Project Summary Alzheimer’s disease (AD) is a neurodegenerative disorder and the primary cause of dementia in the elderly and there is no cure currently available. Necroptosis is a complex and regulated caspase-independent cell death mechanism mediated by various protein members, e.g. receptor-interacting protein kinase 1 (RIP1 or RIPK1) involving inflammation. Notably, RIPK1 is up-regulated by microglial cells in human AD brains and mediates a disease-associated microglial response in AD. Unfortunately, there are no suitable non-invasive neuroimaging tools for investigating these processes in animals or in man. The development of a biomarker for visualizing RIPK1 in vivo represents a key step in understanding both the normal function and pathophysiology of RIPK1 in brain. Moreover, these techniques will accelerate the discovery of small molecule therapeutics that selectively interacts with RIPK1. The project is designed to validate a novel PET imaging probe for RIPK1 imaging in rodents and non-human primates during the R61 phase and perform the first-in-human imaging in the R33 phase. The success of healthy control imaging in this grant period will lead to further imaging study in patients.