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（ECHEM）的目标（R21/R33）是帮助申请人建立一个独立的、具有高度竞争力的化学研究项目申请药物滥用和成瘾问题，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 会增加 2-AG 水平，从而产生抗伤害、抗焦虑和止吐反应，并且已成为治疗药物成瘾和物质使用障碍（SUD）的治疗策略。人类遗传研究已确定 MAGL 突变与成瘾风险增加之间的联系。异常MAGL 已在酒精受试者死后大脑中检测到表达。然而，这些结果是通过离体（破坏性）分析无法提供 MAGL 活性与人类之间的直接实时关联疾病阶段，尤其是大脑等组织。在这种情况下，PET 放射性示踪剂可以填补这一空白提供一种非侵入性工具来量化 MAGL 活性和药物滥用中可能的异常 eCB 功能瘾。然而，阻碍 PET 应用的最大障碍是缺乏针对 MAGL 的放射性示踪剂，代表了我们对这种酶的理解的重大缺陷。第一个脑渗透 MAGL 放射性示踪剂 [11C]SAR127303 最近由 PI 和其他人开发，显示可饱和结合，但该化合物还结合第二种 2-AG 降解酶 ABHD6，从而破坏大脑中的特定结合。为了克服这个选择性问题，我们将利用一种新颖的蛋白质组技术，基于活性的蛋白质分析 (ABPP)，基于一系列新型 MAGL 进行靶点选择性筛选内部开发的抑制剂。氮杂环丁烷氨基甲酸酯 (IC50 0.4 nM) 对 MAGL 的选择性比 FAAH、CB1 和 CB2 受体以及 MAGL 是 ABHD6 的 30 倍以上。初步研究表明 11C 标记氮杂环丁烷可穿过大鼠和非人灵长类动物 (NHP) 的血脑屏障，并表现出 >65% 的特异性结合。尽管尚不清楚这种放射性示踪剂是否适合人类使用，但它显示出作为第一代放射性示踪剂的前景。选择性 MAGL 放射性示踪剂。除了进一步评估该示踪剂之外，我们还将使用该支架同时准备一系列精心挑选的 MAGL 示踪剂，进一步提高选择性，并评估它们的能力使用啮齿动物和 NHP 量化 MAGL 活性。这项工作的影响不仅在于开发第一个有效且用于基础 eCB 研究的选择性 MAGL 神经示踪剂，但最终也将这种成像工具用于转化人类成像研究并调查 MAGL 相关疾病（包括 SUD）的潜在机制。相关性：该提案有可能改善公共健康并帮助患有毒瘾的患者通过使用 MAGL 放射性示踪剂改进 PET 神经成像。