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Toaccelerate the discovery of novel small molecule central nervoussystem (CNS) positron emission tomography (PET) ligands, we aimedto define a property space that would facilitate ligand design andprioritization, thereby providing a higher probability of successfor novel PET ligand development. Toward this end, we built a databaseconsisting of 62 PET ligands that have successfully reached the clinicand 15 radioligands that failed in late-stage development as negativecontrols. A systematic analysis of these ligands identified a setof preferred parameters for physicochemical properties, brain permeability,and nonspecific binding (NSB). These preferred parameters have subsequentlybeen applied to several programs and have led to the successful developmentof novel PET ligands with reduced resources and timelines. This strategyis illustrated here by the discovery of the novel phosphodiesterase2A (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). [ABSTRACT FROM AUTHOR]

Phosphodiesterase 9A inhibitors have shown activity inpreclinicalmodels of cognition with potential application as novel therapiesfor treating Alzheimer’s disease. Our clinical candidate, PF-04447943(2), demonstrated acceptable CNS permeability in ratswith modest asymmetry between central and peripheral compartments(free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemicalproperties outside the range associated with traditional CNS drugs.To address the potential risk of restricted CNS penetration with 2in human clinical trials, we sought to identify a preclinicalcandidate with no asymmetry in rat brain penetration and that couldadvance into development. Merging the medicinal chemistry strategiesof structure-based design with parallel chemistry, a novel seriesof PDE9A inhibitors was identified that showed improved selectivityover PDE1C. Optimization afforded preclinical candidate 19that demonstrated free brain/free plasma ≥1 in rat and reducedmicrosomal clearance along with the ability to increase cyclic guanosinemonophosphosphate levels in rat CSF. [ABSTRACT FROM AUTHOR]