PET Imaging for neuroinflammation in Alzheimer's disease

项目摘要 没有有效的疗法可用于停止或逆转AD进展，这部分归因于， 缺乏适用于临床前疾病模型和人类的翻译跨物种生物标志物， 促进药物发现和开发过程。因此，开发可翻译的成像生物标志物 对于疾病进展和治疗效果的非侵入性评估，有望填补这一差距。 未满足的临床需求。越来越多的证据表明小胶质细胞和神经免疫功能的改变 破坏发生在AD病理生理学的早期。我们还看到，早期干预， 神经炎症可显著影响AD的发生和进展。在此，我们建议使用 一种新的成像策略，用于监测先天免疫功能，神经炎症和小胶质细胞调节， AD治疗中的治疗反应我们的策略是使用一种特殊的正电子发射断层扫描技术 (PET)靶向嘌呤能P2 X7受体（P2 X7 R）的示踪剂[18 F]JNJ-739。P2 X7 R表达增加， 在AD患者和不同的AD小鼠模型中淀粉样斑块周围的小胶质细胞中发现， 与AD进展相似。[18F]JNJ-739是唯一一种经验证的P2 X7 R PET示踪剂， 在非人灵长类动物的大脑中的渗透性和特异性结合，最近已转化为人类使用。 该配体具有优异的结合亲和力（IC 50 1.0 nM）和对任何其他配体的高选择性（>100倍）。 中枢神经系统的主要目标。PI及其团队评价了[18 F]JNJ-739在大鼠中的脑动力学和特异性结合。 神经炎症小鼠模型。我们的初步研究表明，[18 F]JNJ-739-PET可以检测和 监测LPS诱导的神经炎症小鼠模型中的神经炎症，这与 我们的免疫组织学发现 到目前为止，还没有直接的非侵入性体内测量P2 X7 R的分布和表达。 不同的AD阶段，代表了大量的知识差距和研究小胶质细胞激活的机会， [18 F]JNJ-739-PET测定的先天免疫功能。我们的假设是增加P2 X7 R脑结合， 通过[18 F]JNJ-739-PET测定，与AD症状严重程度、神经炎症增加 活化的小胶质细胞和严重的先天免疫破坏，以及高Aβ/tau蛋白的产生。因此，作为我们 具体目的，利用非侵入性[18 F]JNJ-739-PET，我们建议直接监测P2 X7 R的变化， 大脑作为AD中神经炎症和改变的小胶质细胞的指标，并确定靶点参与。 在此之后，我们的长期目标是评估[18 F]JNJ-739-PET作为翻译生物标志物的效用， 提供AD病理生理学的新信息，并在新型AD的临床试验中评价治疗反应 毒品

Project Summary There are no efficacious therapies available to halt or reverse AD progression, which is attributed to, in part, the lack of translational cross-species biomarkers suitable in both preclinical disease models and humans to facilitate drug discovery and development process. Therefore, development of translatable imaging biomarkers for non-invasive assessment of disease progression and therapeutic efficacy hold promises to fill the gap of this urgent and unmet clinical need. Growing evidence indicates altered microglia and neuroimmune function disruption occurs early in the AD pathophysiology. We have also seen that early intervention against neuroinflammation could substantially impact the incidence and progression of AD. Herein we propose the use of a novel imaging strategy for monitoring innate immune function, neuroinflammation, and microglia-modulating treatment response in AD therapy. Our strategy involves the use of a specific positron emission tomography (PET) tracer [18F]JNJ-739 targeting purinergic P2X7 receptor (P2X7R). Increased P2X7R expression has been found in microglial cells surrounding amyloid plaques both in AD patients and different AD mouse models, which parallels with AD progression. [18F]JNJ-739 is the only validated P2X7R PET tracer that showed high permeability and specific binding in the brain of nonhuman primates and has recently translated to human use. The ligand possesses excellent binding affinity (IC50 1.0 nM) and high selectivity (>100 fold) towards any other major CNS targets. The PI and his team have evaluated brain kinetic and specific binding of [18F]JNJ-739 in neuroinflammation mouse models. Our preliminary studies have shown that [18F]JNJ-739-PET can detect and monitor neuroinflammation in LPS-induced neuroinflammation mouse models, which was well-correlated with our immunohistological findings. To date, there is no direct non-invasive in vivo measurement of the distribution and expression of P2X7R in various AD stages, representing a substantial knowledge gap and opportunity to study microglia activation and innate immune function by [18F]JNJ-739-PET. Our hypothesis entails that increased P2X7R brain binding, determined by [18F]JNJ-739-PET, is correlated with AD symptom severity, increased neuroinflammation, activated microglia and severe innate immune disruption, as well as high Aβ/tau production. Therefore, as our specific objectives, utilizing non-invasive [18F]JNJ-739-PET, we propose to directly monitor P2X7R changes in the brain as an index of neuroinflammation and altered microglia in AD, and determine target engagement. Following this, our long-term goal is to assess the utility of [18F]JNJ-739-PET as a translational biomarker to provide new information of AD pathophysiology and to evaluate treatment response in clinical trials of novel AD drugs.