Studies of new [Tc(N)(PS)]-based mixed compounds as analogues of WAY 100635

This study was focused on evaluating the applicability of a new labelling procedure to the preparation of ^99mTc(N)-based target specific compounds. The chemistry is based on the use of the [Tc(N)Cl(PS)(PPh₃)] species (PS=alkyl-phosphino-thiolate ligand), which selectively reacts with an appropriate mono-negative chelate, such as a dithiocarbamate (DTC), to give neutral [Tc(N)(PS)(DTC)] compounds. The 2-methoxyphenylpiperazine (L) pharmacophore, which displays a potent and specific affinity for 5HT_1A receptors, was selected as functional group and conjugated to the dithiocarbamate unit through different spacers.
The synthesis of [^99m/99gTc(N)(PS)(Ln)] complexes, and their stability as well as their biological in vitro and in vivo assays were investigated. [^99mTc(N)(PS)(Ln)] compounds were prepared in high yield (N90%) using a multi-step procedure and their chemical identity was determined by highperformance liquid chromatrography comparison with the ^99gTc-analogues. All complexes were found to be inert toward transchelation with glutathione and sufficiently stable to the in-vitro action of serum and liver enzymes. Nanomolar affinities for the 5-HT_1A receptor were obtained for [^99mTc(N) (PSiso)L³] (IC₅₀=1.5 nM). However, a negligible brain uptake was observed after in-vivo administration of the complex.
This work describes the application of a new labelling procedure for incorporating a bioactive molecule into a stable dissymmetric ^99mTc(N)-complex. Despite the lack of BBB penetration of [^99mTc(N)(PSiso)L³] the favourable binding properties of this compound strongly support the possibility to apply [Tc(N)(PS)]-technology to the preparation of target specific agents useful in peripheral applications.