First-in-Human evaluation of an astrocytic glutamate transporter (EAAT2) PET tracer in healthy and Alzheimer's diseased brain

项目总结 阿尔茨海默病(AD)和相关的痴呆症是一个日益严重的公共卫生问题， 对患者及其家属的影响。有效治疗AD的努力在一定程度上受到不同因素的干扰 关于其启动和发展的假说。不同的假设反映在高度的 用于研究AD及其进展的信息成像方法，如正电子发射断层扫描 (PET)靶向特定的大脑蛋白质。在这个项目中，我们将开发一种新的[18F]标记的PET成像 示踪剂RP-115用于评估健康AD患者和认知受损AD患者星形胶质细胞的变化 兴奋性氨基酸转运蛋白2(EAAT2)的PET定量成像 星形胶质细胞，在AD大脑的特定脑区显著下调。 项目假说是大脑局部RP-115示踪剂与星形胶质细胞EAAT2结合减少 在活体人脑中检测到的PET可作为AD发病的早期和敏感的指标 进步。人类第一个项目目标由两个可转化的发展目标组成：1)到 建立RP-115示踪剂的人体安全性；2)利用该示踪剂评估局部脑EAAT2示踪剂 健康AD患者与抗体、ptau和认知定义的AD患者的结合差异；并比较EAAT2 AD 数据到现有的AD FDG和MAO-B星形细胞相关的PET资料。我们将检验该假设并满足 通过实现三个特定目标来实现翻译项目目标。目标1：建立RP-115的安全性 临床上有男性和女性的PET成像。目的2：获取明确定义的男性的RP-115 EAAT2成像数据 女性健康对照组和AD患者队列。目的3：分析正电子发射计算机断层扫描的影像数据。

PROJECT SUMMARY Alzheimer’s disease (AD) and related dementias represent a growing public health concern with tremendous impact on patients and their families. Efforts to treat AD effectively are partially confounded by different hypotheses regarding its initiation and progression. The varying hypotheses are reflected in the range of highly informative imaging methods used to study AD and its progression, such as positron emission tomography (PET) targeted to specific cerebral proteins. In this project we will develop a novel [18F]-labeled PET imaging tracer, RP-115, to evaluate changes in astrocytes in healthy versus cognitively impaired AD patients by quantitative PET imaging of the excitatory amino acid transporter 2 (EAAT2) that is primarily localized on astrocytes and is significantly down-regulated in select cerebral regions of AD brain. The project hypothesis is that regional cerebral decreases of RP-115 tracer binding to astrocyte EAAT2 detected by PET imaging in live human brain can be used as an early and sensitive measure of AD onset and progression. The first-in-human project objective is composed with two translational development goals: 1) to establish RP-115 tracer human safety, and 2) to utilize the tracer to assess regional cerebral EAAT2 tracer binding differences in healthy vs. Ab-, pTau- and cognitively-defined AD patients; and compare the EAAT2 AD data to existing AD FDG and MAO-B astrocytic-related PET profiles. We will test the hypothesis and satisfy the translational project objective by accomplishing three Specific Aims. Aim 1: Establish RP-115 safety in the clinic with male and female PET imaging. Aim 2: Acquire RP-115 EAAT2 imaging data in well-defined male and female healthy control and AD patient cohorts. Aim 3: Analyze the PET imaging data.