Design, synthesis, and preclinical evaluation of 11C/18F-labeled inhibitors for RIPK1 PET imaging

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a promising target for the diagnosis and treatment of various diseases, especially neurodegenerative disorders. Developing PET imaging probes targeting RIPK1 is beneficial for visualizing the connections between RIPK1 and diseases, as well as for related drug development. In this study, we report the design and synthesis of a series of novel RIPK1 inhibitors. Three potent inhibitors, 7i, 7k, and 8a, with good cell anti-necroptosis potency and physicochemical properties, were identified and selected for PET imaging probe development. Subsequently, three PET imaging radioligands ([¹¹C]7k, [¹⁸F]7i, and [¹⁸F]8a) were successfully synthesized. In mouse PET imaging studies, all three radioligands showed good brain uptake. Among them, probe [¹⁸F]8a exhibited good binding specificity in both in vitro autoradiography and in vivo PET imaging studies. Additionally, [¹⁸F]8a demonstrated good in vivo metabolic stability. This work highlights the potential of probe [¹⁸F]8a for imaging brain RIPK1 in live animals, laying the groundwork for the future development of RIPK1 PET radioligands.