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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Oliver Clauß - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Linda Schäker-Hübner - , Universität Bonn, Universität Leipzig (Autor:in)
  • Barbara Wenzel - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Magali Toussaint - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Winnie Deuther-Conrad - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Daniel Gündel - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Rodrigo Teodoro - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Sladjana Dukić-Stefanović - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Friedrich Alexander Ludwig - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Klaus Kopka - , Professur für Bioanorganische und Radiopharmazeutische Chemie (gB/HZDR) (BC3), Helmholtz-Zentrum Dresden-Rossendorf, Technische Universität Dresden (Autor:in)
  • Peter Brust - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)
  • Finn K. Hansen - , Universität Bonn (Autor:in)
  • Matthias Scheunemann - , Helmholtz-Zentrum Dresden-Rossendorf (Autor:in)

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

OriginalspracheEnglisch
Aufsatznummer324
FachzeitschriftPharmaceuticals
Jahrgang15
Ausgabenummer3
PublikationsstatusVeröffentlicht - März 2022
Peer-Review-StatusJa

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

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