Sigma‐2 Receptor Ligands and Their Perspectives in Cancer Diagnosis and Therapy

<jats:title>Abstract</jats:title><jats:p>The sigma‐2 receptor is highly expressed in various rapidly proliferating cancer cells and regarded as a cancer cell biomarker. Selective sigma‐2 ligands have been shown to specifically label the tumor sites, induce cancer cells to undergo apoptosis, and inhibit tumor growth. Sigma‐2 ligands are potentially useful as cancer diagnostics, anticancer therapeutics, or adjuvant anticancer treatment agents. However, both the cloning of this receptor and the identification of its endogenous ligand have not been successful, and the lack of structural information has severely hindered the understanding of its physiological roles, its signaling pathways, and the development of more selective sigma‐2 ligands. Recent data have implicated that sigma‐2 binding sites are within the lipid rafts and that PGRMC1 (progesterone receptor membrane component 1) complex and sigma‐2 receptor may be coupled with EGFR (epidermal growth factor receptor), mTOR (mammalian target of rapamycin), caspases, and ion channels. Due to its promising applications in cancer management, there are rapidly increasing research efforts that are being directed into this field. This review article updates the current understanding of sigma‐2 receptor and its potential physiological roles, applications, interaction with other effectors, with special focuses on the development of sigma‐2 ligands, their chemical structures, pharmacological profiles, applications in imaging and anticancer therapy.</jats:p>