Nitroimidazole conjugates of bis(thiosemicarbazonato)Cu-64(II) - Potential combination agents for the PET imaging of hypoxia

作者：Bonnitcha Paul D; Bayly Simon R^*; Theobald Mark B M; Betts Helen M; Lewis Jason S; Dilworth Jonathan R

来源：Journal of Inorganic Biochemistry, 2010, 104(2): 126-135.

DOI：10.1016/j.jinorgbio.2009.10.009

• Molecular imaging
• Radiochemistry
• Copper-64
• Bis(thiosemicarbazone)
• 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. Cu-64-ATSM) and nitroimidazoles (e.g. F-18-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 Cu-64 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 Cu-64-ATSM/A derivatives. The 2-nitroimidazole derivative of Cu-64-ATSM/en demonstrated superior hypoxia selectivity to Cu-64-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.

• 出版日期2010-2