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Discovery of Phosphodiesterase 10A (PDE10A) PET Tracer AMG 580 to Support Clinical Studies.
Hu, Essa; Chen, Ning; Kunz, Roxanne K; Hwang, Dah-Ren; Michelsen, Klaus; Davis, Carl; Ma, Ji; Shi, Jianxia; Lester-Zeiner, Dianna; Hungate, Randall; Treanor, James; Chen, Hang; Allen, Jennifer R.
Afiliação
  • Hu E; 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.
  • Chen N; 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.
  • Kunz RK; 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.
  • Hwang DR; 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.
  • Michelsen K; Department of Molecular Structure and Characterization, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Davis C; 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.
  • Ma J; Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Shi J; Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Lester-Zeiner D; Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Hungate R; 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.
  • Treanor J; 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.
  • Chen H; Department of Neuroscience and Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
  • Allen JR; 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.
ACS Med Chem Lett ; 7(7): 719-23, 2016 Jul 14.
Article em En | MEDLINE | ID: mdl-27437084
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.
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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Revista: ACS Med Chem Lett Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos