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Introduction `The growth hormone secretagogue receptor 1a (GHS-R1a) is the orphan G-protein-coupled receptor, and its endogenous ligand is ghrelin. GHS-R1a contributes to regulation of glucose homeostasis, memory and learning, food addiction, and neuroprotection. Several PET tracers for GHS-R1a have been developed, but none have been reported to be clinically applicable to GHS-R1a imaging. In this study, we developed three new PET tracers for GHS-R1a: 18 F-labeled 6-(4-chlorophenyl)-3-((1-(2-fluoroethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3 H )-one ( 1 ), 11 C-labeled 6-(4-chlorophenyl)-3-((1-(2-methoxyethyl)piperidin-3-yl)methyl)-2-(o-tolyl)quinazolin-4(3 H )-one ( 2 ), and 11 C-labeled ( S )-(4-(1 H -indole-6-carbonyl)-3-methylpiperazin-1-yl)(4′-methoxy-[1,1′-biphenyl]-4-yl)methanone ( 3 ). Methods [ 18 F] 1 was synthesized by the 18 F-fluoroethylation; [ 11 C] 2 or [ 11 C] 3 was synthesized by the 11 C-methylation. Biodistribution studies and PET studies were conducted in mice. Results We successfully radiosynthesized [ 18 F] 1, [ 11 C] 2 , and [ 11 C] 3 with appropriate radioactivity for the animal study. In the ex vivo biodistribution study, 60 min following injection, the radioactivity level of [ 18 F] 1 was relatively high in the small intestine, that of [ 11 C] 2 was high in the liver, and that of [ 11 C] 3 was high in the pancreas. The radioactivity levels of the three PET tracers were relatively low in the brain. Under pretreatment with YIL781 (a selective and high affinity antagonist for GHS-R1a), the pancreas radioactivity level at 30 min following [ 11 C] 3 injection was significantly reduced to 55% of control, but the radioactivity in the brain was not changed. In the PET study under control conditions, high radioactivity levels in the liver and pancreas were observed following [ 11 C] 3 injection. With YIL781 pretreatment, the accumulated radioactivity in the pancreas 15–60 min after [ 11 C] 3 injection was significantly decreased to 78% of control. Conclusion [ 11 C] 3 exhibited relatively high uptake and in vivo specific binding to GHS-R1a in the mouse pancreas. [ 11 C] 3 may be a useful PET tracers for in vivo imaging of GHS-R1a in the pancreas. [ABSTRACT FROM AUTHOR]

Introduction A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [ 11 C]BU99008, a more potent PET probe for I 2 -imidazoline receptors (I 2 Rs) imaging, with a conventional SA (mean 76 GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for I 2 Rs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [ 11 C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of I 2 Rs. Methods [ 11 C]BU99008 was prepared by [ 11 C]methylation of N -desmethyl precursor with [ 11 C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats. Results [ 11 C]BU99008 with ultra-high SA in the range of 5400–16,600 GBq/μmol were successfully synthesized ( n = 7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [ 11 C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [ 11 C]BU99008 at 30 min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC 30–60 min ) in the hypothalamus of rats injected with [ 11 C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [ 11 C]BU99008 with ultra-high SA (86% of total binding) for I 2 R was higher than that of conventional SA (76% of total binding). Conclusion A PET study using [ 11 C]BU99008 with ultra-high SA would thus contribute to the detection of small changes in or small regions with I 2 R expression and hence may be useful in elucidating new functions of I 2 R. [ABSTRACT FROM AUTHOR]

Introduction [ 18 F]FEDAC ([ 18 F] 1 ) has potent binding affinity and selectivity for translocator protein (18 kDa, TSPO), and has been used to noninvasively visualize neuroinflammation, lung inflammation, acute liver damage, nonalcoholic fatty liver disease, and liver fibrosis. We had previously synthesized [ 18 F] 1 in two steps: (i) preparation of [ 18 F]fluoroethyl bromide and (ii) coupling of [ 18 F]fluoroethyl bromide with the appropriate precursor ( 2 ) for labeling. In this study, to clinically utilize [ 18 F] 1 as a PET radiopharmaceutical and to transfer the production technique of [ 18 F] 1 to other PET centers, we simplified its preparation by using a direct, one-step, tosyloxy-for-fluorine substitution. We also performed an acute toxicity study as a major non-clinical safety test, and determined radiometabolites using human liver microsomes. Methods [ 18 F] 1 was prepared via direct 18 F-fluorination by heating the corresponding tosylated derivative ( 3 ) with [ 18 F]fluoride as its Kryptofix 222 complex in dimethyl sulfoxide at 110 °C for 15 min, following by HPLC purification. Non-clinical safety tests were performed for the extended single-dose toxicity study in rats, and for the in vitro metabolite analysis with human liver microsomal incubation. Results High quality batches of [ 18 F] 1 , compatible with clinical applications, were obtained. At the end of irradiation, the decay-corrected radiochemical yield of [ 18 F] 1 using 1 and 5 mg of precursor based on [ 18 F]fluoride was 18.5 ± 7.9% ( n = 10) and 52.0 ± 5.8% ( n = 3), respectively. A single-dose of [ 18 F] 1 did not show toxicological effects for 14 days after the injection in male and female rats. In human liver microsomal incubations, [ 18 F] 1 was easily metabolized to [ 18 F]desbenzyl-FEDAC ([ 18 F] 10 ) by CYPs (4.2% of parent compound left 60 min after incubation). Conclusion We successfully synthesized clinical grade batches of [ 18 F] 1 and verified the absence of innocuity of this radiotracer. [ 18 F] 1 will be used to first-in-human studies in our facility. [ABSTRACT FROM AUTHOR]

