Clinical MAO PET Imaging via Trapped Metabolites

激活的单胺氧化酶-B(MAO-B)与阿尔茨海默病及相关疾病有关 (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)定量MAO-B酶活性的试剂。 尽管历史上曾有开发MAO-B显像剂的尝试，但对于广泛使用的 MAO-PET在ADRD中的临床应用以前的研究主要集中在放射性标记自杀抑制剂([11C]L-) D2)和可逆抑制剂([11C]SL25.1188)。然而，基于MAO-B抑制剂的显像剂 有局限性，因为它们可能量化MAO-B水平，但不提供有关酶活性的信息。致信地址 这个脑部PET的关键缺口，这个R21提案的总体目标是翻译一流的底物-- ADRD患者MAO-B功能障碍的临床显像剂。我们的中心假设是PET 使用形成捕获代谢物的MAO-B底物[11C]CuO进行成像是唯一能够定量的位置 MAO-B活性首次与PET结合。拟议的研究将完成临床前实验(PARM- 毒性、剂量测定、化学验证)和临床翻译所需的文件(IND和IRB)(目标1)， 进行基本的第一次人体(FIH)PET研究，以建立人体剂量学，确定我们的动力学模型 在阻断研究中接近并验证PET信号依赖于MAO-B活性(目标2)，并执行 阿尔茨海默病患者的概念验证MAO PET成像(目标3)。这项研究具有重要意义，因为[11C]cou PET 可以解决量化大脑中MAO-B活动的问题，这个问题从最早就是不可行的 20世纪80年代MAO PET成像的日子。[11C]CoU的临床翻译被广泛的临床前证明是合理的 这些结果为这项R21拨款建议的令人兴奋的FIH研究提供了基础。我们的团队在 密歇根大学在大脑PET的前沿领域合作了几十年，并一直在 与[11C]cou在临床前概念验证研究上合作了8年。我们在放射化学方面的专业知识 以及临床前成像(Scott、Brooks、Kilbourn)、动力学建模和PET图像定量(Koeppe) 作为ADRD研究和临床核医学(FREY)的独特定位，我们能够实现建议的 研究。项目目标将通过使用创新的PET对MAO-B活动进行量化来实现 捕获代谢物方法。[11C]CuO是中枢神经系统渗透性的，一旦进入大脑，就会被MAO-B氧化，并 碎片生成[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，我们预计使用一个标准来评估动力学 双组织隔室模型(具有[11C]MDHP的不可逆捕获)将允许使用K3速率常数 估计作为毛活动的一个指数。总体而言，该项目将提供一种量化MAO的新技术 PET的活动将提高我们对MAO-B在衰老以及ADRD(和其他)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。

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.