Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [18F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Oliver Clauß - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Linda Schäker-Hübner - , University of Bonn, Leipzig University (Author)
  • Barbara Wenzel - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Magali Toussaint - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Winnie Deuther-Conrad - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Daniel Gündel - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Rodrigo Teodoro - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Sladjana Dukić-Stefanović - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Friedrich Alexander Ludwig - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Klaus Kopka - , Chair of Bioinorganic and Radiopharmaceutical Chemistry, Helmholtz-Zentrum Dresden-Rossendorf, TUD Dresden University of Technology (Author)
  • Peter Brust - , Helmholtz-Zentrum Dresden-Rossendorf (Author)
  • Finn K. Hansen - , University of Bonn (Author)
  • Matthias Scheunemann - , Helmholtz-Zentrum Dresden-Rossendorf (Author)

Abstract

The degree of acetylation of lysine residues on histones influences the accessibility of DNA and, furthermore, the gene expression. Histone deacetylases (HDACs) are overexpressed in various tumour diseases, resulting in the interest in HDAC inhibitors for cancer therapy. The aim of this work is the development of a novel18F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). BA3, exhibiting high inhibitory potency for HDAC1 (IC50 = 4.8 nM) and HDAC2 (IC50 = 39.9 nM), and specificity towards HDAC3 and HDAC6 (specificity ratios >230 and >2080, respectively), was selected for radiofluorination. The two-step one-pot radiosynthesis of [18F]BA3 was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [18F]BA3 resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (n = 5, EOS). For the characterization of BA3, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of BA3, whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound.

Details

Original languageEnglish
Article number324
JournalPharmaceuticals
Volume15
Issue number3
Publication statusPublished - Mar 2022
Peer-reviewedYes

Keywords

Sustainable Development Goals

Keywords

  • Brain-penetration, Fluorine-18 labelling, Glioblastoma, Glioma, HDAC1/2-specific, Histone deacetylase inhibitor, Positron emission tomography (PET), Radiochemistry