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ACS Chem Neurosci. 2019 May 15;10(5):2263-2275. doi: 10.1021/acschemneuro.8b00591. Epub 2019 Feb 27.

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

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Department of Radiology, Division of Nuclear Medicine and Molecular Imaging , Massachusetts General Hospital and Harvard Medical School , 55 Fruit Street , Boston , Massachusetts 02114 , United States.
Department of Pharmacology , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.
Department of Neurology, Xiangya Hospital , Central South University , Changsha , Hunan 410008 , P. R. China.
Department of Radiology, Massachusetts General Hospital , Harvard Medical School, and the Shriners Burns Hospital , Boston , Massachusetts 02114 , United States.
Department of Chemistry and Biochemistry , University of Oklahoma , Norman , Oklahoma 73019 , United States.
Department of Neurology , Children's Hospital of Chongqing Medical University , Chongqing , 400014 , P. R. China.
Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University & Institute of Molecular and Functional Imaging , Jinan University , Guangzhou 510630 , P. R. China.
Department of Physiology and Pharmacology, Wake Forest School of Medicine , Winston Salem , North Carolina 27157 , United States.
State Key Laboratory of Molecular Vaccinology, Molecular Diagnosis & Center for Molecular Imaging and Translational Medicine, School of Public Health , Xiamen University , Xiamen 361102 , P. R. China.


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)-1 H-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.


18F-labeling; GluN2B subunit; PET imaging; Subtype-selective; autoradiography; spirocyclic iodonium ylide

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