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

Abstract

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-[(18)F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [(18)F]PF-05270430 (5).

Preclinical Evaluation of 18F-PF-05270430, a Novel PET Radioligand for the Phosphodiesterase 2A Enzyme

“…Synthesis of PF-05270430 and the tosylate radiolabeling precursor were prepared according to procedures reported previously (13).…”

“…So far, there has been only one report of an attempt to develop PET imaging agents for PDE2A, but no suitable radioligand was found (12). We have previously defined a set of selection criteria for novel radiotracers for the central nervous system through a systematic analysis of physicochemical properties of validated PET ligands (13). Application of these criteria to our PDE2A inhibitor library led to the identification of PF-05270430, 4-( (Fig.…”

Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284

“…For the development of M 1 -selective PAM radioligands, we used a set of central nervous system (CNS) positron emission tomography (PET) ligand design-and-selection criteria that our group had previously published, considering the similar property requirements between a PET ligand and a [ 3 H] radioligand (Zhang et al, 2013). Specifically, we targeted leads that possessed potent M 1 PAM activity and high selectivity against other mAChR subtypes, and, importantly, demonstrated low nonspecific binding levels.…”

“…Fraction unbound in brain (F u,b ;Di et al, 2011) has been shown to be a useful predictor for nonspecific binding and, specifically, we targeted F u,b . 0.05 to minimize this risk (Zhang et al, 2013). Toward this end, compound 10 was synthesized and its F u,b was measured to monitor nonspecific binding risk.…”

Imaging in Central Nervous System Drug Discovery

“…In recent years, the discovery and development of PET biomarkers has increased in sophistication with the introduction of in silico biomathematical models that provide a quantitative prediction of the compounds in vivo performance based on in vitro data for initial screening of compound libraries [60,61]. Such in silico methods can use estimates of the molecular size and lipholicity to predict the delivery rate constant …”