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

描述(申请人提供)：阿尔茨海默病(AD)是一个日益严重的全球健康问题。目前，还没有可以阻止或逆转疾病进展的药物，所有创造这种疗法的努力都失败了。这些失败的原因之一是缺乏对小鼠模型和人类都有用的可翻译生物标记物，以及适当的生物标记物在药物发现和开发过程中发挥的作用相对较小。识别用于非侵入性评估治疗结果的可翻译生物标志物对于改善AD的治疗是必不可少的。在这里，我们建议使用一种新的成像策略来监测阿尔茨海默病的治疗反应。该策略涉及对转位蛋白18 kDa(TSPO)使用特定的正电子发射断层扫描(PET)放射性配体([18F]Ge-180)。TSPO PET放射性配基用于非侵入性地检测和跟踪活体受试者的小胶质细胞激活(神经炎症的标志)。有证据表明，神经炎症在AD的早期就发生了，甚至在淀粉样斑块形成之前。此外，早期抗炎干预似乎深刻地影响了AD的发生和发展。神经炎症在AD中的早期参与，以及它在整个疾病过程中持续存在并促进神经退变的事实，使其成为追踪病理和监测早期治疗干预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，但[18F]Ge-180具有优越的结合亲和力和体内特性，可用于体内神经炎症过程的成像。虽然这种示踪剂已经进行了首次现场评估，结果令人满意，但它是否能够监测AD的治疗反应仍有待研究。我们的近期目标是评估[18F]Ge-180-PET在AD小鼠模型中跟踪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[18F]-GE180-PET作为AD治疗反应的生物标记物在新型疾病修饰药物临床试验中的实用性。我们的初步研究表明，在疾病的早期阶段，[18F]Ge-180-PET可以检测到AD(APPL/S)小鼠模型中小胶质细胞的激活。在这项建议中，我们的目标是在AD小鼠模型中进一步评估[18F]Ge-180作为AD神经炎症的替代标记物，并监测目前正在评估中的AD治疗新药的反应。我们将通过以下具体目标来实现我们的目标：1)在两个AD小鼠模型中，确定[18F]Ge-180-PET信号是否与小胶质细胞激活和疾病进展的程度相关，以及2)评估[18F]Ge-180-PET对目前正在临床试验的两种AD疗法(即LM11A-31和米诺环素)进行成像反应的敏感性和准确性。[18F]Ge-180的使用可能是一种改变游戏规则的方法，在整个AD生物标记物驱动的诊断和治疗领域具有潜在的深远优势。

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.