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: 8871373
• 负责人: Michelle Louise James
• 金额: $ 23.82万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8871373
• 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; Outcome; 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; 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; 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）：阿尔茨海默氏病（AD）正在日益增长的全球健康问题。目前，尚无停止或反向疾病进展的药物，创建此类疗法的所有努力都失败了。这些失败的原因之一是缺乏可翻译的生物标志物在小鼠模型和人类中都有用，以及适当的生物标志物在药物发现和开发过程中所起的相对较小的作用。可以鉴定可翻译生物标志物用于对治疗结果的非侵入性评估，对于改善AD的治疗至关重要。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氏病的治疗反应。该策略涉及使用特定的正电子发射断层扫描（PET）放射线（[18F] GE-180）进行易位蛋白18 kDa（TSPO）。 TSPO PET放射线用于非侵入性检测和跟踪生命受试者中的小胶质细胞激活（神经炎症的标记）。证据表明，即使在淀粉样斑块形成之前，神经炎症也发生在广告早期。此外，早期的抗炎干预措施似乎对AD的发作和进展产生了深远的影响。神经炎症在AD中的早期参与及其在整个疾病中一直存在并有助于神经退行性的事实，使其成为跟踪病理学和监测对早期治疗干预措施的反应的理想候选生物标志物。尽管有许多可用的TSPO放射性配体，但[18F] GE-180具有较高的结合亲和力和体内特性，用于在体内成像神经炎症过程。尽管该示踪剂已经进行了首次人工评估，并有良好的结果，但由于它可以监视AD中的治疗反应的能力，因此尚待研究。我们的近期目标是评估[18F] GE-180-PET，其能够跟踪AD进展并监测AD小鼠模型中药物疗法的反应的能力。此后，我们的长期目标是评估[18F] -GE180-PET作为AD治疗反应的生物标志物在新型疾病改良药物的临床试验中的生物标志物。我们的初步研究表明，[18F] GE-180-PET可以在疾病早期的AD（Appl/S）小鼠模型中检测小胶质细胞激活。在此提案中，我们旨在在AD小鼠模型中进一步评估[18F] GE-180，以用作AD神经炎症的替代标记，并监测当前正在评估AD治疗的新药物的反应。我们将通过以下特定目的实现目标：1）确定[18F] GE-180-PET信号与两种AD小鼠模型中的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的敏感性和准确性，以对目前在临床试验中对两个AD疗法的响应（I.E.e.e.e.e.e.e.，LM11A-31）进行成像，以对两种AD疗法进行响应。 [18F] GE-180的使用可能是一种“改变游戏规则”的方法，在整个生物标志物驱动的诊断和AD治疗疗法的领域中，潜在的优势可能具有遥远的优势。