Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand

To
accelerate the discovery of novel small molecule central nervous
system (CNS) positron emission tomography (PET) ligands, we aimed
to define a property space that would facilitate ligand design and
prioritization, thereby providing a higher probability of success
for novel PET ligand development. Toward this end, we built a database
consisting of 62 PET ligands that have successfully reached the clinic
and 15 radioligands that failed in late-stage development as negative
controls. A systematic analysis of these ligands identified a set
of preferred parameters for physicochemical properties, brain permeability,
and nonspecific binding (NSB). These preferred parameters have subsequently
been applied to several programs and have led to the successful development
of novel PET ligands with reduced resources and timelines. This strategy
is illustrated here by the discovery of the novel phosphodiesterase
2A (PDE2A) PET ligand 4-(3-[18F]­fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)­phenyl]-1H-pyrazol-4-yl}­imidazo­[5,1-f]­[1,2,4]­triazine,
[18F]­PF-05270430 (5).