PET Imaging for neuroinflammation in Alzheimer's disease

阿尔茨海默病神经炎症的 PET 成像

基本信息

批准号：
10301580
负责人：
Steven H Liang
金额：
$ 24.66万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301580
关键词：
AD transgenic mice Abeta synthesis Affinity Alzheimer&apos s Disease Amyloid beta-Protein Anti-Inflammatory Agents Astrocytes Behavioral Binding Biological Biological Markers Brain CSF1R gene Clinical Clinical Trials Development Disease Disease Progression Disease model Dose Early Intervention Evaluation Functional disorder Goals Human Image Imaging Device Immune Incidence Inflammation Kinetics Knowledge Ligands Measurement Measures Microglia Modeling Monitor Neurodegenerative Disorders Neuroimmune Neurons Outcome Patients Permeability Pharmaceutical Preparations Positron-Emission Tomography Process Production Rodent Role Scientific Advances and Accomplishments Senile Plaques Severities Signal Transduction Symptoms Synapses Testing Therapeutic Therapeutic Intervention Time Tracer Translating Treatment Efficacy United States Work behavioral study density design drug development drug discovery efficacious treatment imaging biomarker imaging study in vivo indexing inhibitor/antagonist innate immune function mouse model neuroinflammation nonhuman primate novel outcome prediction pre-clinical receptor receptor binding receptor expression response tau Proteins treatment response

项目摘要

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.

项目概要没有有效的疗法可以阻止或逆转 AD 的进展，部分原因是：缺乏适用于临床前疾病模型和人类的跨物种转化生物标志物促进药物发现和开发过程，因此，可翻译成像生物标志物的开发。用于疾病进展和治疗效果的非侵入性评估有望填补这一空白越来越多的证据表明小胶质细胞和神经免疫功能具有迫切且未得到满足的临床需求。 AD 病理生理学的破坏发生在早期。我们也看到了针对 AD 的早期干预。神经炎症可能会严重影响 AD 的发生和进展，在此我们建议使用。用于监测先天免疫功能、神经炎症和小胶质细胞调节的新型成像策略我们的策略涉及使用特定的正电子发射断层扫描。 (PET) 示踪剂 [18F]JNJ-739 靶向嘌呤能 P2X7 受体 (P2X7R)，P2X7R 表达增加。在 AD 患者和不同 AD 小鼠模型中淀粉样斑块周围的小胶质细胞中发现 [18F]JNJ-739 是唯一经过验证且显示出高水平的 P2X7R PET 示踪剂。非人类灵长类动物大脑中的渗透性和特异性结合，最近已转化为人类使用。该配体对任何其他配体具有优异的结合亲和力 (IC50 1.0 nM) 和高选择性 (>100 倍) PI 和他的团队评估了 [18F]JNJ-739 的大脑动力学和特异性结合。我们的初步研究表明，[18F]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，该模型与我们的免疫组织学发现。迄今为止，还没有直接的非侵入性体内测量P2X7R在体内的分布和表达。不同的 AD 阶段，代表着巨大的知识差距和研究小胶质细胞激活和 [18F]JNJ-739-PET 的先天免疫功能我们的假设表明 P2X7R 大脑结合增加，由 [18F]JNJ-739-PET 确定，与 AD 症状严重程度、神经炎症增加、激活的小胶质细胞和严重的先天免疫破坏，以及高 Aβ/tau 产量。针对特定目标，利用非侵入性 [18F]JNJ-739-PET，我们建议直接监测 P2X7R 的变化大脑作为 AD 中神经炎症和小胶质细胞改变的指标，并确定目标参与度。在此之后，我们的长期目标是评估 [18F]JNJ-739-PET 作为转化生物标志物的效用提供 AD 病理生理学的新信息并评估新型 AD 临床试验中的治疗反应药物。