Synthesis and biological evaluation of new [Tc-99m(III)( PS)(2)(L)] mixed-ligand compounds (PS= phosphino-thiolate; L=dithiocarbamate), useful in design and development of Tc(III)radiopharmaceuticals

Aim. The trivalent state is one of the most common and stable oxidation states of technetium and rhenium. In spite of this, none of the radiopharmaceuticals currently in clinical use contains the metal in this oxidation state and only a limited number of studies involving the use of M(III)(99mTc/188Re) are reported. We present here a general procedure for the preparation of a new series of neutral, sixcoordinated mixed ligand [99mTcIII(PS)2(Ln)] compounds, (PS = bis-aryl-alkyl or trisalkyl- phosphino-thiolate; Ln = dithiocarbamate) that could be used to design either essential or target specific imaging agents. Methods. The synthesis of [99m/99TcIII(PS)2(Ln)] complexes, and their in-vitro stability as well as their in-vivo biological assay were investigated. Stability studies were performed by considering: i) stability toward transchelation with Cysteine, Glutatione, Histidine and EDTA; ii) binding to the serum proteins; iii) stability in rat serum, human serum and rat liver homogenates. Biodistribution studies of some representative [99mTcIII(PS)2(Ln)] compounds were performed in healthy Sprague-Dawley rats to investigate their organ uptake, excretion pathways and in-vivo stability. Results. [99mTcIII(PS)2(Ln)] complexes were prepared, in high yield, following a one-pot procedure which required the addition of pertechnetate to a reaction vial containing SnCl2 and the selected PS and Ln ligands. The chemical identity of 99mTc-complexes was determined by HPLC comparison with the corresponding 99Tc-complexes. All complexes are constituted by the presence of the [99m/99TcIII(PS)2]+ moiety where two phosphino-thiolate ligands are tightly bound to the metal while the remaining two positions are saturated by a dithiocarbamate chelate, also carrying bioactive molecules (e.g. 2-methoxyphenilpiperazine). All complexes were inert toward ligand exchange reactions. No significant in-vitro serum protein binding and no notable biotransformation of the native compounds into different species by the in-vitro action of the serum and liver enzymes were observed. Biodistribution profiles of the complexes were characterized by a rapid blood clearance, a high lung, liver and spleen uptakes followed by slow wash-out. The activity was mainly eliminated through the hepatobiliary system. In all cases, activity in thyroid and increase of the %ID over the time in the stomach were not found, indicating the high in-vivo stability of the complexes. However, structural modifications are required to improve the pharmacokinetic profile of these compounds. Conclusion. Stable [99mTcIII(PS)2(Ln)] compounds were efficiently prepared in high yield and in physiological conditions. These results could be conveniently utilized to devise a novel class of 99mTcIII-based useful to design either essential or target specific imaging agents.