New N-substituted 9-azabicyclo3.3.1nonan-3α-yl phenylcarbamate analogs as σ2 receptor ligands: synthesis in vitro characterization and evaluation as PET imaging and chemosensitization agents

摘要

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 2,087, 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.