Clinical MAO PET Imaging via Trapped Metabolites

通过捕获的代谢物进行临床 MAO PET 成像

• 批准号: 10285480
• 负责人: KIRK A. FREY
• 金额: $ 31.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285480
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer’s disease biomarker; Amyloid beta-Protein; Astrocytes; Astrocytosis; Biochemical Reaction; Blood - brain barrier anatomy; Blood specimen; Brain; Brain imaging; Cerebrum; Chemistry; Clinical; Clinical Research; Clinical Trials; Data; Dementia; Development; Discipline of Nuclear Medicine; Disease; Documentation; Dose; Epilepsy; Evaluation; FDA approved; Functional disorder; Gliosis; Glucose; Goals; Government; Grant; Heart Diseases; Human; Image; Image Enhancement; Institutional Review Boards; Investigational Drugs; Investigational New Drug Application; Investigational Therapies; Kinetics; Label; Medical; Methods; Michigan; Modeling; Monoamine Oxidase; Monoamine Oxidase B; Monoamine Oxidase Inhibitors; Neurology; Oxides; Paper; Pathway interactions; Patient Care; Patient Monitoring; Patients; Permeability; Pharmacology and Toxicology; Positioning Attribute; Positron-Emission Tomography; Problem Solving; Production; Protocols documentation; Publishing; Radiation Dose Unit; Radiochemistry; Radiolabeled; Reporting; Research; Safety; Scanning; Selegiline; Signal Transduction; Sympathetic Nervous System; Techniques; Testing; Time; Tissues; Tracer; Translating; Translations; United States National Institutes of Health; Universities; Validation; Work; X-Ray Computed Tomography; astrogliosis; base; cholinergic; clinical application; clinical imaging; clinical translation; cohort; cost; dosimetry; drug discovery; effective therapy; experience; experimental study; fighting; first-in-human; fluorodeoxyglucose; imaging agent; imaging biomarker; imaging detection; imaging study; improved; indexing; inhibitor/antagonist; innovation; kinetic model; neuroinflammation; neurotoxicity; novel strategies; patient population; patient response; pharmacokinetic model; pre-clinical; preclinical imaging; radiochemical; radiotracer; socioeconomics; suicide inhibitor; targeted agent; tau Proteins; therapeutic target; whole body imaging

Activated monoamine oxidase-B (MAO-B) has been implicated in Alzheimer’s disease and related disorders (ADRD). In order to capitalize upon MAO-B dysfunction as a potential therapeutic target for ADRD, imaging agents for quantifying MAO-B enzymatic activity using positron emission tomography (PET) are required. Despite historical attempts at developing MAO-B imaging agents, key challenges remain for the widespread clinical application of MAO PET in ADRD. Prior research focused upon radiolabeled suicide inhibitors ([11C]L- deprenyl-D2) and reversible inhibitors ([11C]SL25.1188). However, imaging agents based on MAO-B inhibitors have limitations, as they may quantify MAO-B levels but provide no information on enzymatic activity. To address this critical gap in brain PET, the overall objective of this R21 proposal is to translate a first-in-class substrate- based imaging agent for clinical imaging of MAO-B dysfunction in ADRD. Our central hypothesis is that PET imaging with [11C]COU, an MAO-B substrate that forms a trapped metabolite, is uniquely positioned to quantify MAO-B activity with PET for the first time. The proposed research will complete preclinical experiments (pharm- tox, dosimetry, chemistry validation) and documentation (IND and IRB) necessary for clinical translation (Aim 1), conduct essential first-in-human (FIH) PET studies to establish human dosimetry, determine our kinetic modeling approach, and validate the PET signal is dependent on MAO-B activity in blocking studies (Aim 2), and carry out proof-of-concept MAO PET imaging in AD patients (Aim 3). The research is significant because [11C]COU PET could solve the problem of quantifying MAO-B activity in the brain that has been unfeasible since the earliest days of MAO PET imaging in the 1980s. Clinical translation of [11C]COU is justified by extensive preclinical results that provide groundwork for the exciting FIH studies proposed by this R21 grant. Our team at the University of Michigan has worked together for decades at the cutting edge of brain PET and has been collaborating for 8 years on preclinical proof-of-concept studies with [11C]COU. Our expertise in radiochemistry and preclinical imaging (Scott, Brooks, Kilbourn), kinetic modeling and PET image quantitation (Koeppe), as well as ADRD research and clinical nuclear medicine (Frey) uniquely positions us to accomplish the proposed research. The project goals will be realized through quantitation of MAO-B activity using PET via an innovative trapped metabolite approach. [11C]COU is CNS permeable and, once in the brain, gets oxidized by MAO-B and fragments to generate [11C]1-methyl-2,3-dihydropyridin-4(1H)-one ([11C]MDHP). Since [11C]MDHP cannot penetrate the blood-brain barrier, it is trapped in the CNS and we expect that evaluating kinetics using a standard two-tissue compartment model (with irreversible trapping of [11C]MDHP), will allow use of k3 rate constant estimates as an index of MAO activity. Overall, this project will deliver a new technique for quantitating MAO activity with PET that will improve our understanding of MAO-B function in aging as well as ADRD (and other diseases) and, ultimately, aid in utilizing MAO-B imaging for the detection and treatment of disease.

活化的单胺氧化酶-B（MAO-B）已在阿尔茨海默氏病和相关疾病中隐含 （ADRD）。为了将MAO-B功能障碍作为ADRD的潜在治疗靶点，成像 需要使用极性发射断层扫描（PET）来量化MAO-B酶活性的药物。 尽管有历史尝试开发MAO-B成像剂，但仍有关键挑战仍在宽度上 毛宠物在Adrd中的临床应用。先前的研究重点是放射标记的自杀抑制剂（[11C] L- 脱肾D2）和可逆抑制剂（[11C] SL25.1188）。但是，基于MAO-B抑制剂的成像剂 有局限性，因为它们可能会量化MAO-B水平，但没有提供有关酶活性的信息。解决 R21提案的总体目标是大脑宠物的这一关键差距，是翻译一流的基材 - 基于ADRD中MAO-B功能障碍的临床成像的基于基于的成像剂。我们的中心假设是宠物 用[11C] cou成像，一种形成被困代谢物的MAO-B底物，是独特的定位 首次使用PET的MAO-B活动。拟议的研究将完成临床前实验（Pharm- TOX，剂量法，化学验证）和文档（IND和IRB）需要临床翻译（AIM 1）， 进行必需的首先人类（FIH）PET研究以建立人类剂量法，确定我们的动力学建模 进近，验证宠物信号取决于封闭研究（AIM 2）中的MAO-B活性，并进行 AD患者的概念验证毛宠物成像（AIM 3）。这项研究很重要，因为[11c] cou pet 可以解决量化大脑中MAO-B活性的问题，而MAO-B活性自 1980年代毛宠物成像的日子。 [11C] cou的临床翻译是通过广泛的临床前的 结果为这项R21赠款提出的令人兴奋的FIH研究提供了基础。我们的团队在 密歇根大学在脑宠物的最前沿已经一起工作了数十年 与[11C] COU合作进行了8年的临床前概念验证研究。我们的放射化学专业知识 以及临床前成像（Scott，Brooks，Kilbourn），动力学建模和PET图像定量（Koeppe）， 正如ADRD研究和临床核医学（Frey）所独特地定位了我们的实现 研究。项目目标将通过使用宠物通过创新来定量MAO-B活动来实现 被困的代谢物方法。 [11c] COU是CNS可渗透的，一旦进入大脑，就被MAO-B氧化了 生成[11C] 1-甲基-2,3-二氢吡啶-4（1H）-ONE（[11C] MDHP）的片段。由于[11C] MDHP不能 穿透血脑屏障，它被困在中枢神经系统中，我们希望使用标准评估动力学 两个组织隔室模型（具有[11C] MDHP的不可逆捕获）将允许使用K3速率常数 估计是MAO活动的指数。总体而言，该项目将提供一种用于量化毛泽东的新技术 使用PET的活动将提高我们对MAO-B功能在衰老和ADRD中的理解（以及其他 疾病），最终有助于利用MAO-B成像进行疾病的检测和治疗。