| Title : In Vitro and in Vivo Evaluation of (11)C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies - Cheng_2018_J.Med.Chem_61_2278 |
| Author(s) : Cheng R , Mori W , Ma L , Alhouayek M , Hatori A , Zhang Y , Ogasawara D , Yuan G , Chen Z , Zhang X , Shi H , Yamasaki T , Xie L , Kumata K , Fujinaga M , Nagai Y , Minamimoto T , Svensson M , Wang L , Du Y , Ondrechen MJ , Vasdev N , Cravatt BF , Fowler C , Zhang MR , Liang SH |
| Ref : Journal of Medicinal Chemistry , 61 :2278 , 2018 |
| Abstract : Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including (11)C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [(11)C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold. |
| ESTHER : Cheng_2018_J.Med.Chem_61_2278 |
| PubMedSearch : Cheng_2018_J.Med.Chem_61_2278 |
| PubMedID: 29481079 |
Cheng R, Mori W, Ma L, Alhouayek M, Hatori A, Zhang Y, Ogasawara D, Yuan G, Chen Z, Zhang X, Shi H, Yamasaki T, Xie L, Kumata K, Fujinaga M, Nagai Y, Minamimoto T, Svensson M, Wang L, Du Y, Ondrechen MJ, Vasdev N, Cravatt BF, Fowler C, Zhang MR, Liang SH (2018)
In Vitro and in Vivo Evaluation of (11)C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
Journal of Medicinal Chemistry
61 :2278
Cheng R, Mori W, Ma L, Alhouayek M, Hatori A, Zhang Y, Ogasawara D, Yuan G, Chen Z, Zhang X, Shi H, Yamasaki T, Xie L, Kumata K, Fujinaga M, Nagai Y, Minamimoto T, Svensson M, Wang L, Du Y, Ondrechen MJ, Vasdev N, Cravatt BF, Fowler C, Zhang MR, Liang SH (2018)
Journal of Medicinal Chemistry
61 :2278