Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant ¹⁸F-Labelled σ₂ Receptor Ligand

• Main Authors: Rareş-Petru Moldovan, Daniel Gündel, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Steffen Fischer, Magali Toussaint, Dirk Schepmann, Bernhard Wünsch, Peter Brust, Winnie Deuther-Conrad
• Format: Article
• Language: English
• Published: MDPI AG 2021-05-01
• Series: International Journal of Molecular Sciences
• Subjects: σ₂ receptor; transmembrane protein 97; azaindoles; binding affinity; radiochemistry; fluorine-18 labeling
• Online Access: https://www.mdpi.com/1422-0067/22/11/5447
• ISSN: 1661-6596; 1422-0067

The σ₂ receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ₂ receptors in cancer cells and tissue in combination with the antiproliferative potency of σ₂ receptor ligands motivates the research in the field of σ₂ 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 ¹⁸F and evaluation regarding detection of σ₂ receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [¹⁸F]<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 σ₂ receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ₂ receptor ligand [¹⁸F]<b>RM273</b> has potential to assess by non-invasive molecular imaging the correlation between the availability of σ₂ receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.