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
  • 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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