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| 1 | A novel monoacylglycerol lipase-targeted^(18)F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network显示文摘Monoacylglycerol lipase(MAGL)constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol(2-AG)to arachidonic acid(AA).As such,selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders,metabolic diseases and cancers.Based on a unique 4-piperidinyl azetidine diamide scaffold,we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand[^(18)F]FEPAD.Pharmacokinetics and binding studies on[^(18)F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue(BAT)–a tissue that is known to be metabolically active.We employed[^(18)F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT,which was confirmed by post-mortem tissue analysis.Given the negative regulation of endocannabinoids on the metabolic BAT activity,our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders.Further,we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits,thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system(ECS)-related pathologies. | Ran Cheng Masayuki Fujinaga Jing Yang Jian Rong Ahmed Haider Daisuke Ogasawara Richard S.Van Tuo Shao Zhen Chen Xiaofei Zhang Erick R.Calderon Leon Yiding Zhang Wakana Mori Katsushi Kumata Tomoteru Yamasaki Lin Xie Shaofa Sun Lu Wang Chongzhao Ran Yihan Shao Benjamin Cravatt Lee Josephson Ming-Rong Zhang Steven H.Liang | 2022 | Acta Pharmacologica Sinica2022，43，11： | 0 |
| 2 | Discovery of a highly specific ^(18)F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination显示文摘As a member of cyclic nucleotide phosphodiesterase(PDE)enzyme family,PDE10A is in charge of the degradation of cyclic adenosine(cAMP)and guanosine monophosphates(cGMP).While PDE10A is primarily expressed in the medium spiny neurons of the striatum,it has been implicated in a variety of neurological disorders.Indeed,inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system(CNS)pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component.A PDE10A-targeted positron emission tomography(PET)radioligand would enable a better assessment of the pathophysiologic role of PDE10A,as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate,thus accelerating the development of effective PDE10A inhibitors.In this study,we designed and synthesized a novel ^(18)F-aryl PDE10A PET radioligand,codenamed[^(18)F]P10A-1910([^(18)F]9),in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination.[^(18)F]9 possessed good in vitro binding affinity(IC_(50)=2.1 nmol/L)and selectivity towards PDE10A.Further,[^(18)F]9 exhibited reasonable lipophilicity(logD=3.50)and brain permeability(P_(app)>10×10^(−6) cm/s in MDCK-MDR1 cells).PET imaging studies of[^(18)F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics.Preclinical studies in rodents revealed an improved plasma and brain stability of[^(18)F]9 when compared to the current reference standard for PDE10A-targeted PET,[^(18)F]MNI659.Further,dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of[^(18)F]9 for evaluating target occupancy in vivo in higher species.In conclusion,our results indicated that[^(18)F]9 is a promising PDE10A PET radioligand for clinical translation. | Zhiwei Xiao Huiyi Wei Yi Xu Ahmed Haider Junjie Wei Shiyu Yuan Jian Rong Chunyu Zhao Guocong Li Weibin Zhang Huangcan Chen Yuefeng Li Lingling Zhang Jiyun Sun Shaojuan Zhang Hai-Bin Luo Sen Yan Qijun Cai Lu Hou Chao Che Steven H.Liang Lu Wang | 2022 | Acta Pharmaceutica Sinica B2022，12，4： | 0 |
| 3 | Development of a highly-specific ^(18)F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping显示文摘As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers. | Zhen Chen Wakana Mori Jian Rong Michael A.Schafroth Tuo Shao Richard S.Van Daisuke Ogasawara Tomoteru Yamasaki Atsuto Hiraishi Akiko Hatori Jiahui Chen Yiding Zhang Kuan Hu Masayuki Fujinaga Jiyun Sun Qingzhen Yu Thomas L.Collier Yihan Shao Benjamin F.Cravatt Lee Josephson Ming-Rong Zhang Steven H.Liang | 2021 | Acta Pharmaceutica Sinica B2021，11，6： | 0 |
| 4 | Structure-activity relationship of pyrazol-4-ylpyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4显示文摘There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor4(M4)in schizophrenia and dementia with Lewy bodies,however,a clinically validated M4positron emission tomography(PET)radioligand is currently lacking.As such,the aim of this study was to develop a suitable M4PET ligand that allows the non-invasive visualization of M4in the brain.Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12—a subtype-selective positive allosteric modulator(PAM).The radiofluorinated analogue,[18F]12,was synthesized in 28±10%radiochemical yield,>37 GBq/μmol and an excellent radiochemical purity>99%.Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of[18F]12 for the M4-rich striatum.However,in the presence of carbachol,a significant increase in tracer binding was observed in the rat striatum,which was reduced by>60%under blocking conditions,thus indicating that orthosteric ligand interaction is required for efficient binding o f[18F]12 to the allosteric site.Remarkably,however,the presence of carbachol was not required for high specific binding in the non-human primate(NHP)and human striatum,and did not further improve the specificity and selectivity of[18F]12 in higher species.These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP,where peak brain uptake of[18F]12 was found in the putamen and temporal cortex.In conclusion,we report on the identification and preclinical development of the first radiofluorinated M4PET radioligand with promising attributes.The availability of a clinically validated M4PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging. | Ahmed Haider Xiaoyun Deng Olivia Mastromihalis Stefanie K.Pfister Troels E.Jeppesen Zhiwei Xiao Vi Pham Shaofa Sun Jian Rong Chunyu Zhao Jiahui Chen Yinlong Li Theresa R.Connors April T.Davenport James B.Daunais Vahid Hosseini Wenqing Ran Arthur Christopoulos Lu Wang Celine Valant Steven H.Liang | 2023 | Acta Pharmaceutica Sinica B2023，13，1： | 0 |
| 5 | [^(18)F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models显示文摘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 fibrogenic signaling pathways that induce hepatic stellate cell(HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an;F-labeled MAGL inhibitor([18F]MAGL-4-11)for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [18F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation(BDL) and carbon tetrachloride(CCl_(4)) models of liver cirrhosis;we also assessed the hepatic gene expression of the enzymes 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-4-11 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 fibrosisseverity, 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-4-11 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 | 2022 | Acta Pharmaceutica Sinica B2022，12，1： | 0 |
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