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.
Baidoo
K E
KE
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205-2179.
Lever
S Z
SZ
Scheffel
U
U
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