2017•Journal of Medicinal ChemistryRequires access
The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging
Lei Zhang, Laigao M. Chen, Elizabeth M. Beck, Thomas A. Chappie, Richard V. Coelho, Shawn D. Doran, Kuo‐Hsien Fan, Christopher J. Helal, John M. Humphrey, Zoë A. Hughes, Kyle K. Kuszpit, Erik LaChapelle, John T. Lazzaro, Che‐Wah Lee, Robert J. Mather, Nandini C. Patel, Marc B. Skaddan, Simone Sciabola, Patrick R. Verhoest, Joseph M. Young, Kenneth R. Zasadny, Anabella Villalobos
Open publisher page 36 citations
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 ( B max ) 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, [ 18 F] 8 showed rapid brain uptake and high target specificity, indicating that [ 18 F] 8 is a promising PDE4B-preferring radioligand for clinical PET imaging.