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Open AccessArticle

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

1
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceuticals Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, Germany
2
Center for Radioisotope and Radiopharmaceutical Technology, National Nuclear and Energy Agency (BATAN), Puspiptek Area, Serpong, South Tangerang 15310, Indonesia
3
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Faculty of Medicine, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: Diego Muñoz-Torrero
Molecules 2019, 24(15), 2791; https://doi.org/10.3390/molecules24152791
Received: 24 May 2019 / Revised: 17 July 2019 / Accepted: 26 July 2019 / Published: 31 July 2019
(This article belongs to the Special Issue Radiolabelled Molecules for Brain Imaging with PET and SPECT)
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 (BIT19) 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. View Full-Text
Keywords: Phosphodiesterase 2A (PDE2A); Positron Emission Tomography (PET); Benzoimidazotriazine (BIT); fluorinated; Mouse Liver Microsomes (MLM) Phosphodiesterase 2A (PDE2A); Positron Emission Tomography (PET); Benzoimidazotriazine (BIT); fluorinated; Mouse Liver Microsomes (MLM)
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Ritawidya, R.; Ludwig, F.-A.; Briel, D.; Brust, P.; Scheunemann, M. Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors. Molecules 2019, 24, 2791.

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