Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[]imidazo[2,1-][1,2,4]triazines as Phosphodiesterase 2A Inhibitors.

Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (-) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). displayed an IC for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. studies of using mouse liver microsomes (MLM) disclosed as a suitable ligand for F-labeling. Nevertheless, future metabolism studies are required.