Synthesis and evaluation of 1-(cyclopropylmethyl)-4-(4-[¹¹C]methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([¹¹C]CMDC) for PET imaging of metabotropic glutamate receptor 2 in the rat brain

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• 作者：Yufei Ma^a ; ^b ; ¹ ; Katsushi Kumata^a ; ¹ ; Joji Yui^a ; Yiding Zhang^a ; Tomoteru Yamasaki^a ; Akiko Hatori^a ; Masayuki Fujinaga^a ; Nobuki Nengaki^a ; Lin Xie^a ; Hui Wang^b ; Ming-Rong Zhang^a ; ^{zhang.ming-rong@qst.go.jp}
• 关键词：[11C]CMDC ; In vitro autoradiography ; Metabotropic glutamate receptor 2 ; Positron emission tomography ; Radiotracer ; Schizophrenia
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：1014-1021
• 全文大小：1039 K
• 卷排序：25

文摘

Brain metabotropic glutamate receptor 2 (mGluR2) has been proposed as a therapeutic target for the treatment of schizophrenia-like symptoms arising from increased glutamate transmission in the forebrain. However, there does not exist a reliable tool for the study of mGluR2 in human neuroimaging. The purpose of this study was to radiosynthesize 1-(cyclopropylmethyl)-4-(4-[11C]methoxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([11C]CMDC) and evaluate its potential as a positron emission tomography (PET) radiotracer for imaging mGluR2 in the rat brain. CMDC, a positive allosteric modulator of mGluR2, showed potent functional activity (EC50: 98 nM) for human mGluR2 in vitro. [11C]CMDC was synthesized by O-[11C]methylation of 1-(cyclopropylmethyl)-4-(4-hydroxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) with [11C]methyl iodide. [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 at the end of synthesis. In vitro autoradiography indicated that [11C]CMDC binding was expressed (>50% of total binding) in mGluR2-rich brain regions including the cerebral cortex, striatum and hippocampus. However, small-animal PET showed low in vivo specific binding of [11C]CMDC in the rat brain. While [11C]CMDC has limited potential as a PET tracer for brain mGluR2, it can be used to develop new radiotracers with improved behaviors.