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

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• 作者：Essa Hu ; Ning Chen ; Roxanne K. Kunz ; Dah-Ren Hwang ; Klaus Michelsen ; Carl Davis ; Ji Ma ; Jianxia Shi ; Dianna Lester-Zeiner ; Randall Hungate ; James Treanor ; Hang Chen ; Jennifer R. Allen
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：719-723
• 全文大小：283K
• 年卷期：0
• ISSN：1948-5875

文摘

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 (BP_ND) 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, [¹⁸F]-5 produced a significantly improved BP_ND of 3.1 and was nominated as PDE10A PET tracer clinical candidate for further studies.