Synthesis and biological evaluation of new [Tc(N)(PS)]-based mixed-ligand compounds useful in the design of target-specific radiopharmaceuticals: the 2-methoxyphenylpiperazine dithiocarbamate derivatives as an example.

This study presents the first application of a general procedure based on the use of the [Tc(N)Cl(PS)(PPh(3))] species (PS is an alkyl phosphinothiolate ligand) for the preparation of Tc(N) target-specific compounds. [Tc(N)Cl(PS)(PPh(3))] selectively reacts with an appropriate dithiocarbamate ligand (S(∧)Y) to give [Tc(N)(PS)(S(∧)Y)] compounds. 1-(2-Methoxyphenyl)piperazine, which displays a potent and specific affinity for 5HT(1A) receptors, was selected as a functional group and conjugated to the dithiocarbamate unit through different spacers (L( n )). [(99m)Tc(N)(PS)(L( n ))] complexes were prepared in high yield (more than 90%). The chemical identity of (99m)Tc complexes was determined by high performance liquid chromatography comparison with the corresponding (99g)Tc complexes. All complexes were found to be inert toward transchelation with an excess of glutathione and cysteine. No notable biotransformation of the native compound into different species by the in vitro action of the serum and liver enzymes was shown. Nanomolar affinity for the 5HT(1A) receptor was obtained for [(99m)Tc(N)(PSiso)L(3)] (IC(50) = 1.5 nM); a reduction of the affinity was observed for the other complexes as a function of the shortening of the alkyl chain interposed between the dithiocarbamate and the pharmacophore. Negligible brain uptake was found from in vivo distribution data of [(99m)Tc(N)(PSiso)L(3)]. The key finding of this study is that the complexes maintained good affinity and selectivity for 5HT(1A) receptors, and the IC(50) value for [(99g)Tc(N)(PSiso)L(3)] being comparable to the IC(50) value found for WAY 100635. This result confirmed the possibility of preparing [(99m)Tc(N)(PS)]-based target-specific compounds without affecting the affinity and selectivity of the bioactive molecules for the corresponding receptors.