AbstractThe sigma‐2 receptor has been shown to play important roles in a number of important diseases, including central nervous system (CNS) disorders and cancer. However, mechanisms by which sigma‐2 contributes to these diseases remain unclear. The development of new sigma‐2 ligands that can be used to probe the function of this protein and potentially as drug discovery leads is therefore of great importance. Herein we report the development of a series of tetrahydroindazole compounds that are highly potent and selective for sigma‐2. Structure–activity relationship data were used to generate a pharmacophore model that summarizes the common features present in the potent ligands. Assays for solubility and microsomal stability showed that several members of this compound series possess promising characteristics for further development of useful chemical probes or drug discovery leads.