会議発表用資料 Development of [11C]CMDC for PET imaging of metabotropic glutamate receptor 2 in the rat brain

Kumata, Katsushi  ,  Zhang, Yiding  ,  Hatori, Akiko  ,  Yamasaki, Tomoteru  ,  Ohkubo, Takayuki  ,  Kurihara, Yusuke  ,  Fujinaga, Masayuki  ,  Xie, Lin  ,  Kawamura, Kazunori  ,  Ming-Rong, Zhang

2017-05-15
内容記述
Objectives: Metabotropic glutamate receptor 2 (mGluR2) is predominantly presynaptic and modulates the release of glutamate and GABA through feedback inhibition. In the brain, mGluR2 is abundant mainly in the cerebral cortex, caudate-putamen and nucleus accumbens, hippocampus and amygdala. It has been reported that mGluR2 is involved in numerous brain functions and is a promising target for the treatment of brain disorders such as anxiety, schizophrenia and addiction. The aim of this study was to develop a new PET tracer for imaging mGluR2 in living brains. We established 1-(cyclopropylmethyl)-4-[4-(4-methoxyphenyl)-1-piperidyl]-2-oxo-pyridine-3-carbonitrile (CMDC) as a targeted compound for this purpose. CMDC is considered as a potent, selective, and systemically active PAM of mGluR2 and showed potent PAM activity (EC50: 98 nM) for human mGluR2 in vitro. Therefore, we synthesized and evaluated [11C]CMDC as a PET tracer for mGluR2 in the rat brain. Here, we report the chemical synthesis of unlabeled CMDC and a novel desmethyl phenol precursor, radiosynthesis and characterizations of [11C]CMDC binding for mGluR2 in the mouse and rat brain tissues.Methods: [11C]CMDC was synthesized by the reaction of desmethy precursor with [11C]methyl iodide. The distribution of radioactivity in mice was measured at different time points after injection of [11C] CMDC. In vitro autoradiography, PET scans and metabolite analysis were performed on rat brains.Results: [11C]CMDC (2.2 ± 0.9 GBq; n = 20) was obtained from [11C]CO2 of 14.0–17.8 GBq with >98% radiochemical purity and 86–150 GBq/μmol specific activity. In vitro autoradiography showed that the distribution pattern of [11C]CMDC radioactivity was heterogeneous with high expression in the cerebral cortex, striatum, hippocampus and granular layer of the cerebellum. This distribution pattern was consistent with the distribution of mGluR2 in the rat brain. Co-incubation with unlabeled CMDC decreased radioactivity in brain sections to 41–59% of control (total) radioactivity. In the mouse brain, the initial uptake of [11C]CMDC was 0.96 % ID/g at 1 min. Radioactivity washout from the brain was rapid with 0.56 % ID/g at 60 min (1 min/60 min ratio = 1.71). PET summation images of rat brains showed that the site of highest radioactivity was seen in the cerebral cortex, followed by the cerebellum, striatum and hippocampus. Radioactivity in brain tissues increased rapidly after the injection, peaked at 1.5 min with a SUV of 0.57 in the cerebral cortex, and gradually decreased thereafter. Metabolite analysis suggested that a limited amount (~25% at 30 min) of radiolabeled metabolite entered brain from plasma. Further PET scan did not show significant uptake of radioactivity in the brains between PgP/Bcrp KO and wild-type mice.Conclusion: In this study, we have developed and synthesized [11C]CMDC as a new PET tracer with good radiochemical yield, high radiochemical purity and high specific activity. While [11C]CMDC has limited potential as a PET tracer for brain mGluR2, it can be used to develop new radiotracers with improved behaviors.
22nd International symposium on radiopharmaceutical science (ISRS)

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