| Title : 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 - Chen_2019_J.Med.Chem_62_3336 |
| Author(s) : Chen Z , Mori W , Deng X , Cheng R , Ogasawara D , Zhang G , Schafroth MA , Dahl K , Fu H , Hatori A , Shao T , Zhang Y , Yamasaki T , Zhang X , Rong J , Yu Q , Hu K , Fujinaga M , Xie L , Kumata K , Gou Y , Chen J , Gu S , Bao L , Wang L , Collier TL , Vasdev N , Shao Y , Ma JA , Cravatt BF , Fowler C , Josephson L , Zhang MR , Liang SH |
| Ref : Journal of Medicinal Chemistry , 62 :3336 , 2019 |
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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 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with (11)C or (18)F. [(11)C]8 ([(11)C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [(11)C]17 ([(11)C]PAD) and [(18)F]37 ([(18)F]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. |
| PubMedSearch : Chen_2019_J.Med.Chem_62_3336 |
| PubMedID: 30829483 |
| Gene_locus related to this paper: human-MGLL |
| Gene_locus | human-MGLL |
Chen Z, Mori W, Deng X, Cheng R, Ogasawara D, Zhang G, Schafroth MA, Dahl K, Fu H, Hatori A, Shao T, Zhang Y, Yamasaki T, Zhang X, Rong J, Yu Q, Hu K, Fujinaga M, Xie L, Kumata K, Gou Y, Chen J, Gu S, Bao L, Wang L, Collier TL, Vasdev N, Shao Y, Ma JA, Cravatt BF, Fowler C, Josephson L, Zhang MR, Liang SH (2019)
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
Journal of Medicinal Chemistry
62 :3336
Chen Z, Mori W, Deng X, Cheng R, Ogasawara D, Zhang G, Schafroth MA, Dahl K, Fu H, Hatori A, Shao T, Zhang Y, Yamasaki T, Zhang X, Rong J, Yu Q, Hu K, Fujinaga M, Xie L, Kumata K, Gou Y, Chen J, Gu S, Bao L, Wang L, Collier TL, Vasdev N, Shao Y, Ma JA, Cravatt BF, Fowler C, Josephson L, Zhang MR, Liang SH (2019)
Journal of Medicinal Chemistry
62 :3336