New N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs as σ2 receptor ligands: Synthesis, in vitro characterization, and evaluation as PET imaging and chemosensitization agents

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs were synthesized. Among them, WC-26 and WC-59 were identified as the most potent σ2 receptor ligands (Ki = 2.58 and 0.82 nM, respectively) with high selectivity against σ1 (Ki of σ1/σ2 ratio = 557 and 2087, respectively). [18F]WC-59 was radiolabeled via a nucleophilic substitution of a mesylate precursor by [18F]fluoride, and in vitro direct binding studies of [18F]WC-59 were conducted using membrane preparations from murine EMT-6 solid breast tumors. The results indicate that [18F]WC-59 binds specifically to σ2 receptors in vitro (Kd = ∼2 nM). Biodistribution studies of [18F]WC-59 in EMT-6 tumor-bearing mice indicated that the tracer was a less suitable candidate for clinical imaging studies than existing F-18 labeled σ2 receptor ligands. The ability of WC-26 to enhance the cytotoxic effects of the chemotherapy drug, doxorubicin, was evaluated in cell culture using the mouse breast tumor EMT-6 and the human tumor MDA-MB435. WC-26 greatly increased the ability of doxorubicin to kill these two tumor cell lines in vitro. These results indicate that WC-26 is potentially a useful chemosensitizer for the treatment of cancer when combined with conventional chemotherapeutics.

Two highly selective and potent σ2 receptor ligands, WC-26 and WC-59 were synthesized. WC-26 significantly increases the ability of doxorubicin to kill breast tumor cells at low concentrations where there is no cell kill from either drug alone.Figure optionsDownload as PowerPoint slide