Nitroimidazole conjugates of bis(thiosemicarbazonato)64Cu(II) - Potential combination agents for the PET imaging of hypoxia.
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.
Bonnitcha
Paul D
PD
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Bayly
Simon R
SR
Theobald
Mark B M
MB
Betts
Helen M
HM
Lewis
Jason S
JS
Dilworth
Jonathan R
JR
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
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