Selective histone deacetylase inhibitors as prospective radiotracers for PET imaging


Selective histone deacetylase inhibitors as prospective radiotracers for PET imaging

Clauß, O.; Scheunemann, M.; Hansen, F. K.; Brust, P.

The class I histone deacetylases (HDACs) 1, 2 and 3 are overexpressed in several types of cancer, neurodegenerative diseases and inflammation. The catalyzed deacetylation of lysine residues on histones represents a key epigenetic modification that modulates the chromatin and thus influence the gene expression and transcription. Inhibition of zinc-dependent HDACs relaxes the chromatin structure and can result in transcriptional activation and anticancer effects, e.g. induction of apoptosis. Consequently, radiolabelled HDAC inhibitors have emerged as a potential tool for the diagnostic imaging of tumors by positron emission tomography (PET).
The aim of this work is the development of novel highly affine and selective fluorine containing derivatives of a class I selective HDAC inhibitor to obtain the corresponding 18-fluorine PET radiotracers with an ortho-aminoanilide as zinc-binding motif for targeting class I HDACs in tumors. A series of fluorinated reference compounds will be synthesized and the binding affinities and selectivities towards the HDAC isoforms 1, 2 and 3 will be determined. Our strategy is mainly focused on the medicinal chemistry of fluorine-containing derivatives, which are suitable for direct and indirect nucleophilic radiofluorination. For the most promising compounds, precursors for radiolabeling will be synthesized and a fully automated procedure will be established. The evaluation of physicochemical properties, e.g. stability and lipophilicity of the radiolabelled compounds will be assessed and further in vitro and in vivo investigations performed.

Keywords: Histone deacetylase inhibitors; Positron emission tomography; Fluorinated compounds

  • Poster
    NCT Retreat 2019, 09.-10.05.2019, Heidelberg, Deutschland

Permalink: https://www.hzdr.de/publications/Publ-28945
Publ.-Id: 28945