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.
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/).
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.
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.