Monoacylglycerol lipase(MAGL)is a pivotal enzyme in the endocannabinoid system,which metabolizes 2-arachidonoylglycerol(2-AG)into the proinflammatory eicosanoid precursor arachidonic acid(AA).MAGL and other endogenous cannabinoid(EC)degrading enzymes are involved in the fibro-genic signaling pathways that induce hepatic stellate cell(HSC)activation and ECM accumulation during chronic liver disease.Our group recently developed an 18F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo.In this study,we deter-mined[18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL)and carbon tetrachloride(CC14)models of liver cirrhosis;we also assessed the hepatic gene expression of the en-zymes involved with EC system including MAGL,NAPE-PLD,FAAH and DAGL that as a function of disease severity in these models;[18F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human.[18F]MAGL-4-1 1 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice.We confirmed MAGL and FAAH expression decreases with fibrosis severity,while its levels in normal liver tissue are high;in contrast,the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models.In vitro autoradiography further supported that[18F]MAGL-4-1 1 bound specifically to MAGL in both animal and human fibrotic liver tissues.Our PET ligand[18F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.

Tuo Shao;Zhen Chen;Jian Rong;Vasily Belov;Jiahui Chen;Andre Jeyarajan;Xiaoyun Deng;Hualong Fu;Qingzhen Yu;Steve H.Rwema;Wenyu Lin;Mikhail Papisov;Lee Josephson;Raymond T.Chung;Steven H.Liang

Division of Nuclear Medicine and Molecular Imaging,Department of Radiology,Massachusetts General Hospital and Harvard Medical School,Boston,MA 02114,USA;Liver Center and Gastrointestinal Division,Department of Medicine,Massachusetts General Hospital,Harvard Medical School,Boston,MA 02114,USA;Shriners Hospitals for Children-Boston Boston,MA 02114,USA

药学学报（英文版）

[1]Tuo Shao;Zhen Chen;Jian Rong;Vasily Belov;Jiahui Chen;Andre Jeyarajan;Xiaoyun Deng;Hualong Fu;Qingzhen Yu;Steve H.Rwema;Wenyu Lin;Mikhail Papisov;Lee Josephson;Raymond T.Chung;Steven H.Liang-.[18F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models)[J].药学学报（英文版）,2022(01):308-315

Monoacylglycerol,metabolizes,arachidonoylglycerol,eicosanoid,NAPE,DAGL,autoradiography

18F,MAGL,positron,emission,tomography,molecular,imaging,monoacylglycerol,lipase,changes,preclinical,liver,fibrosis,models,pivotal,endocannabinoid,system,which,into,proinflammatory,precursor,arachidonic,acid,other,endogenous,degrading,enzymes,involved,genic,signaling,pathways,that,induce,hepatic,stellate,HSC,activation,ECM,accumulation,during,chronic,disease,Our,group,recently,developed,labeled,inhibitor,PET,demonstrated,highly,binding,vitro,vivo,In,this,study,we,deter,mined,enabled,levels,bile,duct,ligation,BDL,carbon,tetrachloride,CC14,cirrhosis,also,assessed,gene,expression,including,PLD,FAAH,function,severity,these,was,performed,tracer,frozen,sections,both,animal,human,reduced,signals,early,stages,further,significantly,decreased,progression,compared,control,mice,We,confirmed,decreases,while,its,normal,contrast,synthetic,enhanced,different,supported,bound,specifically,fibrotic,tissues,ligand,shows,excellent,sensitivity,specificity,visualization,accurately,reflects,histological

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