title: Nitroimidazole conjugates of bis(thiosemicarbazonato)64Cu(II) - Potential combination agents for the PET imaging of hypoxia.
abstract: Combination agents comprising two different pharmacophores with the same biological target have the potential to show additive or synergistic activity. Bis(thiosemicarbazonato)copper(II) complexes (e.g. (64)Cu-ATSM) and nitroimidazoles (e.g. (18)F-MISO) are classes of tracer used for the delineation of tumor hypoxia by positron emission tomography (PET). Three nitroimidazole-bis(thiosemicarbazonato)copper(II) conjugates were produced in order to investigate their potential as combination hypoxia imaging agents. Two were derived from the known bifunctional bis(thiosemicarbazone) H(2)ATSM/A and the third from the new precursor diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-ethylamino-3-thiosemicarbazone) - H(2)ATSM/en. Oxygen-dependent uptake studies were performed using the (64)Cu radiolabelled complexes in EMT6 carcinoma cells. All the complexes displayed appreciable hypoxia selectivity, with the nitroimidazole conjugates displaying greater selectivity than a simple propyl derivative used as a control. Participation of the nitroimidazole group in the trapping mechanism is indicated by the increased hypoxic uptake of the 2- vs. the 4-substituted (64)Cu-ATSM/A derivatives. The 2-nitroimidazole derivative of (64)Cu-ATSM/en demonstrated superior hypoxia selectivity to (64)Cu-ATSM over the range of oxygen concentrations tested. Biodistribution of the radiolabelled 2-nitroimidazole conjugates was carried out in EMT6 tumor-bearing mice. The complexes showed significantly different uptake trends in comparison to each other and previously studied Cu-ATSM derivatives. Uptake of the Cu-ATSM/en conjugate in non-target organs was considerably lower than for derivatives based on Cu-ATSM/A.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bonnitcha
authors.forename: Simon R
authors.initials: SR
authors.lastname: Bayly
authors.forename: Mark B M
authors.initials: MB
authors.lastname: Theobald
authors.forename: Helen M
authors.initials: HM
authors.lastname: Betts
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Dilworth
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D005260:Female; D000860:Hypoxia / Q000000981:diagnostic imaging; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013882:Thiosemicarbazones / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009593:Nitroimidazoles; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D010100:Oxygen