Synthesis and preliminary evaluation of novel 11C-labeled GluN2B-selective NMDA receptor negative allosteric modulators

• 作者: Ji-yun Sun Katsushi Kumata Zhen Chen Yi-ding Zhang Jia-hui Chen Akiko Hatori Hua-long Fu Jian Rong Xiao-yun Deng Tomoteru Yamasaki Lin Xie Kuan Hu Masayuki Fujinaga Qing-zhen Yu Tuo Shao Thomas Lee Collier Lee Josephson Yi-han Shao Yun-fei Du Lu Wang Hao Xu Ming-rong Zhang Steven H Liang
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: Drug Discovery
• 页码范围: 491-498
• 页数: 8页
• 语种: 英文

摘要

N-methyl-D-aspartate receptors(NMDARs)play critical roles in the physiological function of the mammalian central nervous system(CNS),including learning,memory,and synaptic plasticity,through modulating excitatory neurotransmission.Attributed to etiopathology of various CNS disorders and neurodegenerative diseases,GluN2B is one of the most well-studied subtypes in preclinical and clinical studies on NMDARs.Herein,we report the synthesis and preclinical evaluation of two 11C-labeled GluN2B-selective negative allosteric modulators(NAMs)containing N,N-dimethyl-2-(1H-pyrrolo[3,2-b]pyridin-1-yl)acetamides for positron emission tomography(PET)imaging.Two PET ligands,namely[11C]31 and[11C]37(also called N2B-1810 and N2B-1903,respectively)were labeled with[11C]CH31 in good radiochemical yields(decay-corrected 28％and 32％relative to starting[11C]C02,respectively),high radiochemical purity(＞99％)and high molar activity(＞74 GBq/μmol).In particular,PET ligand[11C]31 demonstrated moderate specific binding to GluN2B subtype by in vitro autoradiography studies.However,because in vivo PET imaging studies showed limited brain uptake of[11C]31(up to 0.5 SUV),further medicinal chemistry and ADME optimization are necessary for this chemotype attributed to low binding specificity and rapid metabolism in vivo.