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Molecules 2015, 20(6), 9591-9615; doi:10.3390/molecules20069591

Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography

1
Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstraße 15, Leipzig 04318, Germany
2
BioCrea GmbH, Meissner Str. 191, Radebeul 01445, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Svend Borup Jensen
Received: 17 April 2015 / Revised: 4 May 2015 / Accepted: 18 May 2015 / Published: 26 May 2015
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
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Abstract

Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA24) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives. View Full-Text
Keywords: PDE2A; Alzheimer’s disease; PET imaging in brain; micellar HPLC PDE2A; Alzheimer’s disease; PET imaging in brain; micellar HPLC
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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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MDPI and ACS Style

Schröder, S.; Wenzel, B.; Deuther-Conrad, W.; Teodoro, R.; Egerland, U.; Kranz, M.; Scheunemann, M.; Höfgen, N.; Steinbach, J.; Brust, P. Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography. Molecules 2015, 20, 9591-9615.

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