Bifunctional chelator for facile preparation of neutral technetium complexes

The diaminedithiol (DADT) ligand system has proven to be useful as a carrier of technetium-99m in the preparation of a wide variety of site-specific radiopharmaceuticals. To expand the utility of the ligand system, we have designed and synthesized a bifunctional chelating agent based on the ligand system whose adducts generate a neutral technetium complex core and therefore can penetrate intact membranes. We have evaluated both the coupling of the thiolactone reactive moiety of the bifunctional chelate to benzylamine as a model as well as subsequent labeling with technetium-99m. Reaction with benzylamine was complete at room temperature within 2 h, producing the adduct in 74% isolated yield. On coordination of the benzylamine adduct to technetium-99m, one major product was obtained in high yield (> 90%). The product was stable in serum and physiologic saline at 37 degrees C over a 20-h study period. The partition coefficient of the technetium complex was 101 +/- 6.2, indicating that the complex was lipophilic. Biodistribution studies in mice showed that the brain concentration at 5 min postinjection was 0.91 +/- 0.09% injected dose/g indicating that the complex penetrates the intact blood-brain barrier. This is further evidence that the complex is neutral and lipophilic. This bifunctional chelate should facilitate the incorporation of technetium-99m into molecules of biological interest such as drugs, small peptides, and metabolic substrates.