Abstract
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.
Highlights
Cyclic nucleotide Phosphodiesterases (PDEs) represent a class of enzymes catalyzing the hydrolysis of the intracellular second messengers, cyclic Adenosine Monophosphate and cyclic Guanosine
Monophosphate [1]. cyclic Adenosine Monophosphate (cAMP) and cyclic GuanosineMonophosphate (cGMP) are involved in a great variety of cellular functions related to physiological and pathophysiological processes in brain and periphery [2,3,4,5,6]
A series of novel fluorinated Phosphodiesterase 2A (PDE2A) inhibitors based on a BIT scaffold was successfully prepared and evaluated in vitro
Summary
Cyclic nucleotide Phosphodiesterases (PDEs) represent a class of enzymes catalyzing the hydrolysis of the intracellular second messengers, cyclic Adenosine Monophosphate (cAMP) and cyclic GuanosineMonophosphate (cGMP) [1]. cAMP and cGMP are involved in a great variety of cellular functions related to physiological and pathophysiological processes in brain and periphery [2,3,4,5,6].The 11 family members of PDEs are encoded by 21 genes and classified by their substrate specificity [7,8,9,10]. CAMP and cGMP are involved in a great variety of cellular functions related to physiological and pathophysiological processes in brain and periphery [2,3,4,5,6]. The dual substrate enzyme PDE2A is highly expressed in some brain areas, such as nucleus accumbens, cortex, hippocampus [7], striatum, amygdala [12], substantia nigra, and olfactory. The dual substrate enzyme PDE2A is highly expressed in some brain areas, such as nucleus accumbens, cortex, hippocampus [7],instriatum,. PDE2A will intracellular memory, emotion, and related diseases. The inhibition of PDE2A will increase the intracellular levels of cGMP and cAMP in PDE2A-abundant tissues and may result in improvement of neuroplasticity levels of cGMP and [8]. CAMP in PDE2A-abundant tissues and may result in improvement of and memory function neuroplasticity memoryinhibitors function related [8]
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