Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain
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...
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MDPI AG
2022-03-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/3/324 |
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| author | Oliver Clauß Linda Schäker-Hübner Barbara Wenzel Magali Toussaint Winnie Deuther-Conrad Daniel Gündel Rodrigo Teodoro Sladjana Dukić-Stefanović Friedrich-Alexander Ludwig Klaus Kopka Peter Brust Finn K. Hansen Matthias Scheunemann |
| author_facet | Oliver Clauß Linda Schäker-Hübner Barbara Wenzel Magali Toussaint Winnie Deuther-Conrad Daniel Gündel Rodrigo Teodoro Sladjana Dukić-Stefanović Friedrich-Alexander Ludwig Klaus Kopka Peter Brust Finn K. Hansen Matthias Scheunemann |
| author_sort | Oliver Clauß |
| collection | DOAJ |
| description | 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 novel <sup>18</sup>F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). <b>BA3</b>, exhibiting high inhibitory potency for HDAC1 (IC<sub>50</sub> = 4.8 nM) and HDAC2 (IC<sub>50</sub> = 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 [<sup>18</sup>F]<b>BA3</b> was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [<sup>18</sup>F]<b>BA3</b> resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (<i>n</i> = 5, EOS). For the characterization of <b>BA3</b>, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of <b>BA3,</b> whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound. |
| first_indexed | 2024-03-09T13:00:51Z |
| format | Article |
| id | doaj.art-830003203e3b458b81afb939ef4979aa |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T13:00:51Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-830003203e3b458b81afb939ef4979aa2023-11-30T21:54:31ZengMDPI AGPharmaceuticals1424-82472022-03-0115332410.3390/ph15030324Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in BrainOliver Clauß0Linda Schäker-Hübner1Barbara Wenzel2Magali Toussaint3Winnie Deuther-Conrad4Daniel Gündel5Rodrigo Teodoro6Sladjana Dukić-Stefanović7Friedrich-Alexander Ludwig8Klaus Kopka9Peter Brust10Finn K. Hansen11Matthias Scheunemann12Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyPharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyPharmaceutical and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, GermanyDepartment of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Helmholtz-Zentrum Dresden-Rossendorf, 04318 Leipzig, GermanyThe 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 novel <sup>18</sup>F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). <b>BA3</b>, exhibiting high inhibitory potency for HDAC1 (IC<sub>50</sub> = 4.8 nM) and HDAC2 (IC<sub>50</sub> = 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 [<sup>18</sup>F]<b>BA3</b> was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [<sup>18</sup>F]<b>BA3</b> resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (<i>n</i> = 5, EOS). For the characterization of <b>BA3</b>, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of <b>BA3,</b> whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound.https://www.mdpi.com/1424-8247/15/3/324histone deacetylase inhibitorHDAC1/2-specificradiochemistryfluorine-18 labellingpositron emission tomography (PET)brain-penetration |
| spellingShingle | Oliver Clauß Linda Schäker-Hübner Barbara Wenzel Magali Toussaint Winnie Deuther-Conrad Daniel Gündel Rodrigo Teodoro Sladjana Dukić-Stefanović Friedrich-Alexander Ludwig Klaus Kopka Peter Brust Finn K. Hansen Matthias Scheunemann Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain Pharmaceuticals histone deacetylase inhibitor HDAC1/2-specific radiochemistry fluorine-18 labelling positron emission tomography (PET) brain-penetration |
| title | Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain |
| title_full | Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain |
| title_fullStr | Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain |
| title_full_unstemmed | Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain |
| title_short | Development and Biological Evaluation of the First Highly Potent and Specific Benzamide-Based Radiotracer [<sup>18</sup>F]BA3 for Imaging of Histone Deacetylases 1 and 2 in Brain |
| title_sort | development and biological evaluation of the first highly potent and specific benzamide based radiotracer sup 18 sup f ba3 for imaging of histone deacetylases 1 and 2 in brain |
| topic | histone deacetylase inhibitor HDAC1/2-specific radiochemistry fluorine-18 labelling positron emission tomography (PET) brain-penetration |
| url | https://www.mdpi.com/1424-8247/15/3/324 |
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