Redox-active metal complexes for imaging hypoxic tissues: structure–activity relationships in copper(II) bis(thiosemicarbazone) complexes

Abstract

Reduction potential and lipophilicity of the copper(II) bis(thiosemicarbazone) complexes can be independently controlled by alkylation in the diketone backbone and the N-termini of the ligand, allowing optimisation of radiopharmaceuticals strongly selective for hypoxic tissues.

References

1. R. S. Bush, R. D. T. Jenkins, W. E. C. Allt, F. A. Beale, H. Bean, A. J. Dembo and J. F. Pringle, Br. J. Cancer, 1978, 37, Suppl. III, 302.
2. G. R. Cook and I. Fogelman, Eur. J. Nucl. Med., 1998, 25, 335.
3. G. V. Martin, J. H. Caldwell, M. M. Graham, J. R. Grierson, K. Kroll, M. J. Cowan, T. K. Lewellen, J. S. Rasey, J. J. Casciari and K. A. Krohn, J. Nucl. Med., 1992, 33, 2202.
4. M. E. Shelton, C. S. Dence, D.-R. Hwang, M. J. Welch and S. R. Bergmann, J. Nucl. Med., 1989, 30, 351.
5. P. J. Blower, J. S. Lewis and J. Zweit, Nucl. Med. Biol., 1996, 23, 957; D. W. McCarthy, R. E. Schefer, R. E. Klinkowstein, T. A. Perkins, W. H. Margenau III and M. J. Welch, J. Nucl. Med., 1998, 39, 234P.
6. D. H. Petering, in Metal Ions in Biological Systems, ed. H. Sigel, Marcel Dekker, New York, 1988, p. 197.
7. P. Herrero, J. Markham, C. Weinheimer, C. J. Anderson, M. J. Welch, M. A. Green and S. R. Bergmann, Circulation, 1993, 87, 173.
8. W. K. Subczynski, W. E. Antholine, J. S. Hyde and D. H. Petering, J. Am. Chem. Soc., 1987, 109, 46.
9. H. Taniuchi, Y. Fujibayashi, H. Okazowa, Y. Yonekura, J. Konishi and A. Yokoyama, Biol. Pharm. Bull., 1995, 18, 1126.
10. J. S. Lewis, D. W. McCarthy, M. E. Cristel and M. J. Welch, J. Nucl. Med., 1998, 39, 91P.
11. Y. Fujibayashi, H. Taniuchi, Y. Yonekura, H. Ohtani, J. Konishi and A. Yokoyama, J. Nucl. Med., 1997, 38, 1155.
12. H. Taniuchi, Y. Fujibayashi, Y. Yonekura, J. Konishi and A. Yokoyama, J. Nucl. Med., 1997, 38, 1130.
13. M. E. Shelton, M. A. Green, C. J. Mathias, M. J. Welch and S. R. Bergmann, J. Nucl. Med., 1989, 30, 1843.
14. F. Kallinowski, Cancer J., 1996, 9, 37.
15. Small amounts of radioactivity (1.8% to 6.0% of total activity) remained in the pellet even in controls without cells, due to binding of tracer to the centrifuge tube. This is not corrected for and will lead to a slight underestimation of selectivity, whether for hypoxic or normoxic cells. Radioactive CuCl₂ as a control showed negligible uptake in both hypoxic and normal cells. Cell concentrations in suspensions were 10⁶ ml^–1. At this level, 50% uptake corresponds to an intracellular-to-extracellular ⁶⁴Cu concentration ratio of approx. 1900∶1.
16. C. J. Mathias, S. R. Bergmann and M. A. Green, Nucl. Med. Biol., 1992, 20, 343.
17. N. Takahashi, Y. Fujibayashi, Y. Yonekura, M. J. Welch, A. Waki, T. Tsuchida, S. Nakamura, N. Sadato, K. Sugimoto, K. Yamamoto and Y. Ishii, J. Nucl. Med., 1998, 39, 53P.