Brief Communication

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

Ji-yun Sun1,2, Katsushi Kumata3, Zhen Chen2, Yi-ding Zhang3, Jia-hui Chen1,2, Akiko Hatori3, Hua-long Fu2, Jian Rong2, Xiao-yun Deng2, Tomoteru Yamasaki3, Lin Xie3, Kuan Hu3, Masayuki Fujinaga3, Qing-zhen Yu2, Tuo Shao2, Thomas Lee Collier2, Lee Josephson2, Yi-han Shao4, Yun-fei Du5, Lu Wang1,2, Hao Xu1, Ming-rong Zhang3, Steven H Liang2
1 Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
2 Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
3 Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
4 Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
5 Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
Correspondence to: Hao Xu: txh@jnu.edu.cn, Ming-rong Zhang: zhang.ming-rong@qst.go.jp, Steven H Liang: liang.steven@mgh.harvard.edu,
DOI: 10.1038/s41401-020-0456-9
Received: 6 April 2020
Accepted: 3 June 2020
Advance online: 13 July 2020

Abstract

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]CH3I in good radiochemical yields (decay-corrected 28% and 32% relative to starting [11C]CO2, 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.
Keywords: ionotropic glutamate receptors (iGluRs); NMDARs; GluN2B subunit; positron emission tomography (PET); carbon-11

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