PET imaging is a non-invasive methodology frequently used in central nervous system (CNS) applications to quantify the concentration of a drug reaching a target by directly measuring receptor occupancy (RO). PET RO data are extremely useful for optimization of clinical dose selection, differentiation of drug candidates and defining clear and translatable clinical Go/No Go criteria. To enable clinical measurement of RO through PET imaging, one would need to make available a PET ligand with suitable attributes. While many factors that determine the success of a CNS PET ligand are similar to those governing the success of a candidate drug, important differences exist. In particular, achieving low levels of non-specific binding is crucial for enabling clinical measurement of RO through PET imaging. To streamline and accelerate the discovery process of novel CNS PET ligands, we aim to define a chemical space that would facilitate compound prioritization and rational ligand design, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 fit-for-purpose PET ligands, together with 15 radioligands that failed in late-stage as negative controls. Their physicochemical and PK properties were then calculated using a series of in silico models developed within Pfizer and the results were analyzed in a Spotfire visualization tool. Based on this systematic analysis, a set of preferred property parameters were defined for physicochemical properties, permeability, brain penetration and non-specific binding. These preferred parameters have been applied subsequently to several Pfizer programs, which will be exemplied by the successful development of the first PDE2 selective PET ligand [18F]-0430. The efforts described herein tackled the key hurdles associated with PET ligand discovery process, thereby allowed acceleration of the discovery process with reduced resources and higher success rate.

Development of design and selection parameters to accelerate the discovery process of novel CNS PET ligands

244th National Meeting (2012)

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