PET Imaging of Damaging Neuroinflammation in Alzheimer's Disease

阿尔茨海默病损伤性神经炎症的 PET 成像

• 批准号: 10547472
• 负责人: Andrew Christian Larson
• 金额: $ 49.76万
• 依托单位: EINSENCA INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547472
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anti-Inflammatory Agents; Axon; Blood - brain barrier anatomy; Brain; Cells; Clinical Trials; Cyclic GMP; Demyelinations; Development; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Event; Evolution; Functional disorder; Goals; Human; Image; Imaging technology; Immune; Inflammation; Inflammatory; Mediating; Mediator of activation protein; Monitor; Mus; Neurons; Output; Oxidative Stress; Patients; Peroxidases; Phase; Positron-Emission Tomography; Prognosis; Progressive Disease; Proteins; Rattus; Reporting; Technology; Testing; Time; Toxicology; Validation; age related; clinical imaging; clinical translation; first-in-human; fluorodeoxyglucose; glucose metabolism; imaging agent; imaging modality; immunoreactivity; inhibitor; innovation; neuroinflammation; non-invasive imaging; non-invasive monitor; novel marker; response; tau Proteins; treatment response

Alzheimer's disease (AD) is a devastating and progressive disease without a cure. Neuroinflammation is now recognized as a key early event in the development of AD. Aberrant neuroinflammatory response activates immune cells that can increase oxidative stress, and oxidative stress can directly damage neurons and axons, cause demyelination, and break down the blood-brain barrier (BBB). Thus, damaging neuroinflammation is emerging to be a potential treatment target. A non-invasive imaging method to detect and assess early damaging neuroinflammation would be able to detect disease before irreversible damage occurs, and enable monitoring of disease progression and treatment response of current and emerging therapies. However, current clinical imaging technologies do not distinguish between damaging and reparative inflammation. The goal of this proposal is to develop an imaging method to detect and monitor oxidative stress and consequent damaging neuroinflammation in AD. We hypothesize that such an imaging technology will allow early detection of damaging neuroinflammation in AD patients, enable timely treatment decisions, predict progression, and allow non-invasive monitoring of treatment response, particularly for emerging anti-inflammatory therapies. We have found that myeloperoxidase (MPO) is highly expressed by pro-inflammatory cells but not by reparative cells. MPO is a key mediator of oxidative inflammation and has been found to be associated with AD. An increased number of MPO immunoreactive cells have been found in the brains of early AD patients, but not in the brains of normal patients. We have developed an activatable MPO-PET imaging agent (18F-EH301) that can cross the BBB to enable imaging of MPO activity in AD. In Phase 1 we will establish that 18F-EH301 can specifically detect oxidative stress in the brain in the 5XFAD mouse AD model. In Phase 2 we will use 18F- EH301 PET imaging to a) longitudinally track the evolution of oxidative stress in the brain in different AD models, b) compare and correlate with other AD imaging agents: 18F-FDG (glucose metabolism), 18F-florbetapir (β-amyloid), 18F-flortaucipir (tau), 11C-PBR28 (translocator protein), and c) monitor treatment changes using an MPO inhibitor (verdiperstat) with and without donezepil. Finally, to enable clinical translation of this technology, we will synthesize 18F-EH301 under cGMP conditions and perform GLP toxicology studies in rats. This proposal addresses the NIA priority of development and validation of innovative diagnostic tests and novel biomarkers to identify or predict age-related decline, dysfunction, diseases, and conditions, including Alzheimer's disease and AD-related dementias. The output of this proposal will be a translational MPO- targeting PET imaging method with demonstrated efficacy to report damaging neuroinflammation in AD for diagnosis, prognosis, and treatment monitoring. This project will directly enable first-in-man clinical trials to test MPO imaging in human AD and potentially other diseases in which MPO is implicated.

阿尔茨海默病（AD）是一种无法治愈的破坏性和进行性疾病。神经炎症现在 被认为是AD发展的关键早期事件。异常神经炎症反应激活 免疫细胞可以增加氧化应激，而氧化应激可以直接损伤神经元和轴突， 导致脱髓鞘，并破坏血脑屏障（BBB）。因此，破坏性神经炎症是 成为潜在的治疗目标。一种早期检测和评估的非侵入性成像方法 破坏性神经炎症将能够在不可逆损伤发生之前检测疾病， 监测疾病进展以及当前和新兴疗法的治疗反应。然而，在这方面， 目前的临床成像技术不能区分损伤性和修复性炎症。的 该提案的目的是开发一种成像方法，以检测和监测氧化应激和随后的 损害AD的神经炎症。我们假设这样的成像技术将允许早期检测 AD患者的损伤性神经炎症，使及时的治疗决策，预测进展， 允许对治疗反应进行非侵入性监测，特别是对于新兴的抗炎疗法。我们 已经发现髓过氧化物酶（MPO）在促炎细胞中高度表达，但在修复细胞中不表达。 细胞MPO是氧化性炎症的关键介质，并且已被发现与AD相关。一个 在早期AD患者的脑中发现了MPO免疫反应细胞数量的增加，但在晚期AD患者的脑中没有发现。 正常病人的大脑。我们开发了一种可活化的MPO-PET显像剂（18F-EH 301）， 可以穿过BBB，从而能够对AD中的MPO活性进行成像。在第1阶段，我们将确定18F-EH 301可以 特异性检测5XFAD小鼠AD模型中脑中的氧化应激。在第二阶段，我们将使用18F- EH 301 PET成像：a）纵向跟踪不同AD患者脑中氧化应激的演变 模型，B）与其他AD成像剂：18 F-FDG（葡萄糖代谢）、18 F-florbetapir （β-淀粉样蛋白）、18F-flortaucipir（tau）、11 C-PBR 28（转运蛋白），和c）使用免疫组织化学监测治疗变化。 MPO抑制剂（verdiperstat）联合和不联合多奈西匹。最后，为了实现这项技术的临床转化， 我们将在cGMP条件下合成18F-EH 301，并在大鼠中进行GLP毒理学研究。这 该提案提出了NIA优先开发和验证创新诊断测试和新型 生物标志物，以识别或预测年龄相关的衰退，功能障碍，疾病和状况，包括 阿尔茨海默病和AD相关痴呆。该提案的输出将是一个翻译的MPO- 一种靶向PET成像方法，经证实可有效报告AD中的损伤性神经炎症， 诊断、预后和治疗监测。该项目将直接使首次在人体临床试验，以测试 人类AD和其他可能涉及MPO的疾病中的MPO成像。