Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand
The σ<sub>2</sub> receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ<sub>2</sub> receptors in cancer cells and tissue in combination with the antiproliferative poten...
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MDPI AG
2021-05-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/22/11/5447 |
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doaj-97524bcbd2024982a8bdf9445614e972 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Rareş-Petru Moldovan Daniel Gündel Rodrigo Teodoro Friedrich-Alexander Ludwig Steffen Fischer Magali Toussaint Dirk Schepmann Bernhard Wünsch Peter Brust Winnie Deuther-Conrad |
spellingShingle |
Rareş-Petru Moldovan Daniel Gündel Rodrigo Teodoro Friedrich-Alexander Ludwig Steffen Fischer Magali Toussaint Dirk Schepmann Bernhard Wünsch Peter Brust Winnie Deuther-Conrad Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand International Journal of Molecular Sciences σ<sub>2</sub> receptor transmembrane protein 97 azaindoles binding affinity radiochemistry fluorine-18 labeling |
author_facet |
Rareş-Petru Moldovan Daniel Gündel Rodrigo Teodoro Friedrich-Alexander Ludwig Steffen Fischer Magali Toussaint Dirk Schepmann Bernhard Wünsch Peter Brust Winnie Deuther-Conrad |
author_sort |
Rareş-Petru Moldovan |
title |
Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand |
title_short |
Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand |
title_full |
Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand |
title_fullStr |
Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand |
title_full_unstemmed |
Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor Ligand |
title_sort |
design, radiosynthesis and preliminary biological evaluation in mice of a brain-penetrant <sup>18</sup>f-labelled σ<sub>2</sub> receptor ligand |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-05-01 |
description |
The σ<sub>2</sub> receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ<sub>2</sub> receptors in cancer cells and tissue in combination with the antiproliferative potency of σ<sub>2</sub> receptor ligands motivates the research in the field of σ<sub>2</sub> receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1<i>H</i>-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. <b>RM273</b> (2-[4-(6-fluoro-1<i>H</i>-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with <sup>18</sup>F and evaluation regarding detection of σ<sub>2</sub> receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [<sup>18</sup>F]<b>RM273</b> in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ<sub>2</sub> receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ<sub>2</sub> receptor ligand [<sup>18</sup>F]<b>RM273</b> has potential to assess by non-invasive molecular imaging the correlation between the availability of σ<sub>2</sub> receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies. |
topic |
σ<sub>2</sub> receptor transmembrane protein 97 azaindoles binding affinity radiochemistry fluorine-18 labeling |
url |
https://www.mdpi.com/1422-0067/22/11/5447 |
work_keys_str_mv |
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doaj-97524bcbd2024982a8bdf9445614e9722021-06-01T00:44:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-01225447544710.3390/ijms22115447Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant <sup>18</sup>F-Labelled σ<sub>2</sub> Receptor LigandRareş-Petru Moldovan0Daniel Gündel1Rodrigo Teodoro2Friedrich-Alexander Ludwig3Steffen Fischer4Magali Toussaint5Dirk Schepmann6Bernhard Wünsch7Peter Brust8Winnie Deuther-Conrad9Department of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyInstitut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster (WWU), Corrensstraße 48, 48149 Münster, GermanyInstitut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster (WWU), Corrensstraße 48, 48149 Münster, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyDepartment of Neuroradiopharmaceuticals, Research Site Leipzig, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Permoserstraße 15, 04318 Leipzig, GermanyThe σ<sub>2</sub> receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ<sub>2</sub> receptors in cancer cells and tissue in combination with the antiproliferative potency of σ<sub>2</sub> receptor ligands motivates the research in the field of σ<sub>2</sub> receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1<i>H</i>-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. <b>RM273</b> (2-[4-(6-fluoro-1<i>H</i>-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with <sup>18</sup>F and evaluation regarding detection of σ<sub>2</sub> receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [<sup>18</sup>F]<b>RM273</b> in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ<sub>2</sub> receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ<sub>2</sub> receptor ligand [<sup>18</sup>F]<b>RM273</b> has potential to assess by non-invasive molecular imaging the correlation between the availability of σ<sub>2</sub> receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.https://www.mdpi.com/1422-0067/22/11/5447σ<sub>2</sub> receptortransmembrane protein 97azaindolesbinding affinityradiochemistryfluorine-18 labeling |