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Molecules 2018, 23(3), 556; https://doi.org/10.3390/molecules23030556

Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A

1
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Leipzig 04318, Germany
2
BioCrea GmbH, Radebeul 01445, Germany
3
Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Faculty of Medicine, Leipzig University, Leipzig 04103, Germany
*
Author to whom correspondence should be addressed.
Received: 19 January 2018 / Revised: 15 February 2018 / Accepted: 23 February 2018 / Published: 2 March 2018
(This article belongs to the Special Issue Current Aspects of Radiopharmaceutical Chemistry)
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Abstract

Specific radioligands for in vivo visualization and quantification of cyclic nucleotide phosphodiesterase 2A (PDE2A) by positron emission tomography (PET) are increasingly gaining interest in brain research. Herein we describe the synthesis, the 18F-labelling as well as the biological evaluation of our latest PDE2A (radio-)ligand 9-(5-Butoxy-2-fluorophenyl)-2-(2-([18F])fluoroethoxy)-7-methylimidazo[5,1-c]pyrido[2,3-e][1,2,4]triazine (([18F])TA5). It is the most potent PDE2A ligand out of our series of imidazopyridotriazine-based derivatives so far (IC50 hPDE2A = 3.0 nM; IC50 hPDE10A > 1000 nM). Radiolabelling was performed in a one-step procedure starting from the corresponding tosylate precursor. In vitro autoradiography on rat and pig brain slices displayed a homogenous and non-specific binding of the radioligand. Investigation of stability in vivo by reversed-phase HPLC (RP-HPLC) and micellar liquid chromatography (MLC) analyses of plasma and brain samples obtained from mice revealed a high fraction of one main radiometabolite. Hence, we concluded that [18F]TA5 is not appropriate for molecular imaging of PDE2A neither in vitro nor in vivo. Our ongoing work is focusing on further structurally modified compounds with enhanced metabolic stability. View Full-Text
Keywords: Phosphodiesterase 2A (PDE2A); secondary messengers; PDE2A radioligands; positron emission tomography (PET); neuroimaging; metabolic stability; micellar liquid chromatography (MLC) Phosphodiesterase 2A (PDE2A); secondary messengers; PDE2A radioligands; positron emission tomography (PET); neuroimaging; metabolic stability; micellar liquid chromatography (MLC)
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Schröder, S.; Wenzel, B.; Deuther-Conrad, W.; Teodoro, R.; Kranz, M.; Scheunemann, M.; Egerland, U.; Höfgen, N.; Briel, D.; Steinbach, J.; Brust, P. Investigation of an 18F-labelled Imidazopyridotriazine for Molecular Imaging of Cyclic Nucleotide Phosphodiesterase 2A. Molecules 2018, 23, 556.

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