BIS(DITHIOCARBAMATO) NITRIDO TC-99M RADIOPHARMACEUTICALS - A CLASS OFNEUTRAL MYOCARDIAL IMAGING AGENTS

The synthesis and biodistribution in various animal models (rat, dog, pig and monkey) of Tc-99m radiopharmaceuticals containing the Tc=N mul tiple bond are reported. Methods: The complexes are represented by the general formula (TcN)-Tc-99m(L)2, where L is the monoanionic form of a dithiocarbamate ligand of the type [R(1)(R(2))-N-C(=S)S](-), and R(1 ) and R(2) are variable, lateral groups. The preparations were carried out, both as a liquid and freeze-dried formulation, through a simple procedure involving the initial reaction of [(TcO4)-Tc-99m](-) with S- methyl N-methyl dithiocarbazate [H2NN(CH3)C(=S)SCH3], in the presence of tertiary phosphines or Sn2+ ion as reductants, followed by the addi tion of the sodium salt of the ligand (NaL) to afford the final produc t. The chemical identity of the resulting complexes was determined by comparing their chromatographic properties with those of the correspon ding Tc-99 analogs characterized by spectroscopic and x-ray crystallog raphic methods. The complexes are neutral and possess a distorted, squ are pyramidal geometry. Results: No decomposition of the complexes, in physiological solution, was observed over a period of 6 hr. Imaging a nd biodistribution studies demonstrated that these radiopharmaceutical s localize selectively in the myocardium of rats, dogs and primates, b ut that they failed to visualize the pig heart. The kinetics of heart uptake and clearance were studied in rats and dogs, and found to be st rongly influenced by variation of the lateral R(1) and R2 groups. Conc lusion: The high quality of myocardial images obtained in dogs and mon keys demonstrates that the derivative (TCN)-T-99m[E-t(EtO)NCS2](2) [(T CN)-T-99m(NOEt)] exhibits the most favorable distribution properties f or further studies in humans.