Synthesis and characterization of a new Carbon-11 labeled positron emission tomography radiotracer for RIPK1 neuroimaging.

Receptor-interacting serine/threonine protein kinase 1 (RIPK1) is a protein target that regulates necroptosis and immune responses. It plays an important role in inflammation and neurological diseases. RIPK1 inhibitor molecules have entered early clinical trials and have been used to treat neurological diseases such as Alzheimer's disease (AD) and immune system diseases like psoriasis, rheumatoid arthritis, and ulcerative colitis. The development of RIPK1 PET imaging probes can facilitate a comprehensive understanding of the distribution of RIPK1 and its association with related diseases. CMP1 is a potent RIPK1 inhibitor with good druggability to be an RIPK1 PET imaging probe. This study presents the synthesis and characterization of [11C]CMP1 as a RIPK1 PET probe, providing valuable insights into its potential applications in biomedical research. PET imaging of [11C]CMP1 showed high blood-brain barrier (BBB) penetration and the highest brain uptake of % ID/g = 10 post-injections in mice. The analysis of biodistribution in the brain region and studies on blocking demonstrated that [11C]CMP1 exhibited favorable selectivity and specificity in binding. Finally, the autoradiography study further showed that [11C]CMP1 has good specificity binding to RIPK1 and the autoradiography experiment of AD mouse brain slices proved the application potential of the probe in AD. Our research suggests that [11C]CMP1 shows promise as a PET imaging probe for studying the brain's RIPK1 system, paving the way for developing novel RIPK1 PET probes and further investigating.