1区 · 医学
Article
作者: Rong, Jian ; Chen, Jingjin ; Zhang, Ming-Rong ; Collier, Thomas Lee ; Vasdev, Neil ; Yamasaki, Tomoteru ; Xie, Lin ; Shao, Tuo ; Cravatt, Benjamin F. ; Zhang, Yiding ; Fowler, Christopher ; Bao, Liang ; Dahl, Kenneth ; Gu, Shuyin ; Hatori, Akiko ; Ogasawara, Daisuke ; Mori, Wakana ; Josephson, Lee ; Fujinaga, Masayuki ; Wang, Lu ; Chen, Zhen ; Gou, Yuancheng ; Ma, Jun-An ; Schafroth, Michael A. ; Cheng, Ran ; Deng, Xiaoyun ; Yu, Qingzhen ; Zhang, Xiaofei ; Liang, Steven H. ; Fu, Hualong ; Shao, Yihan ; Kumata, Katsushi ; Hu, Kuan ; Zhang, Genwei
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 8 and reversible-binding compounds 17 and 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.
