Identification and Profiling of a Selective and Brain Penetrant Radioligand for in Vivo Target Occupancy Measurement of Casein Kinase 1 (CK1) Inhibitors

To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK15/e) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1 delta/epsilon. inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [H-3]-9 to determine the binding affinity for PF-670462, a literature CK1 delta/epsilon inhibitor tool compound. Lastly, [H-3]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1 delta/epsilon in vivo pharmacology (circadian rhythm modulation).