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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Marc Pretze - , Fakultät Chemie u. Lebensmittelchemie, Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Christin Neuber - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Elisa Kinski - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Birgit Belter - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Martin Köckerling - , Universität Rostock (Autor:in)
  • Amedeo Caflisch - , Universität Zürich (Autor:in)
  • Jörg Steinbach - , Fakultät Chemie u. Lebensmittelchemie, Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Jens Pietzsch - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Constantin Mamat - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)

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

OriginalspracheEnglisch
Seiten (von - bis)3104-3116
Seitenumfang13
FachzeitschriftOrganic & biomolecular chemistry
Jahrgang18
Ausgabenummer16
PublikationsstatusVeröffentlicht - 29 Apr. 2020
Peer-Review-StatusJa

Externe IDs

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

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • 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