Molecular Imaging Of Alzheimer'S Disease-Related Gamma-Secretase In Mice And Nonhuman Primates

The pathogenesis of Alzheimer's disease (AD) is primarily driven by brain accumulation of the amyloid-beta-42 (A beta(42)) peptide generated from the amyloid-beta precursor protein (APP) via cleavages by beta- and gamma-secretase. gamma-Secretase is a prime drug target for AD; however, its brain regional expression and distribution remain largely unknown. Here, we are aimed at developing molecular imaging tools for visualizing gamma-secretase. We used our recently developed gamma-secretase modulators (GSMs) and synthesized our GSM-based imaging agent, [C-11]SGSM-15606. We subsequently performed molecular imaging in rodents, including AD transgenic animals, and macaques, which revealed that our probe displayed good brain uptake and selectivity, stable metabolism, and appropriate kinetics and distribution for imaging gamma-secretase in the brain. Interestingly, rodents and macaques shared certain brain areas with high gamma-secretase expression, suggesting a functional conservation of gamma-secretase. Collectively, we have provided the first molecular brain imaging of gamma-secretase, which may not only accelerate our drug discovery for AD but also advance our understanding of AD.