Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridyl- and 1-pyridinol-substituted imidazo[1,5-a]quinoxalines

Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A) which can be used potentially as lead structure for the development of a F-18 labeled PDE10A imaging agent for positron emission tomography. Fluorine is located in the ortho-postion of pyridine to enable the introduction of F-18 into an appropriate labeling precursor by nucleophilic aromatic substitution for a possible radiosynthesis. 2-Fluoropyridines are introduced by a Suzuki coupling at different positions of the molecule. The reference compounds, 1,8-dipyridylimidazo[1,5-a]quinoxalines and 1-pyridylimidazo[1,5-a]quinoxalines, show inhibitory potencies down to the subnanomolar range and selectivity factors greater than 50. 1,8-Dipyridylimidazo[1,5-a]quinoxalines are more potent inhibitors than 1-pyridylimidazo[1,5-a]quinoxalines. Using 2-fluoro-3-pyridyl as residue gave the most potent inhibitors 11A (IC₅₀ = 0.12 nM), 11B (IC₅₀ = 0.048 nM) and 23 (IC₅₀ = 0.037 nM).