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

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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.