Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain
Authors : Jianrong Liu, Barbara Wenzel, Sladjana Dukic-Stefanovic, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Winnie Deuther-Conrad, Susann Schröder, Jean-Michel Chezal, Emmanuel Moreau, Peter Brust and Aurélie Maisonial-Besset
Abstract:
Phosphodiesterases (PDEs) are enzymes that play a crucial role in cellular signaling by breaking down the secondary messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) in the body and brain. Disruptions in cyclic nucleotide-mediated signaling have been associated with various disorders, including neurodegenerative conditions. Although recent research has implicated PDE5 in neurodegenerative disorders like Alzheimer's disease, its exact function remains unclear. To visualize and measure the expression of this enzyme in the brain, we developed a radiotracer specifically designed for PET imaging of PDE5.
Through structural modifications of a quinoline-based lead compound, we successfully synthesized the fluoroethoxymethyl derivative ICF24027, which exhibited potent inhibitory activity against PDE5 (IC50 = 1.86 nM). We performed radiolabeling with fluorine-18 using a one-step nucleophilic substitution reaction involving a tosylate precursor. The radiotracer showed promising results, with a radiochemical yield (RCY(EOB)) of 12.9% ± 1.8%, radiochemical purity (RCP) greater than 99%, and specific activity (SA(EOS)) ranging from 70 to 126 GBq/μmol.
In vitro autoradiographic studies using [18F]ICF24027 on various mouse tissues and porcine brain slices demonstrated moderate specific binding to PDE5. However, when tested in live mice, we observed metabolic breakdown of [18F]ICF24027, resulting in the formation of radiometabolites capable of crossing the blood-brain barrier. This rendered the radiotracer unsuitable for PET imaging of PDE5 in the brain.
In summary, our study highlights the involvement of PDE5 in neurodegenerative disorders, particularly Alzheimer's disease, and describes the development of a radiotracer, [18F]ICF24027, for PET imaging of PDE5. While this radiotracer exhibited promising binding properties in vitro, its in vivo metabolism generated brain-penetrable radiometabolites, preventing its use in PET imaging of PDE5 in the brain.
Keywords:
PDE5; PET imaging; fluorine-18; quinoline; micellar chromatography
Citation: Jianrong Liu, Barbara Wenzel, Sladjana Dukic-Stefanovic, Rodrigo Teodoro Development of a New Radiofluorinated Quinoline Analog for PET Imaging of Phosphodiesterase 5 (PDE5) in Brain Pharmaceuticals 2016, 9(2), 22; doi:10.3390/ph9020022
Received: 11 March 2016 Accepted: 13 April 2016 Published: 21 April 2016
Copyright: © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
Acknowledgments
The authors would like to thank the China Scholarship Council for supporting the PhD thesis of Jianrong Liu. Campus France together with the German Academic Exchange Service—DAAD kindly supported this project with a travel grant (PHC PROCOPE Project ID: 57129895). We also thank Dr. Karsten Franke for providing [18F]fluoride.
Author Contributions
A.M.B., P.B., E.M., and B.W. designed the study. A.M.B., J.L., E.M. and J.M.C. conceived and performed organic syntheses; B.W., R.T., A.M.B. and J.L. conceived and performed radiosyntheses; W.D.C., B.W., R.T., and S.S. performed in vivo metabolism studies; F.A.L. and B.W. conceived and performed in vitro metabolism studies; S.D.S., W.D.C. and P.B. performed in vitro autoradiographic studies; B.W., A.M.B., J.L., F.A.L., and S.D.S. wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
