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 ß-amyloid (Aß) peptide aggregates, and tangles
comprising highly phosphorylated t proteins. The “Aß hypothesis” proposes that development of AD is driven by
the accumulation and deposition of Aß peptide aggregates in the brain. The amyloidogenic pathway is a two-
step sequential cleavage, first by the enzyme ß-secretase then by ¿-secretase, producing the most
amyloidogenic and neurotoxic Aß42, which is the most prone to aggregation, forming aggregates of insoluble
fibrils in the brain. Because of the neuropharmacological involvement of ¿-secretase, ¿-secretase has attracted
considerable attention as a therapeutic target for AD. Many ¿-secretase inhibitors (GSIs) and modulators (GSMs)
have been identified in the AD pipeline. To better understand the ¿-secretase biology and assist drug discovery
that targets the ¿-secretase, tools to image the ¿-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 ¿-secretase PET probe with appropriate performance
characteristics. The designed analogs of ¿-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 ¿-
secretase in AD brains and support the clinical trial of GSMs in AD intervention.