Ma Yufei, Kumata Katsushi, Yui Joji, Zhang Yiding, Yamasaki Tomoteru, Hatori Akiko, Fujinaga Masayuki, Nengaki Nobuki, Xie Lin, Wang Hui, Zhang Ming-Rong
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.
Department of Radiopharmaceutics Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
Bioorg Med Chem. 2017 Feb 1;25(3):1014-1021. doi: 10.1016/j.bmc.2016.12.011. Epub 2016 Dec 23.
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-[C]methoxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([C]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 (EC: 98nM) for human mGluR2 in vitro. [C]CMDC was synthesized by O-[C]methylation of 1-(cyclopropylmethyl)-4-(4-hydroxyphenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1) with [C]methyl iodide. [C]CMDC (2.2±0.9GBq; n=20) was obtained from [C]CO of 14.0-17.8GBq with >98% radiochemical purity and 86-150GBq/μmol specific activity at the end of synthesis. In vitro autoradiography indicated that [C]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 [C]CMDC in the rat brain. While [C]CMDC has limited potential as a PET tracer for brain mGluR2, it can be used to develop new radiotracers with improved behaviors.
脑代谢型谷氨酸受体2（mGluR2）已被提议作为治疗因前脑谷氨酸传递增加而产生的精神分裂症样症状的治疗靶点。然而，目前尚不存在用于人类神经影像学研究mGluR2的可靠工具。本研究的目的是放射性合成1-（环丙基甲基）-4-（4-[¹¹C]甲氧基苯基）哌啶-1-基-2-氧代-1,2-二氢吡啶-3-腈（[¹¹C]CMDC），并评估其作为正电子发射断层扫描（PET）放射性示踪剂在大鼠脑中成像mGluR2的潜力。CMDC是mGluR2的正变构调节剂，在体外对人mGluR2表现出强大的功能活性（EC₅₀：98 nM）。[¹¹C]CMDC通过1-（环丙基甲基）-4-（4-羟基苯基）哌啶-1-基-2-氧代-1,2-二氢吡啶-3-腈（1）与[¹¹C]甲基碘进行O-[¹¹C]甲基化反应合成。在合成结束时，从14.0 - 17.8 GBq的[¹¹C]CO中获得了[¹¹C]CMDC（比活度为86 - 150 GBq/μmol，放射性化学纯度>98%），放射性活度为2.2±0.9 GBq（n = 20）。体外放射自显影表明，[¹¹C]CMDC结合在富含mGluR2的脑区包括大脑皮层、纹状体和海马体中表达（占总结合的>50%）。然而，小动物PET显示[¹¹C]CMDC在大鼠脑中的体内特异性结合较低。虽然[¹¹C]CMDC作为脑mGluR2的PET示踪剂潜力有限，但它可用于开发具有改善性能的新型放射性示踪剂。
