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.
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205-2179.
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Baidoo
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D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004355:Drug Stability; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology; D012997:Solvents; D017556:Technetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014018:Tissue Distribution
C088401:4-(2,5,5-trimethyl-4-aza-2-mercaptohexyl)-6,6-dimethyl-2-thiomorpholinone; C088402:4-(3,5-dimethyl-3-aza-5-mercaptohexyl)-6,6-dimethyl-2-thiomorpholinone; D001596:Benzylamines; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D005029:Ethylenediamines; D009025:Morpholines; D012997:Solvents; D017556:Technetium Compounds