MAGL PET tracer-guided prognosis and neuroprotective therapy for Alzheimer's disease

MAGL PET 示踪剂引导阿尔茨海默病的预后和神经保护治疗

• 批准号: 10001417
• 负责人: Steven H Liang
• 金额: $ 16.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001417
• 关键词: 2-arachidonylglycerol; AD transgenic mice; Ablation; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animal Model; Animals; Anti-Inflammatory Agents; Arachidonic Acids; Autopsy; Basal Nucleus of Meynert; Behavior; Biochemical Process; Biological; Biological Markers; Brain; Consumption; Data; Development; Disease; Disease Progression; Endocannabinoids; Enzymes; Florida; Genetic; Goals; Image; Imaging Device; Inflammation; Injections; Kinetics; Ligands; London; Longitudinal Studies; MAGL inhibitor; Measurement; Measures; Medical; Memory; Modeling; Molecular; Monitor; Monoacylglycerol Lipases; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Pain; Patient Care; Patients; Pharmacologic Substance; Pharmacotherapy; Phenotype; Positron-Emission Tomography; Process; Prostaglandins; Protocols documentation; Public Health; Quality of life; Radioactive; Radiopharmaceuticals; Research Subjects; Scanning; Senile Plaques; Signal Transduction; Techniques; Testing; Therapeutic Intervention; Time; Tracer; Transgenic Mice; Translating; United States; Validation; Work; attenuation; base; beta amyloid pathology; data acquisition; design; drug discovery; endogenous cannabinoid system; experimental study; human tissue; imaging biomarker; imaging study; improved; in vivo; molecular imaging; mouse model; neuroinflammation; novel; outcome forecast; personalized medicine; radiotracer; response; tau Proteins; tool; treatment planning; treatment response; uptake

Project Summary Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing the endogenous cannabinoid ligand: 2- arachidonylglycerol (2-AG). Inhibition of MAGL, not only increases 2-AG levels, resulting in activation of the endocannabinoid system (eCB), but also reduces levels of arachidonic acid (AA), a pain and inflammation-inducing prostaglandin precursor. This unique synergetic effect provides protection against neuroinflammation and neurodegenerative diseases. Genetic ablation of MAGL has also resulted in an attenuation of neuroinflammation, for example, a substantial reduction of amyloid plaques in transgenic mouse model of Alzheimer’s disease (AD). In autopsy brains of Alzheimer’s patients, MAGL levels in nucleus basalis are 600-800% higher than that of normal brain, and showed a positive correlation (R = 0.8) between enzyme expression levels and AD Braak stage (I-VI). In the past, remarkable advances have been made in the understanding of MAGL and its modulation at the molecular level in neurodegenerative diseases via ex vivo (destructive) analysis, which, by definition, cannot be directly translated to most human tissues in vivo. In this context, positron emission tomography (PET) is a noninvasive molecular imaging tool that can provide such information via targeted radioactive molecules (radiotracers) with exquisite sensitivity, which will be highly advantageous in monitoring disease progression and treatment response. The radiotracer [11C]SAR127303 (abbreviated as [11C]SAR127), developed by the PI, can fill this void and provide a quantitative tool for measuring MAGL activity and possible aberrant eCB function in AD. Our preliminary studies show that [11C]SAR127 is a specific and brain penetrant PET radiotracer that is consistent with the distribution of MAGL in the brain. In this application, we aim to evaluate [11C]SAR127 for its ability to track MAGL changes in vivo to monitor disease progression in transgenic AD mouse models, evaluate target engagement and assess treatment response to MAGL-related pharmacotherapies. This work will represent the first PET biomarker study measuring changes of a potentially disease-modifying enzyme MAGL in the AD progression and treatment. We expect that this proposed work will not only help us to differentiate symptomatic from true neuroprotective response via MAGL inhibition, but also contribute to the development of MAGL-based therapeutic interventions to improve quality of life of AD patients. Relevance: This proposal has the potential to improve public health and help patients suffering from Alzheimer’s disease through the discovery of novel neurotherapeutics using MAGL PET ligands.

项目摘要 单酰基甘油脂肪酶（MAGL）是代谢内源性大麻素配体的主要酶：2-甲基-N-（2-甲基-N-苯基）-N-（2-甲基-N-苯基）-（2-甲基-N-（2-甲基-苯基）-N-（2-甲基-苯基）-N-（2-甲基） 花生四烯酸甘油（2-AG）。MAGL的抑制，不仅增加2-AG水平，导致活化的细胞， 内源性大麻素系统（eCB），但也降低了花生四烯酸（AA），疼痛和炎症诱导水平 前列腺素前体这种独特的协同作用提供了对神经炎症的保护， 神经退行性疾病MAGL的基因消融也导致神经炎症的减弱， 例如，在阿尔茨海默病（AD）的转基因小鼠模型中淀粉样蛋白斑块的显著减少。在 在阿尔茨海默病患者的尸检脑中，基底核中的MAGL水平比正常脑高600-800%， 且与AD Braak分期（I-VI）呈正相关（R = 0.8）。 在过去，在对MAGL及其调制的理解方面已经取得了显着的进展， 通过离体（破坏性）分析在神经退行性疾病中的分子水平，根据定义， 在体内直接翻译到大多数人体组织。在这种情况下，正电子发射断层扫描（PET）是一种非侵入性的 分子成像工具，可以通过靶向放射性分子（放射性示踪剂）提供此类信息， 灵敏度极高，这将在监测疾病进展和治疗反应方面非常有利。 PI开发的放射性示踪剂[11 C] SAR 127303（简称[11 C] SAR 127）可以填补这一空白， 用于测量AD中MAGL活性和可能的异常eCB功能的定量工具。我们的初步研究 表明[11 C] SAR 127是一种特异性和脑渗透性PET放射性示踪剂，与 大脑中的MAGL。在本申请中，我们的目的是评估[11 C] SAR 127在体内追踪MAGL变化的能力 监测转基因AD小鼠模型中的疾病进展，评价靶点接合并评估治疗 对MAGL相关药物治疗的反应。 这项工作将代表第一个PET生物标志物研究，测量潜在的疾病修饰 酶MAGL在AD进展和治疗中的作用。我们希望，这项拟议的工作不仅将有助于我们 通过MAGL抑制区分症状性与真正的神经保护反应，但也有助于 开发基于MAGL的治疗干预措施，以改善AD患者的生活质量。 相关性：这项提案有可能改善公共卫生，帮助阿尔茨海默氏症患者 通过发现使用MAGL PET配体的新型神经治疗剂来治疗疾病。