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.

项目摘要 阿尔茨海默病（AD）和相关痴呆代表了日益增长的公共卫生问题， 对患者及其家属的影响。有效治疗AD的努力部分受到不同的干扰。 关于其启动和进展的假设。不同的假设反映在高度 用于研究AD及其进展的信息性成像方法，如正电子发射断层扫描 (PET)针对特定的大脑蛋白质。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，以评估健康与认知受损AD患者中星形胶质细胞的变化， 兴奋性氨基酸转运蛋白2（EAAT 2）的定量PET成像，主要定位于 在AD脑的选择脑区域中显著下调。 该项目的假设是，RP-115示踪剂与星形胶质细胞EAAT 2结合的局部脑减少 在活体人脑中通过PET成像检测到的AD可以用作AD发作的早期和灵敏的测量， 进展第一个人类项目目标由两个转化发展目标组成：1） 建立RP-115示踪剂的人体安全性，2）利用示踪剂评估局部脑EAAT 2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EAAT 2 AD 现有AD FDG和MAO-B星形胶质细胞相关PET图谱的数据。我们将测试假设并满足 通过实现三个具体目标来实现项目目标。目的1：确定RP-115在 男性和女性的PET成像。目的2：在轮廓分明的男性中采集RP-115 EAAT 2成像数据 以及女性健康对照和AD患者队列。目的3：分析PET成像数据。