title: Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.
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.
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Essa
authors.initials: E
authors.lastname: Hu
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Dah-Ren
authors.initials: DR
authors.lastname: Hwang
authors.affiliation: Department of Molecular Structure and Characterization, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Carl
authors.initials: C
authors.lastname: Davis
authors.affiliation: Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Jianxia
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Randall
authors.initials: R
authors.lastname: Hungate
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: James
authors.initials: J
authors.lastname: Treanor
authors.affiliation: Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
authors.forename: Hang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, Department of Pharmacokinetics and Drug Metabolism, Department of Neuroscience, and Department of Early Development, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 93012-1799, United States.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
keywords: Phosphodiesterase; brain penetration; positron emission tomography; radiotracer; receptor occupancy; tracer