title: 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.
abstract: 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: 98nM) 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±0.9GBq; n=20) was obtained from [11C]CO2of 14.0-17.8GBq with >98% radiochemical purity and 86-150GBq/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.
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Nuclear Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Yiding
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Nuclear Medicine, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200092, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan. Electronic address: zhang.ming-rong@qst.go.jp.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000032:analysis*; D014018:Tissue Distribution
chemical_list: C000621636:1-(cyclopropylmethyl)-4-(4-((11)C)methoxyphenyl)-piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile; D004095:Dihydropyridines; D010880:Piperidines; D011849:Radioactive Tracers; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2
keywords: In vitro autoradiography; Metabotropic glutamate receptor 2; Positron emission tomography; Radiotracer; Schizophrenia; [(11)C]CMDC