title: 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.
abstract: 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.
authors.affiliation: Department of Radiology, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd., St. Louis, MO 63110, USA.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Chu
authors.forename: Jinbin
authors.initials: J
authors.lastname: Xu
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.forename: Fanjie
authors.initials: F
authors.lastname: Zhang
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Jones
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Wheeler
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D048448:Phenylcarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D005462:Fluorine Radioisotopes; D008024:Ligands; D048448:Phenylcarbamates; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D004317:Doxorubicin