Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18 F-Labelled σ 2 Receptor Ligand.

The σ ₂ receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ ₂ receptors in cancer cells and tissue in combination with the antiproliferative potency of σ ₂ receptor ligands motivates the research in the field of σ ₂ receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1 H -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. RM273 (2-[4-(6-fluoro-1 H -pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with ¹⁸ F and evaluation regarding detection of σ ₂ receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [ ¹⁸ F] RM273 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 ₂ receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ ₂ receptor ligand [ ¹⁸ F] RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ ₂ receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.