[en] The radiotracer 3-[¹⁸F]fluoro-5-(2-pyridinylethynyl)benzonitrile, or [¹⁸F]FPEB, is a promising PET imaging agent for the metabotropic glutamate subtype 5 receptor (mGluR5). In an effort to develop a routine production method of this radiotracer for use in clinical research we adapted its radiosynthesis to an automated chemistry module. In the meanwhile, we also developed a simplified “one-pot” method for the preparation of the nitrobenzonitrile radiolabeling precursor for [¹⁸F]FPEB and its reference standard to replace the existing multi-step synthetic approach. - Highlights: • Radiosynthesis of [¹⁸F]FPEB was performed in a Tracerlab FX-FN automated module. • The radiolabeling precursor was prepared from a “one-pot” Suzuki coupling method. • Total synthesis time from EOB to a final injectable dose was about 90 min. • The procedure was applied in the routine preparation of [¹⁸F]FPEB for human use

[en] We have synthesized a ¹⁸F-labeled androgen, [7α-¹⁸F]fluoro-17α-methyl-5α-dihydrotestosterone, in a no-carrier-added radiosynthesis by exchange of ¹⁸F- (tetrabutylammonium fluoride) with the 7β-tosyloxy of 17α-methyl-5α-dihydrotestosterone. The nonradioactive steroid binds with high affinity and specificity to the androgen receptor and binds poorly, if at all, to other steroid receptors and plasma sex hormone binding globulin. The 7α-¹⁸F-androgen concentrates markedly in the prostate of rats by an androgen receptor-dependent mechanism. It is likely that [7α-¹⁸F]fluoro-17α-methyl-5α-dihydrotestosterone will be an excellent positron emission tomography imaging agent for prostate cancer

[en] Positron emission tomography (PET) radioligands specific to α_7 nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α_7-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-["1"8F]-fluorodibenzo[b,d]thiophene 5,5-dioxide (["1"8F]DBT-10), in nonhuman primates. ["1"8F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with ["1"8F]DBT-10 PET, with measurement of ["1"8F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α_7-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of ["1"8F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V_T/f_P). ["1"8F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of ["1"8F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55 %. Uptake of ["1"8F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8 ± 3.4 %. No evidence for radiolabeled ["1"8F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V_T/f_P values were 193-376 ml/cm"3 across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose-dependent blockade of ["1"8F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V_N_D/f_P estimate of 20 ± 16 ml/cm"3. These results demonstrate suitable kinetic properties of ["1"8F]DBT-10 for in vivo quantification of α_7-nAChR binding in nonhuman primates. (orig.)

[en] The α_7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α_7 nAChRs PET radioligands, ["1"8F]ASEM 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-(["1"8F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and ["1"8F]DBT-10 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(["1"8F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of ["1"8F]ASEM in humans. PET scans with high specific activity ["1"8F]ASEM or ["1"8F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional ["1"8F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with ["1"8F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of ["1"8F]ASEM distribution volume (V_T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V_T was assessed. In the rhesus monkey brain ["1"8F]ASEM and ["1"8F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of ["1"8F]ASEM binding was observed, while administration of either nicotine or varenicline did not change ["1"8F]ASEM V_T. ["1"8F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of ["1"8F]ASEM V_T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V_T values ranging from 19.6 ± 2.5 mL/cm"3 in cerebellum to 25.9 ± 2.9 mL/cm"3 in thalamus. Test-retest variability of V_T was 11.7 ± 9.8%. These results confirm ["1"8F]ASEM as a suitable radiotracer for the imaging and quantification of α_7 nAChRs in humans. (orig.)

[en] Introduction: GR103545 is a potent and selective kappa-opioid receptor agonist. Previous studies in non-human primates demonstrated favorable properties of [¹¹C]GR103545 as a positron emission tomography tracer for in vivo imaging of cerebral kappa-opioid receptor. Nonetheless, advancement of [¹¹C]GR103545 to imaging studies in humans was hampered by difficulties of its multiple-step radiosynthesis, which produces a final product with low specific activity (SA), which in turn could induce undesirable physiological side effects resulting from the mass associated with an injected amount of radioactivity. We report herein an alternative radiosynthesis of [¹¹C]GR103545 with higher SA and radiochemical yields. Methods: The TRACERLab FXC automated synthesis module was used to carry out the two-step, one-pot procedure. In the first step, the desmethoxycarbonyl precursor was converted to the carbamic acid intermediate desmethyl-GR103545 via transcarboxylation with the zwitterionic carbamic complex, 1,8-diazabicyclo[5.4.0]undec-7-ene-carbon dioxide, in the presence and/or absence of cesium carbonate and tetrabutylammonium triflate. In the second step, the intermediate was radiolabeled at the carboxyl oxygen with [¹¹C]methyl trifluoromethanesulfonate to give [¹¹C]GR103545. Results: This novel synthesis produced [¹¹C]GR103545 with ≥90% chemical and radiochemical purities and an SA of 290.45±99.9 MBq/nmol at the end of synthesis (n=26). Injectable radioactivity was 1961±814 GBq/μmol with 43 min of average synthesis time from the end of beam. Conclusion: We have developed a practical one-pot method for the routine production of [¹¹C]GR103545 with reliably high SA and radiochemical yield, thus allowing the advancement of this radiotracer to imaging applications in humans.

