PROJECT SUMMARY Alzheimer's disease (AD) is a neurodegenerative disease, characterized by progressive loss of memory which is associated with other cognitive deficits. It is thought to affect about 5.3 million people in the United States and is currently ranked as the sixth leading cause of death. Major neuropathology observations of postmortem AD brain include the presence of senile plaques containing primarily β-amyloid (Aβ) peptide aggregates, and tangles comprising highly phosphorylated τ proteins. The “Aβ hypothesis” proposes that development of AD is driven by the accumulation and deposition of Aβ peptide aggregates in the brain. The amyloidogenic pathway is a two- step sequential cleavage, first by the enzyme β-secretase then by γ-secretase, producing the most amyloidogenic and neurotoxic Aβ42, which is the most prone to aggregation, forming aggregates of insoluble fibrils in the brain. Because of the neuropharmacological involvement of γ-secretase, γ-secretase has attracted considerable attention as a therapeutic target for AD. Many γ-secretase inhibitors (GSIs) and modulators (GSMs) have been identified in the AD pipeline. To better understand the γ-secretase biology and assist drug discovery that targets the γ-secretase, tools to image the γ-secretase in AD human brains will be valuable. The goal of molecular imaging is non-invasive visualization and quantification of molecular entities and correlation to pathophysiological events. Consequently, positron emission tomography (PET) can be regarded as a key molecular imaging tool, allowing for the study of the function and neurochemistry of the human brain. Here, the aim of this research project is to further develop a potent γ-secretase PET probe with appropriate performance characteristics. The designed analogs of γ-secretase modulator GSM-15606 will be radiolabeled with 11C for eventual in vivo PET imaging evaluation. The PET imaging results will be critical to provide novel insights of γ- secretase in AD brains and support the clinical trial of GSMs in AD intervention.