Development of Fluorescent 4-[4-(3H-Spiro[isobenzofuran-1,4?- piperidin]-1?-yl)butyl]indolyl Derivatives as High-Affinity Probes to Enable the Study of ? Receptors via Fluorescence-Based Techniques

Sigma (sigma) receptor subtypes, sigma 1 and sigma 2, are targets of wide pharmaceutical interest. The sigma 2 receptor holds promise for the development of diagnostics and therapeutics against cancer and Alzheimer's disease. Nevertheless, little is known about the mechanisms activated by the sigma 2 receptor. To contribute to the exploitation of its therapeutic potential, we developed novel specific fluorescent ligands. Indole derivatives bearing the N-butyl-3H-spiro[isobenzofuran-1,4 '-piperidine] portion were functionalized with fluorescent tags. Nanomolar-affinity fluorescent sigma ligands, spanning from green to red to near-infrared emission, were obtained. Compounds 19 (sigma pan affinity) and 29 (sigma 2 selective), which displayed the best compromise between pharmacodynamic and photophysical properties, were investigated in flow cytometry, confocal, and live cell microscopy, demonstrating their specificity for the sigma 2 receptor. To the best of our knowledge, these are the first red-emitting fluorescent sigma 2 ligands, validated as powerful tools for the study of sigma 2 receptors via fluorescence-based techniques.

Automated summary

Sigma receptor subtypes, sigma 1 and sigma 2, are potential targets for cancer and Alzheimer's disease therapy. Novel specific fluorescent ligands have been developed, including compounds 19 (sigma pan affinity) and 29 (sigma 2 selective), which show specificity for sigma 2 receptors and can be used as powerful tools for studying these receptors.