2. Academic Validation
  3. AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer

AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer

  • J Pharmacol Exp Ther. 2015 Feb;352(2):327-37. doi: 10.1124/jpet.114.220517.
Hang Chen 1,  Dianna Lester-Zeiner 2,  Jianxia Shi 2,  Silke Miller 2,  Charlie Glaus 2,  Essa Hu 2,  Ning Chen 2,  Jessica Able 2,  Christopher Biorn 2,  Jamie Wong 2,  Ji Ma 2,  Klaus Michelsen 2,  Geraldine Hill Della Puppa 2,  Tim Kazules 2,  Hui Hannah Dou 2,  Santosh Talreja 2,  Xiaoning Zhao 2,  Ada Chen 2,  Shannon Rumfelt 2,  Roxanne K Kunz 2,  Hu Ye 2,  Oliver R Thiel 2,  Toni Williamson 2,  Carl Davis 2,  Amy Porter 2,  David Immke 2,  Jennifer R Allen 2,  James Treanor 2
Affiliations

Affiliations

  • 1 Department of Neuroscience (H.C., D.L.-Z., J.A., C.B., H.H.D., S.T., A.P.), Department of Pharmacokinetics and Drug Metabolism (J.S., J.W., J.M.), and Department of Molecular Structures and Characterization (X.Z., A.C.), Amgen Inc., South San Francisco, California; Department of Neuroscience (S.M., G.H.D.P., D.I., J.T.), Department of Pharmacokinetics and Drug Metabolism (C.D.), Research Imaging Sciences (C.G., T.K., H.Y.), Department of Small Molecule Chemistry (E.H., N.C., S.R., R.K.K., J.R.A.), and Department of Process Development (O.R.T.), Amgen Inc., Thousand Oaks, California; and Department of Molecular Structures and Characterization (K.M.) and Department of Discovery Toxicology (T.W.), Amgen Inc., Cambridge, Massachusetts (K.M.) hangc@amgen.com.
  • 2 Department of Neuroscience (H.C., D.L.-Z., J.A., C.B., H.H.D., S.T., A.P.), Department of Pharmacokinetics and Drug Metabolism (J.S., J.W., J.M.), and Department of Molecular Structures and Characterization (X.Z., A.C.), Amgen Inc., South San Francisco, California; Department of Neuroscience (S.M., G.H.D.P., D.I., J.T.), Department of Pharmacokinetics and Drug Metabolism (C.D.), Research Imaging Sciences (C.G., T.K., H.Y.), Department of Small Molecule Chemistry (E.H., N.C., S.R., R.K.K., J.R.A.), and Department of Process Development (O.R.T.), Amgen Inc., Thousand Oaks, California; and Department of Molecular Structures and Characterization (K.M.) and Department of Discovery Toxicology (T.W.), Amgen Inc., Cambridge, Massachusetts (K.M.).
PMID: 25502803 DOI: 10.1124/jpet.114.220517
Abstract

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

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