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.