Visualization of Receptor-Interacting Protein Kinase 1 (RIPK1) by Brain Imaging with Positron Emission Tomography

We report the development of the first positron emission tomography (PET) radiotracer, [18F]­CNY-07, based on a highly specific and potent RIPK1 inhibitor, Nec-1s, for RIPK1/necroptosis brain imaging in rodents. [18F]­CNY-07 was synthesized through copper-mediated 18F-radiolabeling from an aryl boronic ester precursor and studied in vivo PET imaging in rodents. PET imaging results showed that [18F]­CNY-07 can penetrate the blood–brain barrier with a maximum percent injected dose per unit volume of 3 at 10 min postinjection in the brain in vivo. Self-blocking studies of [18F]­CNY-07 by pretreating with unlabeled molecules in rodents showed reduced radioactivity in animal brains (30% radioactivity decreased), indicating the binding specificity of our radiotracer. Our studies demonstrate that [18F]­CNY-07 has provided a useful PET radioligand enabling brain RIPK1 imaging, which could be a valuable research tool in studying RIPK1-related neurological disorders in animals and potentially humans.