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

对健康和阿尔茨海默病大脑中星形细胞谷氨酸转运蛋白 (EAAT2) PET 示踪剂的首次人体评估

• 批准号: 10683344
• 负责人: JOHN M GERDES
• 金额: $ 81.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683344
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid; Animals; Astrocytes; Binding; Blood; Blood specimen; Brain; Brain Mapping; Brain region; Cells; Cerebrum; Clinic; Clinical; Clinical Protocols; Clinical Research; Cognitive; Coupled; Data; Data Analyses; Development; Disease Progression; Dose; Evaluation; Excitatory Amino Acid Transporter 2; Family; Female; Functional disorder; Funding; Glucose Transporter; Glutamate Transporter; Glutamates; Glycoproteins; Goals; Homeostasis; Human; Image; Impaired cognition; Inflammation; Inflammatory Response; Institutional Review Boards; Investigational Drugs; Investigational New Drug Application; Label; Literature; Location; Magnetic Resonance Imaging; Maps; Measures; Membrane; Membrane Proteins; Memory; Methods; Modeling; Monoamine Oxidase B; Neuroglia; New Drug Approvals; Onset of illness; Organ; Pathology; Patient Recruitments; Patients; Persons; Play; Positron-Emission Tomography; Proteins; Protocols documentation; Public Health; Radioactive; Reporting; Role; Safety; Scanning; Synapses; Synaptic Vesicles; Testing; Therapeutic Intervention; Time; Tracer; aquaporin 4; cohort; dimer; dosimetry; first-in-human; fluorodeoxyglucose; hyperphosphorylated tau; imaging biomarker; imaging modality; insight; interest; male; neuroinflammation; neurotransmitter uptake; novel; postsynaptic neurons; presynaptic neurons; radioligand; radiotracer; safety study

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.

项目概要 阿尔茨海默病 (AD) 和相关痴呆症是一个日益严重的公共卫生问题，其影响巨大 有效治疗 AD 的努力在一定程度上因不同的因素而受到影响。 关于其起始和进展的假设 不同的假设反映在高度的范围内。 用于研究 AD 及其进展的信息成像方法，例如正电子发射断层扫描 （PET）针对特定的脑蛋白在这个项目中，我们将开发一种新型的[18F]标记的PET成像。 示踪剂 RP-115，用于评估健康 AD 患者与认知障碍患者星形胶质细胞的变化 兴奋性氨基酸转运蛋白 2 (EAAT2) 的定量 PET 成像主要位于 星形胶质细胞在 AD 大脑的某些大脑区域中显着下调。 该项目假设是 RP-115 示踪剂与星形胶质细胞 EAAT2 结合的区域性大脑减少 通过 PET 成像在活体人脑中检测到的 AD 可以作为 AD 发病的早期、敏感的测量方法 首次人类项目的目标由两个转化发展目标组成：1) 到 建立RP-115示踪剂的人体安全性，以及2)利用该示踪剂评估区域脑部EAAT2示踪剂 健康与 Ab、pTau 和认知定义的 AD 患者的结合差异，并比较 EAAT2 AD 我们将验证假设并满足现有的 AD FDG 和 MAO-B 星形胶质细胞相关 PET 数据。 通过实现三个具体目标 1：建立 RP-115 安全性来实现转化项目目标。 目标 2：获取明确的男性 RP-115 EAAT2 成像数据。 目标 3：分析 PET 成像数据。