction with BH(3) at 80 degrees C. The radiochemical yield (EOB) of 2 synthesized from precursor 1 and 8 was 5.7+/-2.4% (n=6) and 14.8+/-4.0% (n=5), respectively, in a synthesis time of 120 min from EOB. The specific activity of 2 was 3 Ci/micromol or 111 GBq/micromol (EOB). Thus, this new synthetic method has significantly improved the radiochemical yield of 4-[(18)F]-ADAM and makes this radioligand more accessible to PET Centers without a cyclotron.

N,N -dimethyl-2-(2-amino-4-[ 18 F]fluorophenylthio)benzylamine (4-[ 18 F]-ADAM, 3 ) is a potent serotonin transporter (SERT) imaging agent. In order to fulfill the demand of pre-clinical studies, we have developed an automated synthesis unit to synthesize this radioligand. The 4-[ 18 F]-ADAM was synthesized using TracerLab FN and FE modules and a modified module control program (TracerLab-Fx). The synthesis sequences were similar to that of the manual synthesis, i.e. nucleophilic fluorination of N,N -dimethyl-2-(2,4-dinitrophenylthio)benzylamine ( 1 ) with K[ 18 F]/K 2.2.2 followed by reduction with NaBH 4 /Cu(OAc) 2 and purifications with high-performance liquid chromatography (HPLC) and solid phase extraction. The radiochemical yield of 3 was 1.5±0.3% ( n =13, EOS). The synthesis time was 120 min and the specific activity was 1.75±0.77 Ci/μmol ( n =13, EOS). The 4-[ 18 F]-ADAM synthesized by this module was stable over 4 h at room temperature and is suitable for imaging SERT in humans.

Background [18 F]AFM is a potent and promising PET imaging agent for the serotonin transporter. We carried out an acute toxicity study in rats and radiation dosimetry in monkeys before the translation of the tracer to humans. Methods Single- and multiple-dose toxicity studies were conducted in Sprague–Dawley rats. Male and female rats were injected intravenously with AFM tartrate as a single dose of 98.7 or 987 μg/kg (592 or 5,920 μg/m2, 100× or 1,000× the proposed human dose of 8 μg, respectively) on day 1 or as five consecutive daily doses of 98.7 μg/kg/day (592 μg /m2/day, 100× human dose, total dose 493.5 μg/kg). PET/CT scans were performed in four Formosan rock monkeys (two males and two females, each monkey scanned twice) using a Siemens BIOGRAPH scanner. After injection of [18 F]AFM (88.5 ± 20.3 MBq), a low-dose CT scan and a series of eight whole-body PET scans in 3-D mode were performed. Time-activity data of source organs were used to calculate the residence times and estimate the absorbed radiation dose using the OLINDA/EXM software. Results In the rats, neither the single dose nor the five daily doses of AFM tartrate produced overt adverse effects clinically. In the monkeys, the radiation doses received by most organs ranged between 8.3 and 39.1 μGy/MBq. The osteogenic cells, red marrow, and lungs received the highest doses of 39.1, 35.4, and 35.1 μGy/MBq, respectively. The effective doses extrapolated to male and female adult humans were 18.0 and 18.3 μSv/MBq, respectively. Conclusions Toxicity studies in Sprague–Dawley rats and radiation dosimetry studies in Formosa rock monkeys suggest that [18 F]AFM is safe for use in human PET imaging studies. Trial registration IACUC-12-200.

In the early 1990s, 9-(+)-11C-dihydrotetrabenazine (9-(+)-11C-DTBZ) was shown to be a useful positron emission tomography (PET) imaging agent for various neurodegenerative disorders. Here, we described the radiosynthesis and evaluation of the 9-(+)-11C-DTBZ analog, 10-(+)-11C-DTBZ, as a vesicular monoamine transporter 2 (VMAT2) imaging agent and compare it with 9-(+)-11C-DTBZ. 10-(+)-11C-DTBZ was obtained by 11C-MeI methylation with its 10 hydroxy precursor in the presence of 5 M NaOH. It had a slightly better average radiochemical yield of 35.3 ± 3.6% (decay-corrected to end of synthesis (EOS)) than did 9-(+)-11C-DTBZ (30.5 ± 2.3%). MicroPET studies showed that 10-(+)-11C-DTBZ had a striatum-to-cerebellum ratio of 3.74 ± 0.21 at 40 min post-injection, while the ratio of 9-(+)-11C-DTBZ was 2.50 ± 0.33. This indicated that 10-(+)-11C-DTBZ has a higher specific uptake in VMAT2-rich brain regions, and 10-(+)-11C-DTBZ may be a potential VMAT2 radioligand. Our experiment is the first study of 10-(+)-11C-DTBZ to include dynamic brain distribution in rat brains.

[(18) F]AFM is a potent and promising PET imaging agent for the serotonin transporter. We carried out an acute toxicity study in rats and radiation dosimetry in monkeys before the translation of the tracer to humans.Single- and multiple-dose toxicity studies were conducted in Sprague-Dawley rats. Male and female rats were injected intravenously with AFM tartrate as a single dose of 98.7 or 987 μg/kg (592 or 5,920 μg/m(2), 100× or 1,000× the proposed human dose of 8 μg, respectively) on day 1 or as five consecutive daily doses of 98.7 μg/kg/day (592 μg /m(2)/day, 100× human dose, total dose 493.5 μg/kg). PET/CT scans were performed in four Formosan rock monkeys (two males and two females, each monkey scanned twice) using a Siemens BIOGRAPH scanner. After injection of [(18) F]AFM (88.5 ± 20.3 MBq), a low-dose CT scan and a series of eight whole-body PET scans in 3-D mode were performed. Time-activity data of source organs were used to calculate the residence times and estimate the absorbed radiation dose using the OLINDA/EXM software.In the rats, neither the single dose nor the five daily doses of AFM tartrate produced overt adverse effects clinically. In the monkeys, the radiation doses received by most organs ranged between 8.3 and 39.1 μGy/MBq. The osteogenic cells, red marrow, and lungs received the highest doses of 39.1, 35.4, and 35.1 μGy/MBq, respectively. The effective doses extrapolated to male and female adult humans were 18.0 and 18.3 μSv/MBq, respectively.Toxicity studies in Sprague-Dawley rats and radiation dosimetry studies in Formosa rock monkeys suggest that [(18) F]AFM is safe for use in human PET imaging studies.IACUC-12-200.