Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Valérie Weber - , Université Clermont Auvergne (Author)
  • Lucie Arnaud - , Université Clermont Auvergne (Author)
  • Sladjana Dukic-Stefanovic - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Barbara Wenzel - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Valérie Roux - , Université Clermont Auvergne (Author)
  • Jean Michel Chezal - , Université Clermont Auvergne (Author)
  • Thu Hang Lai - , Helmholtz-Zentrum Dresden-Rossendorf, ROTOP Pharmaka GmbH (Author)
  • Rodrigo Teodoro - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Klaus Kopka - , Chair of Bioinorganic and Radiopharmaceutical Chemistry, Helmholtz-Zentrum Dresden-Rossendorf, TUD Dresden University of Technology (Author)
  • Elisabeth Miot-Noirault - , Université Clermont Auvergne (Author)
  • Winnie Deuther-Conrad - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Aurélie Maisonial-Besset - , Université Clermont Auvergne (Author)

Abstract

Isocitrate dehydrogenases (IDHs) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukaemia, chondrosarcoma, and intrahepatic cholangiocarcinoma). These mutated variants of IDH (mIDH) acquire a neomorphic activity, namely, conversion of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate involved in tumourigenesis. Thus, mIDHs have emerged as highly promising therapeutic targets, and several mIDH specific inhibitors have been developed. However, the evaluation of mIDH status, currently performed by biopsy, is essential for patient stratification and thus treatment and follow-up. We report herein the development of new radioiodinated and radiofluorinated analogues of olutasidenib (FT-2102) as tools for noninvasive single photon emission computed tomography (SPECT) or positron emission tomog-raphy (PET) imaging of mIDH1 up-and dysregulation in tumours. Nonradiolabelled derivatives 2 and 3 halogenated at position 6 of the quinolinone scaffold were synthesised and tested in vitro for their inhibitory potencies and selectivities in comparison with the lead compound FT-2102. Using a common organotin precursor, (S)-[125I]2 and (S)-[18F]3 were efficiently synthesised by radio-io-dodemetallation and copper-mediated radiofluorination, respectively. Both radiotracers were stable at room temperature in saline or DPBS solution and at 37 °C in mouse serum, allowing future planning of their in vitro and in vivo evaluations in glioma and chondrosarcoma models.

Details

Original languageEnglish
Article number3766
JournalMolecules
Volume27
Issue number12
Publication statusPublished - 11 Jun 2022
Peer-reviewedYes

External IDs

PubMed 35744895

Keywords

Sustainable Development Goals

Keywords

  • FT-2102, mIDH1, radiofluorination, radioiodination, SPECT/PET imaging