Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders...Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.展开更多
基金supported by NCI T32CA275777support provided,in part,by the NIH grants(S10OD034326,DA038000 and DA043507,USA)+1 种基金Emory Radiology Startup and Chair FundEmory School of Medicine Endowed Directorship.
文摘Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.
