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

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.