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

Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A

“…Out of our series of fluorinated PDE10A inhibitors bearing a 2‐fluoropyridinyl moiety, AQ28A (Scheme ) was selected for 18 F‐radiolabeling because of the high inhibitory potency toward PDE10A and the high selectivity toward all other PDE isoforms. We introduced the fluorine at an aromatic position to reduce the formation of brain penetrant radiometabolites, which has been observed for PDE radioligands labeled via an 18 F‐alkyl chain …”

“…Specific activity was determined on the basis of a calibration curve obtained under isocratic HPLC conditions (system D) using chromatograms acquired at 240 nm, an appropriate maximum UV absorbance of the corresponding reference compound AQ28A (8‐bromo‐6‐methoxy‐3,4‐dimethyl‐1‐(6‐fluoropyridin‐3‐yl)imidazo[1,5‐a]quinoxaline) …”

“…The affinity of [ 18 F] AQ28A for rat striatal PDE10A has been determined in vitro by a homologous competitive binding experiment with a K D value of 4.3 nM, which corresponds with the previously determined inhibitory potency of AQ28A (IC 50 value = 2.95 nM) …”

“…1‐arylimidazo[1,5‐ a ]quinoxalines were reported as a new class of compounds characterized by high inhibitory potency and selectivity for PDE10A as well as pronounced in vitro stability . On the basis of this hit, very recently we reported on the synthesis of 16 new fluorinated arylimidazo[1,5‐ a ]quinoxalines by introducing fluorine at an aromatic position to increase the metabolic stability of potential PET radioligands and evaluated their inhibitory potential (IC 50 = 2.95 nM) and selectivity toward PDE10A (IC 50 for all other PDEs >1000 nM) . From this series of PDE10A inhibitors, we identified AQ28A as most suitable for the development of a corresponding radioligand.…”

“…37 On the basis of this hit, very recently we reported on the synthesis of 16 new fluorinated arylimidazo [1,5-a]quinoxalines by introducing fluorine at an aromatic position to increase the metabolic stability of potential PET radioligands and evaluated their inhibitory potential (IC 50 = 2.95 nM) and selectivity toward PDE10A (IC 50 for all other PDEs >1000 nM). 38,39 From this series of PDE10A inhibitors, we identified AQ28A as most suitable for the development of a corresponding radioligand. Herein we report on the development and evaluation of [ 18 F]AQ28A (Scheme 1) including precursor synthesis, 18 F-radiolabeling optimization and transfer to a fully automated setup.…”