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Pharmaceuticals 2016, 9(2), 22; doi:10.3390/ph9020022

Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain

1
INSERM—Université d’Auvergne, UMR 990, IMTV, BP 184, F-63005 Clermont-Ferrand Cedex, France
2
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Permoserstrasse 15, 04318 Leipzig, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Michel Monclus
Received: 11 March 2016 / Revised: 12 April 2016 / Accepted: 13 April 2016 / Published: 21 April 2016
(This article belongs to the Special Issue New Challenges in Radiochemistry)
View Full-Text   |   Download PDF [1738 KB, uploaded 21 April 2016]   |  

Abstract

Phosphodiesterases (PDEs) are enzymes that play a major role in cell signalling by hydrolysing the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) throughout the body and brain. Altered cyclic nucleotide-mediated signalling has been associated with a wide array of disorders, including neurodegenerative disorders. Recently, PDE5 has been shown to be involved in neurodegenerative disorders such as Alzheimer’s disease, but its precise role has not been elucidated yet. To visualize and quantify the expression of this enzyme in brain, we developed a radiotracer for specific PET imaging of PDE5. A quinoline-based lead compound has been structurally modified resulting in the fluoroethoxymethyl derivative ICF24027 with high inhibitory activity towards PDE5 (IC50 = 1.86 nM). Radiolabelling with fluorine-18 was performed by a one-step nucleophilic substitution reaction using a tosylate precursor (RCY(EOB) = 12.9% ± 1.8%; RCP > 99%; SA(EOS) = 70–126 GBq/μmol). In vitro autoradiographic studies of [18F]ICF24027 on different mouse tissue as well as on porcine brain slices demonstrated a moderate specific binding to PDE5. In vivo studies in mice revealed that [18F]ICF24027 was metabolized under formation of brain penetrable radiometabolites making the radiotracer unsuitable for PET imaging of PDE5 in brain. View Full-Text
Keywords: PDE5; PET imaging; fluorine-18; quinoline; micellar chromatography PDE5; PET imaging; fluorine-18; quinoline; micellar chromatography
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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

Liu, J.; Wenzel, B.; Dukic-Stefanovic, S.; Teodoro, R.; Ludwig, F.-A.; Deuther-Conrad, W.; Schröder, S.; Chezal, J.-M.; Moreau, E.; Brust, P.; Maisonial-Besset, A. Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain. Pharmaceuticals 2016, 9, 22.

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