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.

激活的单胺氧化酶 B (MAO-B) 与阿尔茨海默病和相关疾病有关 （ADRD）。为了利用 MAO-B 功能障碍作为 ADRD 的潜在治疗靶点，成像 需要使用正电子发射断层扫描 (PET) 量化 MAO-B 酶活性的试剂。 尽管历史上尝试过开发 MAO-B 显像剂，但广泛应用的关键挑战仍然存在 MAO PET在ADRD中的临床应用先前的研究集中在放射性标记的自杀抑制剂（[11C]L- deprenyl-D2) 和可逆抑制剂 ([11C]SL25.1188)。然而，基于 MAO-B 抑制剂的显像剂 存在局限性，因为它们可以量化 MAO-B 水平，但不提供有关酶活性的信息。致地址 鉴于大脑 PET 中的这一关键差距，该 R21 提案的总体目标是转化一种一流的基质 - 用于 ADRD 中 MAO-B 功能障碍的临床成像的显像剂。我们的中心假设是 PET [11C]COU（一种形成捕获代谢物的 MAO-B 底物）成像，具有独特的定位来量化 首次用 PET 检测 MAO-B 活性。拟议的研究将完成临床前实验（药物- 毒理学、剂量测定、化学验证）和临床转化（目标 1）所需的文件（IND 和 IRB）， 进行必要的首次人体 (FIH) PET 研究，以建立人体剂量测定，确定我们的动力学模型 方法，并在阻断研究中验证 PET 信号依赖于 MAO-B 活性（目标 2），并进行 AD 患者的 MAO PET 成像概念验证（目标 3）。这项研究意义重大，因为 [11C]COU PET 可以解决量化大脑中 MAO-B 活性的问题，该问题自最早以来一直是不可行的 20 世纪 80 年代 MAO PET 成像的时代。 [11C]COU 的临床转化经过广泛的临床前验证 结果为 R21 资助提出的令人兴奋的 FIH 研究提供了基础。我们的团队在 密歇根大学在大脑 PET 的前沿领域合作了数十年，并已 与 [11C]COU 合作进行 8 年临床前概念验证研究。我们在放射化学方面的专业知识 和临床前成像（Scott、Brooks、Kilbourn）、动力学建模和 PET 图像定量（Koeppe）以及 ADRD 研究和临床核医学 (Frey) 使我们具有独特的优势来完成拟议的目标 研究。该项目目标将通过创新性方法使用 PET 定量 MAO-B 活性来实现 捕获代谢物的方法。 [11C]COU 具有中枢神经系统渗透性，一旦进入大脑，就会被 MAO-B 氧化， 片段生成[11C]1-甲基-2,3-二氢吡啶-4(1H)-酮([11C]MDHP)。由于 [11C]MDHP 不能 穿透血脑屏障，它被困在中枢神经系统中，我们期望使用标准评估动力学 两组织室模型（具有不可逆捕获 [11C]MDHP），将允许使用 k3 速率常数 估计作为 MAO 活性的指数。总体而言，该项目将提供一种定量 MAO 的新技术 PET 活动将提高我们对 MAO-B 在衰老以及 ADRD（和其他疾病）中的功能的理解 疾病），并最终帮助利用 MAO-B 成像来检测和治疗疾病。