2. Academic Validation
  3. The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging

The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging

  • J Med Chem. 2017 Oct 26;60(20):8538-8551. doi: 10.1021/acs.jmedchem.7b01050.
Lei Zhang 1,  Laigao Chen 2,  Elizabeth M Beck 1,  Thomas A Chappie 1,  Richard V Coelho 3,  Shawn D Doran 4,  Kuo-Hsien Fan 3,  Christopher J Helal 5,  John M Humphrey 5,  Zoe Hughes 6,  Kyle Kuszpit 3,  Erik A Lachapelle 5,  John T Lazzaro 4,  Chewah Lee 5,  Robert J Mather 6,  Nandini C Patel 1,  Marc B Skaddan 3,  Simone Sciabola 1,  Patrick R Verhoest 1,  Joseph M Young 5,  Kenneth Zasadny 3,  Anabella Villalobos 7
Affiliations

Affiliations

  • 1 Medicine Design, Medicinal Chemistry, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
  • 2 Clinical & Translational Imaging, Early Clinical Development, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
  • 3 Bioimaging Center, Pfizer Inc. , Groton, Connecticut 06340, United States.
  • 4 Medicine Design, Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc. , Groton, Connecticut 06340, United States.
  • 5 Medicine Design, Medicinal Chemistry, Pfizer Inc. , Groton, Connecticut 06340, United States.
  • 6 Internal Medicine Research Unit, Pfizer Inc. , Cambridge, Massachusetts 02139, United States.
  • 7 Medicinal Synthesis Technologies, Pfizer Inc. , Groton, Connecticut 06340, United States.
PMID: 28957634 DOI: 10.1021/acs.jmedchem.7b01050
Abstract

As part of our effort in identifying phosphodiesterase (PDE) 4B-preferring inhibitors for the treatment of central nervous system (CNS) disorders, we sought to identify a positron emission tomography (PET) ligand to enable target occupancy measurement in vivo. Through a systematic and cost-effective PET discovery process, involving expression level (Bmax) and biodistribution determination, a PET-specific structure-activity relationship (SAR) effort, and specific binding assessment using a LC-MS/MS "cold tracer" method, we have identified 8 (PF-06445974) as a promising PET lead. Compound 8 has exquisite potency at PDE4B, good selectivity over PDE4D, excellent brain permeability, and a high level of specific binding in the "cold tracer" study. In subsequent non-human primate (NHP) PET imaging studies, [18F]8 showed rapid brain uptake and high target specificity, indicating that [18F]8 is a promising PDE4B-preferring radioligand for clinical PET imaging.

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