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， 需要使用正电子发射断层摄影术（PET）定量MAO-B酶活性的试剂。 尽管在开发MAO-B显像剂方面进行了历史性的尝试，但对于广泛使用的MAO-B显像剂来说，关键的挑战仍然存在。 MAOPET在ADRD中的临床应用以前的研究集中在放射性标记的自杀抑制剂（[11 C] L- 丙炔苯丙胺-D2）和可逆抑制剂（[11C] SL25.1188）。然而，基于MAO-B抑制剂的成像剂 有局限性，因为它们可以定量MAO-B水平，但不能提供有关酶活性的信息。解决 这个关键的差距，脑PET，这一R21提案的总体目标是翻译一流的基板- 用于ADRD中MAO-B功能障碍的临床成像。我们的核心假设是PET 用[11 C] COU（一种形成捕获代谢物的MAO-B底物）成像， MAO-B活性首次与PET。该研究将完成临床前实验（pharm- 毒理学、剂量测定、化学验证）和临床翻译所需的文件（IND和IRB）（目标1）， 进行必要的首次人体（FIH）PET研究，以建立人体剂量学，确定我们的动力学模型 方法，并验证PET信号依赖于阻断研究中的MAO-B活性（目的2），并进行 AD患者的概念验证MAO PET成像（目标3）。这项研究是有意义的，因为[11 C] COU PET 可以解决定量大脑中MAO-B活性的问题，这一问题从最早开始就不可行。 在20世纪80年代，[11 C] COU的临床转化通过广泛的临床前研究证明是合理的 这些结果为这项R21资助提出的令人兴奋的FIH研究奠定了基础。我们的团队 密歇根大学已经在大脑PET的前沿领域合作了几十年， 与[11 C] COU在临床前概念验证研究方面合作了8年。我们在放射化学领域的专业知识 和临床前成像（Scott，布鲁克斯，Kilbourn），动力学建模和PET图像定量（Koeppe），以及 作为ADRD研究和临床核医学（弗雷）独特的位置，我们来完成拟议的 research.该项目的目标将通过使用PET定量MAO-B活性来实现， 捕获代谢物方法。[11C] COU是CNS可渗透的，一旦进入大脑，就会被MAO-B氧化， 片段生成[11 C] 1-甲基-2，3-二氢吡啶-4（1H）-酮（[11 C] MDHP）。由于[11C] MDHP不能 穿透血脑屏障，它被困在中枢神经系统，我们预计，评价动力学使用的标准 双组织室模型（具有[11 C] MDHP的不可逆捕获）将允许使用k3速率常数 估计作为MAO活性的指数。总的来说，这个项目将提供一个新的技术，定量单胺氧化酶 PET的活性，这将提高我们对MAO-B在衰老以及ADRD（和其他 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.