New N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl phenylcarbamate analogs as sigma2 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-3alpha-yl phenylcarbamate analogs were synthesized. Among them, WC-26 and WC-59 were identified as the most potent sigma(2) receptor ligands (K(i)=2.58 and 0.82 nM, respectively) with high selectivity against sigma(1) (K(i) of sigma(1)/sigma(2) ratio=557 and 2087, respectively). [(18)F]WC-59 was radiolabeled via a nucleophilic substitution of a mesylate precursor by [(18)F]fluoride, and in vitro direct binding studies of [(18)F]WC-59 were conducted using membrane preparations from murine EMT-6 solid breast tumors. The results indicate that [(18)F]WC-59 binds specifically to sigma(2) receptors in vitro (K(d)= approximately 2 nM). Biodistribution studies of [(18)F]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 sigma(2) 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.