Open AccessIdentification and Development of a New Positron Emission Tomography Ligand 4-(2-Fluoro-4-[11C]methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide for Imaging Metabotropic Glutamate Receptor Subtype 2 (mGlu2)
Author(s) -
Tomoteru Yamasaki,
Xiaofei Zhang,
Katsushi Kumata,
Yiding Zhang,
Xiaoyun Deng,
Masayuki Fujinaga,
Zhen Chen,
Wakana Mori,
Kuan Hu,
Hidekatsu Wakizaka,
Akiko Hatori,
Lin Xie,
Michio Ogawa,
Nobuki Nengaki,
Richard Van,
Yihan Shao,
Douglas J. Sheffler,
Nicholas D. P. Cosford,
Steven H. Liang,
MingRong Zhang
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01991
Subject(s) - chemistry , positron emission tomography , ligand (biochemistry) , lipophilicity , in vivo , glutamate receptor , receptor , stereochemistry , nuclear medicine , biochemistry , medicine , microbiology and biotechnology , biology
Metabotropic glutamate receptor 2 (mGlu 2 ) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu 2 , we identified new candidates 5a - i that are potent negative allosteric modulators (NAMs) of mGlu 2 . Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1 H -pyrazol-3-yl)methoxy)picolinamide ( 5i , also named as [ 11 C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 ( 11 C) to obtain [ 11 C] 5i in high radiochemical yield and high molar activity by O -[ 11 C]methylation of the phenol precursor 12 with [ 11 C]CH 3 I. In vitro autoradiography with [ 11 C] 5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [ 11 C] 5i indicated in vivo specific binding of mGlu 2 in the rat brain. Based on the [ 11 C] 5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu 2 .