<p> Sigma-2 receptors are a new target in cancer research. These receptors tend to be overexpressed in cancers compared to normal tissue, this expression is also high during proliferation. Fluorescent and radio-labeled sigma-2 receptors show increased uptake in tumors, and this uptake seems to be largely endocytotic. Many sigma-2 receptor ligands demonstrated anticancer properties either as sole treatments or adjunct therapies where they act as chemosensitizers that increase the activity of DNA-targeting drugs. Some sigma-2 receptors ligands have been utilized as cancer-selective, cargo-delivering moieties, showing potent cytotoxicity both in vitro and in vivo with minimal off target toxicity.</p><p> In this research, we synthesize sigma-2 receptor ligands based on previously discovered bicycloheptyl- and cyclohexylamines with high selectivity and affinity towards the sigma-2 receptors. The new novel ligands fall into two categories, fluorescent sigma-2 ligands, and doxorubicin-conjugated ligands. The compounds were synthesized, purified and analyzed in our laboratory. after which they were sent to the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) where they underwent receptor binding studies to determine binding affinities on a panel of a 45 central nervous system receptors. The three synthesized fluorescent compounds displayed varying affinities to sigma-2 receptors ranging from high (32 nM) to medium (557 nM). Absorption and emission spectra for the fluorescent compounds were determined and showed consistency with other compounds in literature containing the same fluorescent moiety (NBD-chloride, i.e. 4-chloro-7-nitrobenzofurazan). Uptake into cancer cells (PANC-1, HT-29, and HCT-116 cells) known to express the sigma-2 receptors was assessed. Results show that higher sigma-2 affinity translates into increased uptake into these cancer cells. The doxorubicin-conjugated ligands showed superior anticancer activity compared to either doxorubicin alone or in combination with another sigma-2 ligand. This effect was significantly reduced by using a pan-caspase inhibitor (Z-VAD-FMK). Furthermore, the higher affinity conjugate (22) (MA-28C) was more active than the low affinity one (25) (MA-30C). These two conjugated ligands where submitted to the NCI-60 Human Tumor Cell Line Screen program. The results showed that in eight out of the nine cell lines known to overexpress sigma-2 receptors, the high affinity conjugate was much more potent than doxorubicin at reaching LC50 (lethal dose to 50% of cells), while both drugs were mostly comparable in their IG50, and TGI concentrations (concentration that reduce growth by 50% and total growth inhibition concentration, respectively).</p><p>