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Research ArticleDrug Discovery and Translational Medicine

AMG580: a Novel Small Molecule Phosphodiesterase 10A (PDE10A) PET Tracer

Hang Chen, Dianna Lester-Zeiner, Jianxia Shi, Silke Miller, Charlies Glaus, Essa Hu, Ning Chen, Jessica Able, Christopher Biorn, Jamie Wong, Ji Ma, Klaus Michelsen, Geraldine Hill Della Puppa, Tim Kazules, Hui Hannah Dou, Santosh Talreja, Xiaoning Zhao, Ada Chen, Shannon Rumfelt, Roxanne Kunz, Hu Ye, Oliver R Thiel, Toni Williamson, Carl Davis, Amy Poter, David Immke, Jennifer R Allen and James Treanor
Journal of Pharmacology and Experimental Therapeutics December 11, 2014, jpet.114.220517; DOI: https://doi.org/10.1124/jpet.114.220517
Hang Chen
Amgen
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Dianna Lester-Zeiner
Amgen
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Jianxia Shi
Amgen
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Silke Miller
Amgen
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Charlies Glaus
Amgen
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Essa Hu
Amgen
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Ning Chen
Amgen
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Jessica Able
Amgen
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Christopher Biorn
Amgen
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Jamie Wong
Amgen
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Ji Ma
Amgen
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Klaus Michelsen
Amgen
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Geraldine Hill Della Puppa
Amgen
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Tim Kazules
Amgen
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Hui Hannah Dou
Amgen
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Santosh Talreja
Amgen
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Xiaoning Zhao
Amgen
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Ada Chen
Amgen
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Shannon Rumfelt
Amgen
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Roxanne Kunz
Amgen
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Hu Ye
Amgen
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Oliver R Thiel
Amgen
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Toni Williamson
Amgen
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Carl Davis
Amgen
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Amy Poter
Amgen
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David Immke
Amgen
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Jennifer R Allen
Amgen
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James Treanor
Amgen
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Abstract

Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurological disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful CNS 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, a novel, selective small molecule antagonist with sub-nanomolar 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 LC-MS/MS technology. [3H]-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, [18F]-AMG 580 demonstrated prominent uptake by positron emission tomography (PET) in rats suggesting that radiolabelled AMG 580 may be suitable for further development as a non-invasive 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.

  • cAMP
  • CNS pharmacokinetics
  • drug discovery
  • phosphodiesterases
  • schizophrenia
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 365 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 365, Issue 2
1 May 2018
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Research ArticleDrug Discovery and Translational Medicine

AMG580: a Novel Small Molecule Phosphodiesterase 10A (PDE10A) PET Tracer

Hang Chen, Dianna Lester-Zeiner, Jianxia Shi, Silke Miller, Charlies Glaus, Essa Hu, Ning Chen, Jessica Able, Christopher Biorn, Jamie Wong, Ji Ma, Klaus Michelsen, Geraldine Hill Della Puppa, Tim Kazules, Hui Hannah Dou, Santosh Talreja, Xiaoning Zhao, Ada Chen, Shannon Rumfelt, Roxanne Kunz, Hu Ye, Oliver R Thiel, Toni Williamson, Carl Davis, Amy Poter, David Immke, Jennifer R Allen and James Treanor
Journal of Pharmacology and Experimental Therapeutics December 11, 2014, jpet.114.220517; DOI: https://doi.org/10.1124/jpet.114.220517

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Research ArticleDrug Discovery and Translational Medicine

AMG580: a Novel Small Molecule Phosphodiesterase 10A (PDE10A) PET Tracer

Hang Chen, Dianna Lester-Zeiner, Jianxia Shi, Silke Miller, Charlies Glaus, Essa Hu, Ning Chen, Jessica Able, Christopher Biorn, Jamie Wong, Ji Ma, Klaus Michelsen, Geraldine Hill Della Puppa, Tim Kazules, Hui Hannah Dou, Santosh Talreja, Xiaoning Zhao, Ada Chen, Shannon Rumfelt, Roxanne Kunz, Hu Ye, Oliver R Thiel, Toni Williamson, Carl Davis, Amy Poter, David Immke, Jennifer R Allen and James Treanor
Journal of Pharmacology and Experimental Therapeutics December 11, 2014, jpet.114.220517; DOI: https://doi.org/10.1124/jpet.114.220517
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