ABSTRACT The objective of this project is to develop, validate, and translate novel positron emission tomography (PET) imaging probes for rho-associated coiled-coil containing protein kinase 2 (ROCK2). Consistent with prior postmortem studies, significant synaptic loss was found using SV2A PET in the hippocampus and frontal cortex of patients with MCI and early AD, indicating progressive synaptic loss along the disease path. The synapse loss in MCI/AD patients is expected to be mediated through activation of rho/ROCK2 signaling pathway. Elevated ROCK2 has been observed in postmortem brain tissues of asymptomatic AD and MCI patients and in transgenic rodent models of familial AD. These data demonstrate the potential of detecting preclinical and prodromal AD through ROCK2 PET imaging, which may lead to identification of new therapeutic targets with a defined early intervention time window to delay or prevent the synapse loss and onset of dementia. Therefore, we propose to develop and translate ROCK2 PET imaging probes for future clinical investigations. Successful completion of this project will yield a ROCK2 PET imaging probe ready to be tested in humans as a sensitive and quantitative in vivo biomarker for preclinical and prodromal AD, which will allow early interventions to slow or halt disease progression.