Introduction The functions of I 2 -imidazoline receptors (I 2 Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I 2 R ligands have been developed, of which [ 11 C]FTIMD and [ 11 C]BU99008 were evaluated as PET I 2 R imaging ligands in monkeys, no human PET imaging study using an I 2 R-selective PET ligand has been conducted yet. Thus, we synthesized an 18 F-labeled I 2 R-selective ligand (BU99018 or FEBU, K i for I 2 Rs = 2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I 2 R PET imaging ligand. Methods [ 18 F]FEBU was synthesized by the reaction of its precursor and [ 18 F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively. Results [ 18 F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation ( n = 10) based on 18 F − ). The specific activity at end of synthesis (EOS) was 40–147 TBq/mmol ( n = 10). The radiochemical purity was > 99% at EOS and remained > 99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I 2 R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I 2 R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection. Conclusion [ 18 F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I 2 Rs in rats and mice. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: [11C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, (E)-ABP688 has a greater affinity towards mGlu5 receptors than (Z)-ABP688. Therefore, a high ratio of E-isomer is required when using [11C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect (Z)-[11C]ABP688 on the synthesis of [11C]ABP688 to be used for binding (E)-[11C]ABP688 in the brain. Methods: We synthesized and separated (E)- and (Z)-[11C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using (E)- and (Z)-[11C]ABP688. Results: (E)- and (Z)-[11C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the K d value of (E)-[11C]ABP688 (5.7 nmol/L) was higher than that of (Z)-[11C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of (E)-[11C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of (Z)-[11C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BP ND in the striatum and hippocampus was highly correlated (R 2 = 0.99) with the percentage of (E)-[11C]ABP688 of the total radioactivity of (E)- and (Z)-[11C]ABP688 in the injection. Conclusion: We demonstrated that including (Z)-[11C]ABP688 in the [11C]ABP688 injection can decrease BP ND in regions rich in mGlu5 receptors. Routine production of (E)-[11C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies. [Copyright &y& Elsevier]

Abstract: Introduction: Irinotecan is a semisynthetic derivative of camptothecin that exerts potent antitumor activity by inhibiting topoisomerase I. Despite much research into the complex pharmacokinetic profile and pharmacodynamic effects of irinotecan, unpredictable and severe side effects are still commonly observed. In this study, we synthesized [11C]irinotecan as a positron emission tomography (PET) probe, performed the metabolite analysis, and evaluated the biodistribution and kinetics of [11C]irinotecan using small animal PET. Methods: [11C]Irinotecan was synthesized by two routes using [11C]phosgene and [11C]carbon dioxide fixation. Metabolites in the plasma of mice following injection of [11C] irinotecan were investigated using a combination of column-switching high-performance liquid chromatography (HPLC) and on-line solid-phase extraction (SPE). Whole-body PET studies were conducted in wild-type mice and P-glycoprotein and breast cancer resistance protein (Pgp/Bcrp) knockout mice. Results: [11C]Irinotecan was successfully synthesized by the two abovementioned routes. Decay-corrected radiochemical yields based on [11C]carbon dioxide using [11C]phosgene and [11C]carbon dioxide fixation were 8.8±2.0% (n =8) and 16.9±2.9 % (n =5), respectively. Metabolite analysis of the plasma of mice following injection of [11C]irinotecan was successfully performed using the column-switching HPLC and on-line SPE combination resulting in greater than 87 % recovery of radioactivity from HPLC. In the PET study in mice, the radioactivity levels in the brain, liver, and small intestine were slightly increased by inhibition of the Pgp/Bcrp function for more than 30min after [11C]irinotecan injection. This result demonstrated that in vivo behavior of [11C] irinotecan and radioactive metabolites are influenced by the Pgp/Bcrp function. Conclusion: PET studies using [11C]irinotecan combined with metabolite analysis may be a useful tool for evaluating irinotecan pharmacokinetics and toxicity. [Copyright &y& Elsevier]