Open AccessNovel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold
Author(s) -
Jian Rong,
Wakana Mori,
Xiaotian Xia,
Michael A. Schafroth,
Chunyu Zhao,
Richard Van,
Tomoteru Yamasaki,
Jiahui Chen,
Zhiwei Xiao,
Ahmed Haider,
Daisuke Ogasawara,
Atsuto Hiraishi,
Tuo Shao,
Yiding Zhang,
Zhe Chen,
Fuwen Pang,
Kuan Hu,
Lin Xie,
Masayuki Fujinaga,
Katsushi Kumata,
Yuancheng Gou,
Yuwei Fang,
Shuyin Gu,
Huiyi Wei,
Liang Bao,
Hao Xu,
Thomas Collier,
Yihan Shao,
Richard E. Carson,
Benjamin F. Cravatt,
Lu Wang,
MingRong Zhang,
Steven H. Liang
Publication year - 2021
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.1c00747
Subject(s) - monoacylglycerol lipase , chemistry , biodistribution , 2 arachidonoylglycerol , radioligand , azetidine , pharmacology , serine protease , endocannabinoid system , biochemistry , enzyme , binding site , stereochemistry , protease , medicine , receptor , cannabinoid receptor , in vitro , agonist
Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [ 18 F] 10 and [ 18 F] 15 ([ 18 F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [ 18 F] 15 demonstrated a better performance. In conclusion, [ 18 F] 15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.