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Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzoeimidazo2,1-c1,2,4triazines as Phosphodiesterase 2A Inhibitors
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Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzoeimidazo2,1-c1,2,4triazines as Phosphodiesterase 2A Inhibitors
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Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzoeimidazo2,1-c1,2,4triazines as Phosphodiesterase 2A Inhibitors
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Journal Article
Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzoeimidazo2,1-c1,2,4triazines as Phosphodiesterase 2A Inhibitors
2019
Overview
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.
Publisher
MDPI AG,MDPI
Subject
/ Animals
/ Cyclic Nucleotide Phosphodiesterases, Type 2 - antagonists & inhibitors
/ Cyclic Nucleotide Phosphodiesterases, Type 2 - chemistry
/ Humans
/ Ligands
/ Mice
/ Mouse Liver Microsomes (MLM)
/ Phenols
/ Phosphodiesterase 2A (PDE2A)
/ Positron Emission Tomography (PET)
/ Positron-Emission Tomography
/ Radiopharmaceuticals - chemical synthesis
/ Radiopharmaceuticals - chemistry
/ Radiopharmaceuticals - pharmacology
