Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.

We report the discovery of PDE10APET tracer AMG 580 developed to support proof of concept studies with PDE10Ainhibitors in the clinic. To find a tracer with higher binding potential(BPND) in NHP than our previously reported tracer 1, we implemented a surface plasmon resonance assay to measure the binding off-rate to identify candidates with slower washoutrate in vivo. Five candidates (2–6) from two structurally distinct scaffolds were identified that possessed both the in vitro characteristics that would favor central penetration and the structural features necessary for PET isotope radiolabeling. Two cinnolines(2, 3) and one keto-benzimidazole (5) exhibited PDE10Atarget specificity and brain uptake comparable to or better than 1 in the in vivo LC–MS/MS kinetics distribution study in SD rats. In NHP PET imaging study, [18F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10APET tracer clinical candidate for further studies.