Novel PET Tracers for Imaging Monoacylglycerol Lipase in Endocannabinoid Signaling

用于内源性大麻素信号传导中单酰甘油脂肪酶成像的新型 PET 示踪剂

基本信息

批准号：
9923963
负责人：
Steven H Liang
金额：
$ 41.66万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923963
关键词：
2-arachidonylglycerol ABHD6 gene Affinity Alzheimer&apos s Disease Animals Anti-Anxiety Agents Antiemetics Autopsy Autoradiography Award Back Basic Science Binding Biochemical Process Blood - brain barrier anatomy Brain CNR1 gene CNR2 gene Cannabinoids Carbamates Carbon Dioxide Chemistry Clinical Clinical Research Data Development Disease Docking Drug Addiction Drug Kinetics Drug abuse Endocannabinoids Enzymes Evaluation Exhibits Generations Genetic study Goals Human Human Genetics Image Imaging Device In Vitro Kinetics Knockout Mice Label Lead Ligands Link MAGL inhibitor Measures Medical Mental disorders Methods Methylation Modeling Molecular Monoacylglycerol Lipases Mutation Patient Care Patient imaging Patients Pharmacology Phase Plasma Play Positron-Emission Tomography Pre-Clinical Model Process Proteomics Public Health Radiation Toxicity Radioactive Radiolabeled Radioligand Assay Radiometry Radiopharmaceuticals Rattus Research Research Subjects Risk Rodent Role Sampling Scientific Advances and Accomplishments Series Serine Hydrolase Severities Site Specificity Substance Use Disorder System Techniques Technology Therapeutic Time Tissues Tracer Transgenic Organisms Translations United States Validation Work activity-based protein profiling addiction azetidine base carboxylate career chemoproteomics design endocannabinoid signaling endogenous cannabinoid system fatty acid amide hydrolase human disease human imaging imaging study improved in vivo in vivo evaluation in vivo imaging mouse model neuroimaging neuropsychiatric disorder nonhuman primate novel problem drinker programs radiotracer response sample fixation scaffold screening small molecule tool uptake ylide

项目摘要

Project Summary: The goal of the Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM) (R21/R33) is to help applicant establish an independent and highly-competitive chemistry research program applied to drug abuse and addiction, with a major focus of developing radiopharmaceuticals for PET imaging study of monoacylglycerol lipase (MAGL) in the endocannabinoid signaling system. MAGL is the principle enzyme for metabolizing endogenous cannabinoid ligand: 2-arachidonylglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in anti-nociceptive, anxiolytic and anti-emetic responses, and has emerged as a therapeutic strategy to treat drug addiction and substance-use disorders (SUDs). Human genetic studies have identified the link between MAGL mutations and increased risk for addiction. Abnormal MAGL expression has been detected in the post-mortem brain of alcoholic subjects. However, these results discovered via ex vivo (destructive) analysis cannot provide a direct and real-time correlation between MAGL activity and human disease stages, particularly for tissues such as the brain. In this context, a PET radiotracer can fill this void and provide a noninvasive tool for quantifying MAGL activity and possible aberrant eCB function in drug abuse and addiction. However, the foremost barrier holding back PET applications for this purpose is the scarcity of radiotracers targeting MAGL, representing a significant deficiency in our understanding of this enzyme. The first brain penetrant MAGL radiotracer, [11C]SAR127303 recently developed by the PI and others, showed saturable binding but this compound also binds a second 2-AG degrading enzyme, ABHD6, thereby undermining the specific binding in the brain. To overcome this selectivity problem, we will utilize a novel proteomic technology, activity based protein profiling (ABPP) to perform target selectivity screening based on an array of novel MAGL inhibitors developed in house. An azetidine carbamate (IC50 0.4 nM) exhibits >500-fold selectivity to MAGL over FAAH, CB1 and CB2 receptors, and >30-fold MAGL over ABHD6. Preliminary studies indicate the 11C-labeled azetidine crosses the blood brain barrier in rat and nonhuman primate (NHP), and shows >65% specific binding. Although it is not clear if this radiotracer will be satisfactory for human use, it shows promise as a first generation of selective MAGL radiotracers. In addition to further evaluation of this tracer, we will use this scaffold to concurrently prepare a series of carefully chosen MAGL tracers with further improved selectivity, and evaluate their ability to quantify MAGL activity using rodents and NHPs. The impact of this work is not only to develop the first potent and selective MAGL neurotracer for basic eCB research, but also ultimately to progress this imaging tool for translational human imaging studies and investigate underlying mechanisms of MAGL-linked diseases including SUDs. Relevance: This proposal has the potential to improve public health and help patients suffering from addiction through advancement of PET neuroimaging using MAGL radiotracers.

项目摘要：药物滥用和成瘾化学早期职业奖的目标（Echem）（R21/R33）是为了帮助申请人建立应用独立且高度竞争的化学研究计划吸毒和成瘾，重点是开发用于宠物成像研究的放射性药物内源性大麻素信号系统中的单酰甘油脂肪酶（MAGL）。 MAGL是代谢内源性大麻素配体的原理酶：2-芳基酮甘油（2-AG）。 MAGL的封锁增加了2-AG水平，导致抗伤害感，抗焦虑和抗神经反应，以及已成为治疗药物成瘾和物质使用疾病（SUD）的一种治疗策略。人遗传研究已经确定了MAGL突变与增加成瘾风险之间的联系。异常磁虫在酒精受试者的验尸后大脑中已经检测到表达。但是，这些结果是通过离体（破坏性）分析不能提供MAGL活动与人类之间的直接和实时相关性疾病阶段，特别是对于大脑等组织。在这种情况下，宠物放射性示踪剂可以填补这一空白，并且提供一种无创的工具来量化MAGL活性以及在药物滥用中可能异常的欧洲央行功能瘾。但是，为此目的，阻止宠物申请的最重要的障碍是稀缺靶向MAGL的放射性示例，代表了我们对这种酶的理解。 PI和其他人最近开发的第一个脑渗透磁性弹药片[11C] SAR127303 可饱和结合，但该化合物还结合了第二个2 ag降解酶Abhd6，从而破坏了大脑中的特定结合。为了克服这个选择性问题，我们将利用一种新型的蛋白质组学技术，基于活性的蛋白质分析（ABPP），根据一系列新型MAGL执行目标选择性筛选室内发展的抑制剂。氮杂氨酸氨基甲酸酯（IC50 0.4 nm）表现出> 500倍的选择性 FAAH，CB1和CB2受体，ABHD6上的MAGL> 30倍。初步研究表明11C标记氮杂氨酸在大鼠和非人类灵长类动物（NHP）中越过血脑屏障，显示> 65％的特异性结合。尽管目前尚不清楚这种放射性示例是否对人类使用感到满意，但它显示出有望作为第一代选择性MAGL放射性示例。除了对该示踪剂的进一步评估外，我们还将使用此脚手以进一步提高选择性，准备一系列精心挑选的MAGL示踪剂，并评估其能力使用啮齿动物和NHP量化MAGL活性。这项工作的影响不仅是发展第一个有效的和选择性MAGL神经粒子用于基本欧洲央行研究人类成像研究和研究包括SUD在内的MAGL连接疾病的潜在机制。相关性：该提案有可能改善公共卫生并帮助患者成瘾通过使用MAGL放射性示例提高PET神经影像学。