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 in vivo 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 (BIT1–9) were obtained
by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over
other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives
(82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 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. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as
a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required
