New bis(dithiocarboxylato) nitridotechnetium-99m radiopharmaceuticals for leucocyte labelling: in vitro and in vivo studies.

Dithiocarboxylate ligands were synthesized and characterised. New nitrido 99m-technetium complexes were obtained with these ligands and identified by thin layer chromatography. The nitrido complexes were tested in vitro in whole blood for leucocyte labelling and the design of the ligand was optimized. Best results were obtained with aliphatic linear ligands, containing 9 to 11 atoms of carbon. The in vivo experiment failed because an inflammated area could not be visualized by gamma imaging, the cell labelling mechanism being probably different.

Influence of a 99mTcN core on the biological and physicochemical behavior of 99mTc complexes of L,L-EC and L,L-ECD.

99mTc-nitrido complexes of L,L-ethylene dicysteine (99mTcN-L,L-EC) and 99mTcN-L,L-ethylene dicysteine diethylester (99mTcN-L,L-ECD) were prepared and their characteristics compared to those of the respective 99mTc-oxo complexes. 99mTcN-L,L-EC and 99mTcO-L,L-EC migrate to similar extents during electrophoresis at pH 12, but, at pH6, 99mTcN-L,L-EC migrates further than 99mTcO-L,L-EC. Renal excretion of 99mTcN-L,L-EC is inferior to that of 99mTcO-L,L-EC, indicating that the TcN-glycine sequence has lower affinity for the renal tubular system. Both 99mTcO-L,L-ECD and 99mTcN-L,L-ECD are neutral, but 99mTcN-L,L-ECD is hydrophilic and shows minimal brain uptake in both mice and the baboon.

Comparison of reversed phase and reversed phase ion pair high performance liquid chromatography for analysis of TcO and TcN complexes of L,L-ethylene dicysteine di-ethylester and its acid analogues.

99mTc(V)-oxo complexes of L,L-ethylene dicysteine (L,L-EC) and its di-ester derivative L,L-ethyl cysteinate dimer (L,L-ECD) are useful tracer agents for evaluation of renal function and cerebral blood flow respectively. Labelling of these molecules with a 99mTc(V)-nitrido core instead of the 99mTc(V)-oxo core alters their biological and physiochemical behavior. In the reversed phase high performance liquid chromatography (HPLC) method presently used to analyse 99mTc(V)-oxo preparations of L,L-EC and L,L-ECD, the 99mTc(V)-nitrido-L,L-EC complex and the possible impurities of a 99mTc(V)-nitrido-L,L-ECD preparation were found to elute with the void volume. In this study, a reversed phase ion pair HPLC method has been developed that is useful for the analysis of both 99mTc(V)-oxo and 99mTc(V)-nitrido preparations of L,L-EC and L,L-ECD. Tetrabutylammonium hydroxide is used as a cationic ion pairing agent.

Synthesis and biodistribution of nitrido technetium-99m radiopharmaceuticals with dithiophosphinate ligands: a class of brain imaging agents.

The symmetrical complexes [99mTc][TcN(R2PS2)2] [R = CH3, CH2CH3, CH2CH2CH3, CH2(CH3)2], and the unsymmetrical complex [99mTc][TcN(Me2PS2)(Et2PS2)] have been prepared, at tracer level, through a two-step procedure involving the preliminary formation of a prereduced technetium nitrido intermediate followed by substitution reaction onto this species by the appropriate dithiophosphinate ligand [R2PS2]Na. The chemical identity of the resulting complexes have been established by comparison with the corresponding 99Tc-analogs prepared, at macroscopic level, by reacting the complex [99TcNCl4] [n-Bu4N] (n-Bu = n-butyl) with an excess of ligand in methanol, and characterized by elemental analyses and spectroscopic techniques. The complexes are neutral and lipophilic, and possess a square pyramidal geometry, with an apical Tc identical to N group and two dithiophosphinate ligands spanning the four positions on the basal plane through the four sulfur atoms of the > PS2 group. In vitro studies showed that these radiopharmaceuticals are stable in solution and that their chemical identity was not altered after incubation with rat blood. Biodistribution studies have been carried out in rats and primates. The results demonstrate that these compounds are significantly retained into the brain of these animals for a prolonged time. Planar gamma camera images have been obtained in monkeys showing a good visualization of the cerebral region. However, the existence of persistent blood activity yields a brain/blood ratio lower than that observed with other 99mTc-based brain perfusion imaging agents.

Synthesis, characterization and biodistribution of new 99mTc oxo and nitrido complexes with bi- and tetradendate unsaturated NS and N2S2 Schiff bases derived from 2-aminocyclopentene-1-dithiocarboxylic acid as potential heart imaging agents.

The synthesis, characterization and 99mTc labelling of unsaturated diamino dithiol ligands with methyl dithiocarboxylate functions: 2-aminocyclopentene-1-dithiocarboxylic methyl ester (H2L1), N,N'-ethylene bis(methyl 2-aminocyclopentene-1-dithiocarboxylate) (H2L2) and N,N'-propylene bis (methyl 2-aminocyclopentene-1-dithiocarboxylate) (H2L3) are described. Cationic oxo (Tc = O) and neutral nitrido (Tc = N) complexes were obtained. Biodistribution studies in rat showed a good heart uptake of 99mTcN-L2 (2% ID at 5 min) with a high heart-to-blood ratio (5.8 at 5 min), but this complex also exhibited high lung and liver uptake.

Bis(dithiocarbamato) nitrido technetium-99m radiopharmaceuticals: a class of neutral myocardial imaging agents.

UNLABELLED: The synthesis and biodistribution in various animal models (rat, dog, pig and monkey) of 99mTc radiopharmaceuticals containing the Tc = N 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.