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 Phosphodieste

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• 作者：Lei Zhang ; Anabella Villalobos ; Elizabeth M. Beck ; Thomas Bocan ; Thomas A. Chappie ; Laigao Chen ; Sarah Grimwood ; Steven D. Heck ; Christopher J. Helal ; Xinjun Hou ; John M. Humphrey ; Jiemin Lu ; Marc B. Skaddan ; Timothy J. McCarthy ; Patrick R. Verhoest ; Travis T. Wager ; Kenneth Zasadny
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4568-4579
• 全文大小：572K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

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).