Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([F-18]N2B-0518) for GluN2B Subunit in the Brain

• Type of Material: Article
• Authors: Hualong Fu, Harvard Medical School; Weiting Tang, Emory University; Zhen Chen, Harvard Medical School; Vasily V. Belov, Harvard Medical School; Genwei Zhang, University of Oklahoma; Tuo Shao, Harvard Medical School; Xiaofei Zhang, Harvard Medical School; Qingzhen Yu, Harvard Medical School; Jian Rong, Harvard Medical School; Xiaoyun Deng, Harvard Medical School; Wei Han, Emory university; Scott Myers, Emory University; Pilar Giffenig, Harvard Medical School; Lu Wang, Harvard Medical School; Lee Josephson, Harvard Medical School; Yihan Shao, University of Oklahoma; April T. Davenport, Wake Forest University; James B. Daunais, Wake Forest University; Mikhail Papisov, Harvard Medical School; Hongjie Yuan, Emory University; Zijing Li, Xiamen University; Stephen Traynelis, Emory University; Steven H. Liang, Harvard Medical School
• Language: English
• Date: 2019-05-01
• Publisher: ACS Publications
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Chemical Society
• Final Published Version (URL): http://dx.doi.org/10.1021/acschemneuro.8b00591
• Title of Journal or Parent Work: ACS Chemical Neuroscience
• Volume: 10
• Issue: 5
• Start Page: 2263
• End Page: 2275
• Grant/Funding Information: Financial support from the NIH grants (NINDS NS065371 to S.F.T.; NICHD HD082373 to H.Y.; NIAAA AA019431 to J.B.D. and NIAAA AA014106 to David P. Friedman) is gratefully acknowledged.; Z.L. acknowledges financial supports from the National Natural Science Foundation of China (81501534), Fourth Round Fujian Health Education Joint Research Projects (WKJ2016-2-08), Fundamental Research Funds for the Central Universities (20720180050), Fujian Province Young Teacher Research Program (JA15010) and Scientific Research Foundation of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (2016ZY002).
• Keywords: Biochemistry & Molecular Biology; Functional properties; Life Sciences & Biomedicine; Molecular basis; In vitro; Optimization; Subtype-selective; Binding; Subtype; PET imaging; F-18-labeling spirocyclic iodonium ylide; GluN2B subunit; System; autoradiography; NR2B subunit; Neurosciences; Neurosciences & Neurology; NMDA receptors; Allosteric modulators; Science & Technology; Chemistry, Medicinal; Pharmacology & Pharmacy
• Research Categories: Health Sciences, Pharmacology; Biology, Molecular; Health Sciences, Pharmacy; Chemistry, Biochemistry; Biology, Neuroscience

Abstract

GluN2B is the most studied subunit of N-methyl-d-aspartate receptors (NMDARs) and implicated in the pathologies of various central nervous system disorders and neurodegenerative diseases. As pan NMDAR antagonists often produce debilitating side effects, new approaches in drug discovery have shifted to subtype-selective NMDAR modulators, especially GluN2B-selective antagonists. While positron emission tomography (PET) studies of GluN2B-selective NMDARs in the living brain would enable target engagement in drug development and improve our understanding in the NMDAR signaling pathways between normal and disease conditions, a suitable PET ligand is yet to be identified. Herein we developed an 18F-labeled potent antagonist, 2-((1-(4-[18F]fluoro-3-methylphenyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methoxypyrimidine ([18F]13; also called [18F]N2B-0518) as a PET tracer for imaging the GluN2B subunit. The radiofluorination of [18F]13 was efficiently achieved by our spirocyclic iodonium ylide (SCIDY) method. In in vitro autoradiography studies, [18F]13 displayed highly region-specific binding in brain sections of rat and nonhuman primate, which was in accordance with the expression of GluN2B subunit. Ex vivo biodistribution in mice revealed that [18F]13 could penetrate the blood-brain barrier with moderate brain uptake (3.60% ID/g at 2 min) and rapid washout. Altogether, this work provides a GluN2B-selective PET tracer bearing a new chemical scaffold and shows high specificity to GluN2B subunit in vitro, which may pave the way for the development of a new generation of GluN2B PET ligands.