Misonidazole retention by normal tissues: a distinction between label on the ring and side chain.

The retention of misonidazole by mouse normal tissues and EMT6/Ed tumors was studied 24 hr after injection of ring labelled (2-14C) and side chain-labelled (3H) drug. Slightly more 3H than 14C was retained by tumors, but this was considered to be within experimental error of no difference. The ring label (14C) activity retained by tumors was 5-12 times greater than that retained by heart, kidney, brain, muscle and spleen. However, in the same animals, the side chain label (3H) was retained to an appreciably greater extent by the normal tissues, so that the ratio of activities retained in tumors and normal tissues was 3 to 4. This difference in discrimination between tumors and normal tissues implies that gamma-emitting or NMR-active analogues of misonidazole will detect hypoxia in tumors in situ more efficiently, if the active isotope is situated on the ring. The data also indicate that fragmentation products of the metabolism of misonidazole, which contain the side chain and exclude the 2-carbon, are responsible for 50-70% of the misonidazole retained by normal tissues when a side chain-label is used.