New PET imaging agent for monitoring treatment response in Alzheimer's disease

用于监测阿尔茨海默病治疗反应的新型 PET 显像剂

• 批准号: 9134599
• 负责人: Michelle Louise James
• 金额: $ 19.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134599
• 关键词: Affect; Affinity; Aftercare; Age; Alzheimer' s Disease; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Autoradiography; Binding; Biological Markers; Blood; Brain; Brain region; Cerebrospinal Fluid; Clinical; Clinical Trials; Dementia; Diagnostic; Disease; Disease Progression; Evaluation; Failure; Future; Goals; Health; Hippocampus (Brain); Histology; Human; Image; Inflammation; Intervention; Kinetics; Life; Magnetic Resonance Imaging; Microglia; Minocycline; Molecular; Monitor; Mus; Nerve Degeneration; Neuronal Dysfunction; Pathology; Patient Care; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Positron-Emission Tomography; Pre-Clinical Model; Process; Property; Proteins; Rodent; Role; Senile Plaques; Signal Transduction; Specificity; Staging; Surrogate Markers; Therapeutic; Therapeutic Intervention; Tracer; Transgenic Mice; Translating; Translations; base; behavioral study; biomarker-driven; candidate marker; clinically relevant; cost; drug development; drug discovery; global health; hyperphosphorylated tau; imaging agent; imaging modality; improved; in vivo; inflammatory marker; man; mouse model; neuroinflammation; novel; novel therapeutics; radioligand; response; success; tau Proteins; therapeutic development; therapy outcome; treatment response

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is growing global health issue. At present, there are no drugs available to halt or reverse disease progression, and all efforts to create such therapies have failed. One reason for these failures is the lack of translatable biomarkers useful in both mouse models and humans, and the relatively small role that appropriate biomarkers have played in the drug discovery and development process. Identification of translatable biomarkers for non-invasive assessment of therapeutic outcomes is imperative to improving the treatment of AD. Here we propose the use of a new imaging strategy for monitoring treatment response in Alzheimer's disease. The strategy involves using a specific positron emission tomography (PET) radioligand ([18F]GE-180) for the translocator protein 18 kDa (TSPO). TSPO PET radioligands are used to non-invasively detect and track microglial activation (a marker of neuroinflammation) in a living subject. Evidence suggests that neuroinflammation takes place very early in the AD, even before the formation of amyloid plaques. In addition, early anti-inflammatory intervention appears to profoundly impact the onset and progression of AD. The early involvement of neuroinflammation in AD, and the fact that it persists throughout disease and contributes to neurodegeneration, make it an ideal candidate biomarker for tracking pathology and monitoring response to early therapeutic interventions. Although there are a number of available TSPO radioligands, [18F]GE-180 has superior binding affinity and in vivo properties for imaging neuroinflammation processes in vivo. And while this tracer has undergone first in-man evaluation with favorable results, it is yet to be studied for it ability to monitor treatment response in AD. Our immediate goal is to evaluate [18F]GE-180-PET for its ability to track AD progression and monitor response to drug therapies in AD mouse models. Following this, our long- term goal is to assess the utility of [18F]-GE180-PET as a biomarker of AD treatment response in clinical trials of novel disease-modifying drugs. Our preliminary studies show that [18F]GE-180-PET can detect microglial activation in a mouse model of AD (APPL/S) at early stages of disease. In this proposal we aim to further evaluate [18F]GE-180 in AD mouse models for its use as a surrogate marker of AD neuroinflammation, and for monitoring response to novel drugs currently under evaluation for AD treatment. We will achieve our goals through the following specific aims: 1) determine whether [18F]GE-180-PET signal correlates with the extent of microglial activation and disease progression in two mouse models of AD, and 2) assess the sensitivity and accuracy of [18F]GE-180-PET for imaging response to two AD therapeutics currently in clinical trials (i.e., LM11A-31 and minocycline). The use of [18F]GE-180 could be a `game-changing' approach with potential far- reaching advantages in the whole arena of biomarker driven diagnostics and therapeutics for AD.

描述（由申请人提供）：阿尔茨海默病（AD）是日益严重的全球健康问题。目前，没有药物可以阻止或逆转疾病进展，所有创造这种疗法的努力都失败了。这些失败的一个原因是缺乏可翻译的生物标志物，可用于小鼠模型和人类，以及适当的生物标志物在药物发现和开发过程中发挥的作用相对较小。识别可翻译的生物标志物用于治疗结果的非侵入性评估对于改善AD的治疗是必要的。在这里，我们提出了一种新的成像策略，用于监测阿尔茨海默病的治疗反应。该策略涉及使用特定的正电子发射断层扫描（PET）放射性配体（[18 F]GE-180）的转运蛋白18 kDa（TSPO）。TSPO PET放射性配体用于非侵入性检测和跟踪活体中的小胶质细胞活化（神经炎症的标志物）。有证据表明，神经炎症发生在AD的早期，甚至在淀粉样斑块形成之前。此外，早期抗炎干预似乎对AD的发病和进展有深远的影响。AD中神经炎症的早期参与，以及它在整个疾病中持续存在并有助于神经变性的事实，使其成为跟踪病理学和监测对早期治疗干预的反应的理想候选生物标志物。虽然有许多可用的TSPO放射性配体，[18 F]GE-180具有上级结合亲和力和体内特性，可用于体内神经炎症过程成像。虽然这种示踪剂已经进行了首次人体评估并取得了良好的结果，但其监测AD治疗反应的能力还有待研究。我们的近期目标是评估[18F]GE-180-PET在AD小鼠模型中追踪AD进展和监测药物治疗反应的能力。在此之后，我们的长期目标是评估[18 F]-GE 180-PET作为新型疾病缓解药物临床试验中AD治疗反应的生物标志物的效用。我们的初步研究表明，[18 F]GE-180-PET可以在疾病的早期阶段检测AD小鼠模型（APPL/S）中的小胶质细胞活化。在本提案中，我们旨在进一步评估AD小鼠模型中[18 F]GE-180作为AD神经炎症替代标志物的用途，以及监测对目前正在评估的AD治疗新药的反应。我们将通过以下具体目标实现我们的目标：1）确定[18 F]GE-180-PET信号是否与两种AD小鼠模型中小胶质细胞激活和疾病进展的程度相关，以及2）评估[18 F]GE-180-PET的灵敏度和准确性目前临床试验中的两种AD治疗方法（即，LM 11 A-31和米诺环素）。[18 F]GE-180的使用可能是一种“改变游戏规则”的方法，在生物标志物驱动的AD诊断和治疗的整个竞技场中具有潜在的深远优势。