NONINVASIVE PROBES OF TISSUE HYPOXIA - SYNTHESIS, RADIOLABELING AND EVALUATION OF HYDROXYACETOPHENONE DERIVATIVES OF 2-NITROIMIDAZOLE

A series of radioiodinated 1-substituted 2-nitroimidazoles were synthesised and evaluated as non-invasive probes for the detection of hypoxic tissues. The compounds synthesised were 2-(2-nitroimidazolyl)-3',5'-diiodo-4'-hydroxyacetophenone 4 and the 3'-monoiodo analog 5, the equivalent 3'-hydroxyacetophenone 6 and 2-(2-nitroimidazolyl)-1-(3,5-diiodo-4-hydroxyphenyl)ethanol 8. These compounds were prepared as their radioiodinated derivatives directly from the appropriate precursors, by electrophilic aromatic substitution reactions using I-125. The in vivo distribution of {I-125}-4 in male B6D2F1 mice bearing a subcutaneous Lewis lung tumor indicated very slow blood clearance (42.8% remaining at 4 hours and 22.9% at 24 hours) and excretion of only about 10% of the dose over 24 hours. Lung and tumor tissue accumulated the greatest concentrations of activity, reaching maximum organ to blood ratios of 0.52 and 0.48 respectively at 24 hours after administration of the drug. Compounds 4 and 5 exhibited no significant toxicity to EMT-6 cell cultures under either oxic or hypoxic conditions. The compounds generally showed selective binding to EMT-6 cells under hypoxic incubation with initial binding rates similar to misonidazole 1.