Synthesis and functional evaluation of tetrahydroisoquinoline and polysubstituted benzylamine derivatives as sigma-2 receptor-targeted small-molecule probes

The sigma-2 receptor has been identified as a marker of abnormal tumor proliferation. Novel sigma-2 small molecule probes have been developed to assist in localizing tumor sites, tracking in vivo tumor cell proliferation and migration, and facilitating cancer diagnosis and treatment. A series of tetrahydroisoquinoline- and polysubstituted benzylamine-based sigma-2 small molecule probes were synthesized, and compounds 6–8 were found to exhibit moderate to high affinity and selectivity for sigma-2 receptors, with Ki values ranging from 7.8 to 53.2 nM. Functional analysis confirmed that the three active compounds act as sigma-2 receptor antagonists. Lower cytotoxicity was observed for compounds 6–8, with no significant or only weak cytotoxic effects detected in the MCF-7 cell line. In the tumor cell fluorescence imaging experiment, it could be clearly observed from the merged images that fluorescence was localized within MCF-7 cells, and target compounds 6–8 were able to enter target cells and exhibit obvious fluorescence. Among them, the fluorescence of compound 6 was the most distinct.