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dc.contributor.authorWang, Luen_US
dc.contributor.authorMori, Wakanaen_US
dc.contributor.authorCheng, Ranen_US
dc.contributor.authorYui, Jojien_US
dc.contributor.authorHatori, Akikoen_US
dc.contributor.authorMa, Longleen_US
dc.contributor.authorZhang, Yidingen_US
dc.contributor.authorRotstein, Benjamin H.en_US
dc.contributor.authorFujinaga, Masayukien_US
dc.contributor.authorShimoda, Yokoen_US
dc.contributor.authorYamasaki, Tomoteruen_US
dc.contributor.authorXie, Linen_US
dc.contributor.authorNagai, Yujien_US
dc.contributor.authorMinamimoto, Takafumien_US
dc.contributor.authorHiguchi, Makotoen_US
dc.contributor.authorVasdev, Neilen_US
dc.contributor.authorZhang, Ming-Rongen_US
dc.contributor.authorLiang, Steven H.en_US
dc.date.accessioned2016-07-14T19:16:44Z
dc.date.issued2016en_US
dc.identifier.citationWang, L., W. Mori, R. Cheng, J. Yui, A. Hatori, L. Ma, Y. Zhang, et al. 2016. “Synthesis and Preclinical Evaluation of Sulfonamido-based [11C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipase.” Theranostics 6 (8): 1145-1159. doi:10.7150/thno.15257. http://dx.doi.org/10.7150/thno.15257.en
dc.identifier.issn1838-7640en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:27662206
dc.description.abstractMonoacylglycerol lipase (MAGL) is a 33 kDa member of the serine hydrolase superfamily that preferentially degrades 2-arachidonoylglycerol (2-AG) to arachidonic acid in the endocannabinoid system. Inhibition of MAGL is not only of interest for probing the cannabinoid pathway but also as a therapeutic and diagnostic target for neuroinflammation. Limited attempts have been made to image MAGL in vivo and a suitable PET ligand for this target has yet to be identified and is urgently sought to guide small molecule drug development in this pathway. Herein we synthesized and evaluated the physiochemical properties of an array of eleven sulfonamido-based carbamates and ureas with a series of terminal aryl moieties, linkers and leaving groups. The most potent compounds were a novel MAGL inhibitor, N-((1-(1H-1,2,4-triazole-1-carbonyl)piperidin-4-yl) methyl)-4-chlorobenzenesulfonamide (TZPU; IC50 = 35.9 nM), and the known inhibitor 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(((4-chlorophenyl)sulfonamido) methyl)piperidine-1-carboxylate (SAR127303; IC50 = 39.3 nM), which were also shown to be selective for MAGL over fatty acid amide hydrolase (FAAH), and cannabinoid receptors (CB1 & CB2). Both of these compounds were radiolabeled with carbon-11 via [11C]COCl2, followed by comprehensive ex vivo biodistribution and in vivo PET imaging studies in normal rats to determine their brain permeability, specificity, clearance and metabolism. Whereas TZPU did not show adequate specificity to warrant further evaluation, [11C]SAR127303 was advanced for preliminary PET neuroimaging studies in nonhuman primate. The tracer showed good brain permeability (ca. 1 SUV) and heterogeneous regional brain distribution which is consistent with the distribution of MAGL.en
dc.language.isoen_USen
dc.publisherIvyspring International Publisheren
dc.relation.isversionofdoi:10.7150/thno.15257en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893642/pdf/en
dash.licenseLAAen_US
dc.subjectpositron emission tomographyen
dc.subjectmonoacylglycerol lipaseen
dc.subjectMAGLen
dc.subjectcarbon-11en
dc.subjectnonhuman primateen
dc.subjectSAR127303.en
dc.titleSynthesis and Preclinical Evaluation of Sulfonamido-based [11C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipaseen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalTheranosticsen
dash.depositing.authorWang, Luen_US
dc.date.available2016-07-14T19:16:44Z
dc.identifier.doi10.7150/thno.15257*
dash.authorsorderedfalse
dash.contributor.affiliatedMa, Longle
dash.contributor.affiliatedLiang, Huan
dash.contributor.affiliatedVasdev, Neil
dash.contributor.affiliatedWang, Lu


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