The design, synthesis and evaluation of the first carbon-11 positron emission tomography radiotracer for ASK1 imaging.

Apoptosis signal regulating kinase 1 (ASK1) plays a central role in the molecular pathogenesis of various neurological disorders by mediating inflammation, oxidative stress, and apoptosis. ASK1 has emerged as an important therapeutic target in a range of neurodegenerative and neuroinflammatory disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein, we describe the development and preclinical evaluation of [11C]HYF038 as the first positron emission tomography radiotracer for imaging ASK1. In vitro autoradiography, [11C]HYF038 performed good specific binding to the ASK1 proteins in the mice brain regions, data are expressed as the density light units per square millimeter (DLU/mm2) in the blocking group was reduced by 28%. In vivo PET imaging of [11C]HYF038 in rodent model demonstrated a certain blood-brain barrier (BBB) penetration with SUV = 0.5, the biodistribution result of [11C]HYF038 in different organs showed that [11C]HYF038 is mainly metabolized in the liver. These findings indicate that [11C]HYF038 can act as a promising lead for the further development of PET tracers to image ASK1 in neurodegenerative disease progression.