학술논문
Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a “Tail Switching” Strategy on a Piperazinyl Azetidine Skeleton
Document Type
Article
Author
Chen, Zhen; Mori, Wakana; Deng, Xiaoyun; Cheng, Ran; Ogasawara, Daisuke; Zhang, Genwei; Schafroth, Michael A.; Dahl, Kenneth; Fu, Hualong; Hatori, Akiko; Shao, Tuo; Zhang, Yiding; Yamasaki, Tomoteru; Zhang, Xiaofei; Rong, Jian; Yu, Qingzhen; Hu, Kuan; Fujinaga, Masayuki; Xie, Lin; Kumata, Katsushi; Gou, Yuancheng; Chen, Jingjin; Gu, Shuyin; Bao, Liang; Wang, Lu; Collier, Thomas Lee; Vasdev, Neil; Shao, Yihan; Ma, Jun-An; Cravatt, Benjamin F.; Fowler, Christopher; Josephson, Lee; Zhang, Ming-Rong; Liang, Steven H.
Source
Journal of Medicinal Chemistry; April 2019, Vol. 62 Issue: 7 p3336-3353, 18p
Subject
Language
ISSN
00222623; 15204804
Abstract
Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of “tail switching” on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8and reversible-binding compounds 17and 37, which are amenable for radiolabeling with 11C or 18F. [11C]8([11C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [11C]17([11C]PAD) and [18F]37([18F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms.