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[^(18)F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models

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Acta Pharmaceutica Sinica B 2022年第1期12卷 308-315页

作者： 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 RadiologyMassachusetts General Hospital and Harvard Medical SchoolBostonmA 02114USA Liver Center and Gastrointestinal Division Department of MedicineMassachusetts General HospitalHarvard Medical SchoolBostonA 02114USA Shriners hospitals for Children-Boston Boston BostonMA 02114USA

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.

关键词： [18F]MAGL-4-11 PET imaging Liver fibrosis MAGL

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

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Acta Pharmaceutica Sinica B 2021年第2期11卷 373-393页

作者： Lingling Zhang Kuan hu Tuo Shao Lu hou Shaojuan Zhang Weijian Ye Lee Josephson Jeffrey h.Meyer Ming-Rong Zhang Neil Vasdev Jinghao Wang hao Xu Lu Wang steven h.liang Center of Cyclotron and PET Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI CenterThe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China Department of Neurology the First Affiliated Hospital of Jinan UniversityGuangzhou 510630China Department of Radiopharmaceuticals Development National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and TechnologyChiba 263-8555Japan Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital&Department of RadiologyHarvard Medical SchoolBostonMA 02114USA Azrieli Centre for Neuro-Radiochemistry Brain Health Imaging CentreCentre for Addiction and Mental Health&Department of PsychiatryUniversity of TorontoToronto ON M5T 1R8Canada Department of Pharmacy the First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

The 18 kDa translocator protein(TSPO),previously known as the peripheral benzodiazepine receptor,is predominately localized to the outer mitochondrial membrane in steroidogenic *** TSPO expression is relatively low under physiological conditions,but is upregulated in response to glial cell *** the primary index of neuroinflammation,TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases,including Alzheimer’s disease(AD),amyotrophic lateral sclerosis(ALS),Parkinson’s disease(PD),multiple sclerosis(MS),major depressive disorder(MDD)and obsessive compulsive disorder(OCD).In this context,numerous TSPO-targeted positron emission tomography(PET)tracers have been *** them,several radioligands have advanced to clinical research *** this review,we will overview the recent development of TSPO PET tracers,focusing on the radioligand design,radioisotope labeling,pharmacokinetics,and PET imaging ***,we will consider current limitations,as well as translational potential for future application of TSPO *** review aims to not only present the challenges in current TSPO PET imaging,but to also provide a new perspective on TSPO targeted PET tracer discovery *** these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

关键词： TSPO Microglial activation Neuroinflammation Positron emission tomography(PET) CNS disorders

Discovery of a highly specific ^(18)F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1963-1975页

作者： 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 Center of Cyclotron and PET Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital&Department of RadiologyHarvard Medical SchoolBostonMA 02114USA Department of Cardiology the First Affiliated Hospital of Jinan UniversityGuangzhou 510630China State Key Laboratory of Chemical Oncogenomics Key Laboratory of Chemical GenomicsPeking University Shenzhen Graduate SchoolShenzhen 518055China Guangdong Landau Biotechnology Co.Ltd. Guangzhou 510555China Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical SciencesHainan UniversityHaikou 570228China Guangdong-hongkong-Macao Institute of CNS Regeneration Ministry of Education CNS Regeneration Collaborative Joint LaboratoryJinan UniversityGuangzhou 510632China

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 ***,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 *** 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 ***,[^(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 *** 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]***,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 *** conclusion,our results indicated that[^(18)F]9 is a promising PDE10A PET radioligand for clinical translation.

关键词： Phosphodiesterase 10A PET radioligand 18F Spirocyclic iodonium ylide Nonhuman primate Target occupancy

Development of a highly-specific ^(18)F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1686-1695页

作者： 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 Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital&Department of RadiologyHarvard Medical SchoolBostonMA 02114USA Department of Advanced Nuclear Medicine Sciences National Institute of Radiological SciencesNational Institutes for Quantum and Radiological Science and TechnologyChiba 263-8555Japan The Skaggs Institute for Chemical Biology and Department of Chemical Physiology The Scripps Research InstituteLa JollaCA 92037USA Department of Chemistry and Biochemistry University of OklahomaNormanOK 73019USA

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 *** 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 ***,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor *** 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 *** 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.

关键词： Monoacylglycerol lipase(MAGL) Central nervous system(CNS) 2-Arachidonylglycerol(2-AG) Arachidonic acid(AA) Positron emission tomography(PET) Fluorine-18

Structure-activity relationship of pyrazol-4-ylpyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

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Acta Pharmaceutica Sinica B 2023年第1期13卷 213-226页

作者： 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 Department of Radiology Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical SchoolBostonMA 02114USA Department of Nuclear Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Drug Discovery Biology Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia Neuromedicines Discovery Centre Monash Institute of Pharmaceutical SciencesMonash UniversityParkvilleVIC 3052Australia hubei Collaborative Innovation Centre for Non-power Nuclear Technology College of Nuclear Technology&Chemistry and BiologyHubei University of Science and TechnologyXianning 437100China Department of Neurology Massachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Department of Physiology and Pharmacology Wake Forest School of MedicineWinston SalemNC 27157USA Terasaki Institute for Biomedical Innovation(TIBI) Los AngelesCA 90024USA Center of Cyclotron and PET Radiopharmaceuticals Department of Nuclear Medicine and PET/CT-MRI Centerthe First Affiliated Hospital of Jinan UniversityGuangzhou 510630China

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 *** such,the aim of this study was to develop a suitable M4PET ligand that allows the non-invasive visualization of M4in the ***-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 ***,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 ***,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 *** 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 *** conclusion,we report on the identification and preclinical development of the first radiofluorinated M4PET radioligand with promising *** availability of a clinically validated M4PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

关键词： Muscarinicacetylcholine receptor Positronemission tomography Neuroimaging Neuropharmacology Neurological disorders

Conventional and micro scale finite element modeling for metal cutting process:A review

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Chinese Journal of Aeronautics 2024年第2期37卷 199-232页

作者： Le WANG Caixu YUE Xianli LIU Ming LI Yongshi XU steven Y.liang Key Laboratory of Advanced Manufacturing and Intelligent Technology Ministry of EducationHarbin University of Science and TechnologyHarbin 150080China George W.Woodruff School of Mechanical Engineering Georgia Institute of TechnologyAtlanta 30332USA

The metal cutting process is accompanied by complex stress field,strain field,temperature *** comprehensive effects of process parameters on chip morphology,cutting force,tool wear and residual stress are complex and *** element method(FEM)is considered as an effective method to predict process variables and reveal microscopic physical phenomena in the cutting ***,the finite element(FE)simulation is used to research the conventional and micro scale cutting process,and the differences in the establishment of process variable FE simulation models are distinguished,thereby improving the accuracy of FE *** reliability and effectiveness of FE simulation model largely depend on the accuracy of the simulation method,constitutive model,friction model,damage model in describing mesh element,the dynamic mechanical behavior of materials,the tool-chip-workpiece contact process and the chip formation *** this paper,the FE models of conventional and micro process variables are comprehensively and up-to-date reviewed for different materials and machining *** purpose is to establish a FE model that is more in line with the real cutting conditions,and to provide the possibility for optimizing the cutting process *** development direction of FE simulation of metal cutting process is discussed,which provides guidance for future cutting process modeling.

关键词： Conventional and micro scale Finite element simulation Metal cutting process Micro cutting Modeling

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异常热报告的确认

电化学（中英文） 2024年第2期30卷 46-51页

作者： steven B.Krivit Melvin h.Miles New Energy Times 369-B 3rd St.#556San RafaelCA94901USA University of La Verne(Retired) 19503rd StLa VerneCA 91750USA

本文首次确认Nathan Lewis及其合作者于1989年5月1日在美国马里兰州巴尔的摩举行的美国物理学会(APS)会议上所犯的关键计算错误。Lewis等人分析了Martin Fleischmann及其合作者报告的9轮实验中的热测量结果,并报告在没有催化复合的情况... 详细信息

本文首次确认Nathan Lewis及其合作者于1989年5月1日在美国马里兰州巴尔的摩举行的美国物理学会(APS)会议上所犯的关键计算错误。Lewis等人分析了Martin Fleischmann及其合作者报告的9轮实验中的热测量结果,并报告在没有催化复合的情况下每轮实验都显示出异常的热功率损失。而本文使用相同的原始数据,经过正确的计算,再次确认每轮实验都显示出异常的功率增益。因此,这些数据意味着可能存在一种能产生能量的新物理现象。

关键词：低能核反应 LENR 超热

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互利作用促进了高山树线幼苗的存活

Journal of Plant Ecology 2024年第3期17卷 115-127页

作者： Wensheng Chen Jiangrong Li Jesús Julio Camarero huihui Ding Fangwei Fu Yueyao Li Xiangyu Zheng Xiaoxia Li Wei Shen Shalik Ram Sigdel steven W.Leavitt Eryuan liang Institute of Tibet Plateau Ecology Tibet Agricultural&Animal Husbandry UniversityNyingchi 860000China Key Laboratory of Forest Ecology in Tibet Plateau(Tibet Agricultural&Animal husbandry University) Ministry of EducationNyingchi 860000China National Forest Ecosystem Observation&Research Station of Nyingchi Tibet Nyingchi 860000China Key Laboratory of Alpine Vegetation Ecological Security in Tibet Nyingchi 860000China Zhejiang Zhoushan Archipelago Observation and Research Station Zhejiang Tiantong Forest Ecosystem National Observation and Research Stationand Shanghai Key Lab for Urban Ecological Processes and Eco-RestorationSchool of Ecological and Environmental SciencesEast China Normal UniversityShanghai 200241China State Key Laboratory of Tibetan Plateau Earth System Resources and Environment(TPESRE)Institute of Tibetan Plateau ResearchChinese Academy of SciencesBeijing 100101China Instituto Pirenaico de Ecología(IPE-CSIC) Zaragoza 50059Spain Anhui Province Key Lab of Farmland Ecological Conservation and Pollution Prevention Key Laboratory of JiangHuai Arable Land Resources Protection and Eco-restorationMinistry of Natural ResourcesCollege of Resources and EnvironmentAnhui Agricultural UniversityHefei 230036China Laboratory of Tree-Ring Research University of ArizonaTucsonAZ 85721USA

高山树线被视为记录气候变化对树木和森林影响的生态监测器。迄今为止,大多数树线研究都集中在气候变化如何驱动树线动态的变化。然而,关于生物相互作用如何调节树线变化,特别是在树木更新这一树线动态的瓶颈方面,人们知之甚少。本研究... 详细信息

高山树线被视为记录气候变化对树木和森林影响的生态监测器。迄今为止,大多数树线研究都集中在气候变化如何驱动树线动态的变化。然而,关于生物相互作用如何调节树线变化,特别是在树木更新这一树线动态的瓶颈方面,人们知之甚少。本研究假设种间和种内促进作用决定了高山树线树苗的定居和存活。为了验证这一假设,我们在青藏高原东南部的色季拉山高山树线交错区(海拔4300–4500 m)的3个生长生境(林冠内、林冠外和草地)中共计移植了630株不同年龄(4–6年、7–9年和10–15年)的急尖长苞冷杉(Abies georgei ***)幼苗,连续3年监测了移植后幼苗的微气候、高度生长、死亡率和叶片功能性状。结果发现,叶片功能性状的变化是由微气候驱动的。移植后,叶片可溶性糖和淀粉浓度以及C:P比增加,而叶面积减小。幼苗的资源利用逐渐转向更保守的策略,其背后机制主要受到了生理性状(非结构性碳水化合物和植物养分)的介导。同时,由结构方程模型发现太阳辐射、温度和水分条件在植物相互作用下,通过介导叶片形态性状的变化最终影响了幼苗的死亡率和年生长。上述研究结果表明,植物间的互利作用通过改变太阳辐射和叶片功能性状,最终在决定幼苗生长和存活上起到至关重要的作用,同时也为理解全球气候变化背景下高山树线动态变化的驱动机制提供了新的见解。

关键词：青藏高原移栽实验叶片功能性状太阳辐射

Development and application of photocatalytic coating for roadside NO_(x) mitigation in hong Kong

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Chinese Chemical Letters 2024年第3期35卷 153-157页

作者： Xinwei Li Pengge Wang Shuwen han Yu huang Wingkei ho steven Sai hang ho Shun-cheng Lee Meng Wang Department of Civil and Environmental Engineering The Hong Kong Polytechnic UniversityHong KongChina State Key Laboratory of Loess and Quaternary Geology(SKLLQG)and Key Laboratory of Aerosol Chemistry and Physics Institute of Earth EnvironmentChinese Academy of SciencesXi'an 710061China Department of Science and Environmental Studies The Education University of Hong KongHong KongChina Division of Atmospheric Sciences Desert Research InstituteRenoNV 89512United States

A facile chemical method for the development of photocatalytic coating products was proposed based on practical application perspective for the hong Kong roadside nitrogen oxides(NO_(x))***_(2)-based photocatalytic coating PC-C film with crystallized size of around 5–6 nm was synthesized with the peptization of h_(2)O_(2).The PC-C coating possesses a super-hydrophilicity surface and is proven to have a NO_(x)degradation rate of 46.8%with an optimum ph level of *** addition,the PC-C coating presents a promising photocatalytic NO_(x)degradation compared with other commercially available coating products and P25 when applied on two building materials of poly-methyl methacrylate(PMMA)and concrete surface.A weather resistance simulation and a 180-day on-site field trial were carried out the attenuation effects of photocatalytic coating applied in outdoor *** on epidemiological estimation and field investigation,hospital admissions for respiratory diseases(hARD)and mortality cases(MC)could be reduced with the application of PC-C coating along the street *** work demonstrates the feasibility of air pollution control measures for the local roadside NO_(x)using photocatalytic technology,offering promising health benefits with environmental remediation.

关键词： Photocatalysis Coating NO_(x) mitigation hong Kong Roadside