Strategies to facilitate the discovery of novel CNS PET ligands

Positron Emission Tomography (PET), as a non-invasive translatable imaging technology, can be incorporated into various stages of the CNS drug discovery process to provide valuable information for key preclinical and clinical decision-making. Novel CNS PET ligand discovery efforts in the industry setting, however, are facing unique challenges associated with lead design and prioritization, and budget constraints. In this review, three strategies aiming toward improving the central nervous system (CNS) PET ligand discovery process are described: first, early determination of receptor density (B(max)) and bio-distribution to inform PET viability and resource allocation; second, rational design and design prioritization guided by CNS PET design parameters; finally, a cost-effective in vivo specific binding assessment using a liquid chromatography-mass spectrometry (LC-MS/MS) “cold tracer” method. Implementation of these strategies allowed a more focused and rational CNS PET ligand discovery effort to identify high quality PET ligands for neuroimaging.