| Literature DB >> 27437084 |
Essa Hu1, Ning Chen1, Roxanne K Kunz1, Dah-Ren Hwang1, Klaus Michelsen2, Carl Davis1, Ji Ma3, Jianxia Shi3, Dianna Lester-Zeiner3, Randall Hungate1, James Treanor1, Hang Chen3, Jennifer R Allen1.
Abstract
We report the discovery of PDE10A PET tracer AMG 580 developed to support proof of concept studies with PDE10A inhibitors 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 washout rate 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 PDE10A target 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, [(18)F]-5 produced a significantly improved BPND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.Entities:
Keywords: Phosphodiesterase; brain penetration; positron emission tomography; radiotracer; receptor occupancy; tracer
Year: 2016 PMID： 27437084 PMCID： PMC4948002 DOI： 10.1021/acsmedchemlett.6b00185
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345