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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：
9293777
负责人：
Steven H Liang
金额：
$ 21.37万
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 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9293777
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 Injectable Kinetics Knockout Mice Label Lead Ligands Link MAGL inhibitor Measures Medical Mental disorders Methods Methylation Modeling Molecular Monoacylglycerol Lipases Mutation Patient Care Patients Pharmacology Phase Plasma Play Positron-Emission Tomography Pre-Clinical Model Process Proteomics Public Health 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 Toxic effect 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 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（ECHEM）的目标 (R21/R33）是帮助申请人建立一个独立的和高度竞争力的化学研究计划，药物滥用和成瘾，主要重点是开发用于PET成像研究的放射性药物，内源性大麻素信号系统中的单酰基甘油脂肪酶（MAGL）。 MAGL是代谢内源性大麻素配体2-花生四烯酸甘油（2-AG）的主要酶。阻断MAGL可增加2-AG水平，导致抗伤害、抗焦虑和止吐反应，已经成为治疗药物成瘾和物质使用障碍（SUD）的治疗策略。人类遗传研究已经确定了MAGL突变与成瘾风险增加之间的联系。异常MAGL 在酒精中毒者的死后脑中检测到了这种表达。然而，这些结果通过离体（破坏性）分析不能提供MAGL活性和人免疫缺陷之间的直接和实时相关性。疾病阶段，特别是对于诸如大脑的组织。在这种情况下，PET放射性示踪剂可以填充该空隙，提供了一种非侵入性工具，用于定量药物滥用中MAGL活性和可能的异常eCB功能，成瘾然而，阻碍PET应用于此目的的最主要障碍是缺乏放射性示踪剂靶向MAGL，代表了我们对这种酶的理解的重大缺陷。 PI和其他人最近开发的第一种脑渗透剂MAGL放射性示踪剂[11 C] SAR 127303显示，但该化合物也结合第二种2-AG降解酶ABHD 6，从而破坏了大脑中的特异性结合。为了克服这种选择性问题，我们将利用一种新的蛋白质组学技术，基于活性的蛋白质谱分析（ABPP），以基于新型MAGL阵列进行靶选择性筛选，内部开发的抑制剂。氮杂环丁烷氨基甲酸酯（IC 50 0.4 nM）对MAGL的选择性超过 FAAH、CB 1和CB 2受体，以及超过ABHD 6的>30倍的MAGL。初步研究表明，11 C标记的氮杂环丁烷在大鼠和非人灵长类动物（NHP）中穿过血脑屏障，并显示>65%的特异性结合。虽然尚不清楚这种放射性示踪剂是否能令人满意地用于人类，但它显示出作为第一代放射性示踪剂的希望。选择性MAGL放射性示踪剂。除了进一步评估这种示踪剂，我们将使用这种支架同时制备一系列精心挑选的MAGL示踪剂，进一步提高选择性，并评估其能力，使用啮齿动物和NHP定量MAGL活性。这项工作的影响不仅是开发第一个有效的，选择性MAGL神经示踪剂用于基础eCB研究，但最终也要将这种成像工具用于翻译人类成像研究和调查MAGL相关疾病的潜在机制，包括SUD。相关性：该提案有可能改善公共卫生，帮助成瘾患者通过使用MAGL放射性示踪剂的PET神经成像的进步。