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

• Published in: Journal of medicinal chemistry Vol. 56; no. 11; pp. 4568 - 4579
• Main Authors: Zhang, Lei, Villalobos, Anabella, Beck, Elizabeth M, Bocan, Thomas, Chappie, Thomas A, Chen, Laigao, Grimwood, Sarah, Heck, Steven D, Helal, Christopher J, Hou, Xinjun, Humphrey, John M, Lu, Jiemin, Skaddan, Marc B, McCarthy, Timothy J, Verhoest, Patrick R, Wager, Travis T, Zasadny, Kenneth
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13-06-2013
• Subjects: Animals; Azabicyclo Compounds - chemical synthesis; Azabicyclo Compounds - chemistry; Azabicyclo Compounds - pharmacokinetics; Azetidines - chemical synthesis; Azetidines - chemistry; Azetidines - pharmacokinetics; Brain - diagnostic imaging; Brain - enzymology; Computer Simulation; Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism; Databases, Factual; Dogs; Drug Design; Fluorine Radioisotopes; Humans; Ligands; Macaca fascicularis; Male; Models, Biological; Permeability; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Wistar; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400312y

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).