[en] Introduction: ¹⁸F-Fluoropropyl-(+)-dihydrotetrabenazine (¹⁸F-FP-(+)-DTBZ) is a vesicular monoamine transporter type 2 (VMAT2) radiotracer for positron emission tomography (PET) imaging to quantify human β-cell mass. Renal cortex and spleen have been suggested as reference regions, however, little is known about ¹⁸F-FP-(+)-DTBZ binding in these regions including the fraction of radiometabolite. We compared the kinetics of ¹⁸F-FP-(+)-DTBZ and its inactive enantiomer ¹⁸F-FP-(−)-DTBZ in baboons, estimated the non-displaceable binding (V_ND) of the tracers, and used ex vivo studies to measure radiometabolite fractions. Methods: PET scans were conducted for up to 4 h with (+) and (−) enantiomers. Displacement experiments using unlabeled (+) and (−) enantiomers of FP-DTBZ and fluvoxamine (to evaluate sigma-1 receptor binding) were performed. SUV curves were used to calculate displacement values in the pancreas, renal cortex, and spleen. Distribution volumes (V_T) were computed, and three approaches for calculation of V_ND were compared: (1) ¹⁸F-FP-(+)-DTBZ reference V_T, (2) ¹⁸F-FP-(−)-DTBZ pancreatic V_T, and (3) a scaled ¹⁸F-FP-(+)-DTBZ reference V_T values. Ex vivo study was conducted to measure radiometabolite fraction in homogenized tissue samples from baboons at 90 min post-injection. Results: Spleen uptake was lowest for both tracers. Highest uptake was in the pancreas with ¹⁸F-FP-(+)-DTBZ and renal cortex with ¹⁸F-FP-(−)-DTBZ. Substantial displacement effect was observed only with unlabeled FP-(+)-DTBZ in the ¹⁸F-FP-(+)-DTBZ studies. Radiometabolite fraction was higher in the renal cortex than the spleen. Approaches (1) and (3) with spleen to estimate V_ND provided lowest inter-subject variability of BP_ND. Conclusions: V_T differences among organs and between enantiomers indicated that scaling of reference region values is needed for quantification of VMAT2 binding in the pancreas with ¹⁸F-FP-(+)-DTBZ. Since the kidney PET signal has greater partial volume averaging and more radiometabolites, the spleen was considered a more practical candidate for use as a scaled-reference region in the quantification of ¹⁸F-FP-(+)-DTBZ in the pancreas.

[en] Introduction: The aim of this study was to evaluate a newly reported positron emission tomography (PET) radioligand [¹¹C]MP-10, a potent and selective inhibitor of the central phosphodiesterase 10A enzyme (PDE10A) in vivo, using PET. Methods: A procedure was developed for labeling MP-10 with carbon-11. [¹¹C]MP-10 was evaluated in vivo both in the pig and baboon brain. Results: Alkylation of the corresponding desmethyl compound with [¹¹C]methyl iodide produced [¹¹C]MP-10 with good radiochemical yield and specific activity. PET studies in the pig showed that [¹¹C]MP-10 rapidly entered the brain reaching peak tissue concentration at 1-2 min postadministration, followed by washout from the tissue. Administration of a selective PDE10A inhibitor reduced the binding in all brain regions to the levels of the cerebellum, demonstrating the saturability and selectivity of [¹¹C]MP-10 binding. In the nonhuman primate, the brain tissue kinetics of [¹¹C]MP-10 were slower, reaching peak tissue concentrations at 30-60 min postadministration. In both species, the observed rank order of regional brain signal was striatum>diencephalon>cortical regions=cerebellum, consistent with the known distribution and concentration of PDE10A. [¹¹C]MP-10 brain kinetics were well described by a two-tissue compartment model, and estimates of total volume of distribution (V_T) were obtained. Blocking studies with unlabeled MP-10 revealed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential (BP_ND) as the outcome measure of specific binding. Quantification of [¹¹C]MP-10 binding using the simplified reference tissue model with cerebellar input function produced BP_ND estimates consistent with those obtained by the two-tissue compartment model. Conclusion: We demonstrated that [¹¹C]MP-10 possesses good characteristics for the in vivo quantification of the PDE10A in the brain by PET.

[en] [¹¹C]P943 is a novel, highly selective 5-HT_1B PET radioligand. The aim of this study was to determine the test-retest reliability of [¹¹C]P943 using two different modeling methods and to perform a power analysis with each quantification technique. Seven healthy volunteers underwent two PET scans on the same day. Regions of interest (ROIs) were the amygdala, hippocampus, pallidum, putamen, insula, frontal, anterior cingulate, parietal, temporal and occipital cortices, and cerebellum. Two multilinear radioligand quantification techniques were used to estimate binding potential: MA1, using arterial input function data, and the second version of the multilinear reference tissue model analysis (MRTM2), using the cerebellum as the reference region. Between-scan percent variability and intraclass correlation coefficients (ICC) were used to assess test-retest reliability. We also performed power analyses to determine the method that would allow the least number of subjects using within-subject or between-subject study designs. A voxel-wise ICC analysis for MRTM2 BP_ND was performed for the whole brain and all the ROIs studied. Mean percent variability between two scans across regions ranged between 0.4 % and 12.4 % for MA1 BP_ND, 0.5 % and 11.5 % for MA1 BP_P, 16.7 % and 28.3 % for MA1 BP_F, and between 0.2 % and 5.4 % for MRTM2 BP_ND. The power analyses showed a greater number of subjects were required using MA1 BP_F compared with other outcome measures for both within-subject and between-subject study designs. ICC values were the highest using MRTM2 BP_ND and the lowest with MA1 BP_F in ten ROIs. Small regions and regions with low binding had lower ICC values than large regions and regions with high binding. Reliable measures of 5-HT_1B receptor binding can be obtained using the novel PET radioligand [¹¹C]P943. Quantification of 5-HT_1B receptor binding with MRTM2 BP_ND and with MA1 BP_P provided the least variability and optimal power for within-subject and between-subject designs. (orig.)