Synthesis, radiolabelling and initial biological characterisation of 18F-labelled xanthine derivatives for PET imaging of Eph receptors

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Marc Pretze - , Faculty of Chemistry and Food Chemistry, Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Christin Neuber - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Elisa Kinski - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Birgit Belter - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Martin Köckerling - , University of Rostock (Author)
  • Amedeo Caflisch - , University of Zurich (Author)
  • Jörg Steinbach - , Faculty of Chemistry and Food Chemistry, Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Jens Pietzsch - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Constantin Mamat - , Helmholtz-Zentrum Dresden-Rossendorf (Author)

Abstract

Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC50 values in the low nanomolar range (1-40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([18F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([18F]3) rather than the methyl group of the phenoxy moiety ([18F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [18F]2 and [18F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq μmol-1. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [18F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [18F]2 did not accumulate at these cells. Since both tracers [18F]3 and [18F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.

Details

Original languageEnglish
Pages (from-to)3104-3116
Number of pages13
JournalOrganic & biomolecular chemistry
Volume18
Issue number16
Publication statusPublished - 29 Apr 2020
Peer-reviewedYes

External IDs

Scopus 85084167984
ORCID /0000-0002-6432-5694/work/146644233

Keywords

Sustainable Development Goals

Keywords

  • Animals, Binding Sites, Cell Line, Tumor, Ephrin-A2/analysis, Fluorine Radioisotopes/chemistry, Humans, Melanoma/diagnostic imaging, Molecular Imaging/methods, Positron-Emission Tomography/methods, Radiopharmaceuticals/chemical synthesis, Rats, Receptor, EphA2, Receptor, EphB4/analysis, Receptors, Eph Family/analysis, Xanthines/chemistry