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Bis(Dithiocarbamato) Nitrido Technetium-99m Radiopharmaceuticals: A Class of Neutral Myocardial Imaging Agents

CIS Bio International, Gif-sur-Yvette, France
Dipartimento di Chimica, Fisica ed Inorganica, Università di Bologna, Bologna, Italy
LRT/DPTE C.E.A., Bruyere-le-Chatel, France
URA 1287 CNRS, Grenoble, France

Correspondence: For correspondence or reprints contact: A. Duatti, Dipartimento di Chimica Fisica ed Inorganica, Università di Bologna, Viale Risorgimento, 4, 40136 Bologna, Italy.

ABSTRACT

The synthesis and biodistribution in various animal models (rat, dog, pig and monkey) of ^99mTc radiopharmaceuticals containing the TcN multiple bond are reported. Methods: The complexes are represented by the general formula ^99mTcN(L)₂, where L is the monoanionic form of a dithiocarbamate ligand of the type [R¹(R²)-N-C(=S)S]^–, and R¹ and R² 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 [^99mTcO₄]^– 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 addition of the sodium salt of the ligand (NaL) to afford the final product. The chemical identity of the resulting complexes was determined by comparing their chromatographic properties with those of the corresponding ⁹⁹Tc analogs characterized by spectroscopic and x-ray crystallographic methods. The complexes are neutral and possess a distorted, square pyramidal geometry. Results: No decomposition of the complexes, in physiological solution, was observed over a period of 6 hr. Imaging and biodistribution studies demonstrated that these radiopharmaceuticals localize selectively in the myocardium of rats, dogs and primates, but 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 strongly influenced by variation of the lateral R¹ and R² groups. Conclusion: The high quality of myocardial images obtained in dogs and monkeys demonstrates that the derivative ^99mTcN[E-t(EtO)NCS₂]₂ [^99mTcN(NOEt)] exhibits the most favorable distribution properties for further studies in humans.

Key Words: myocardial imaging agents • technetium-99-bis(dithiocarbamato) nitrido compounds

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