New [3+1] Chelating System for Rhenium (V) Nitrido Radiopharmaceuticals

Aim. Radionuclide therapy still remains one of the potentially most effective approaches for the treatment of cancer. A common strategy entails the radiolabelling of an appropriate biologically active molecule, such as proteins, peptides or drugs, which is known to selectively target cancerous cells. The usual challenge comes from the need to incorporate the radioactive tag within the structure of the bioactive molecule without affecting its primitive biological properties. This problem becomes more relevant with metallic radionuclides, which constitutes the largest set of radioelements having suitable nuclear properties for therapeutic purposes. At present, the most popular method, dubbed ‘bifunctional approach’, consists of tethering a strong chelating group for the metal to a point of the bioactive molecule that is irrelevant for preserving its biological properties. The resulting bifunctional ligand would act as a bridging backbone between the biomolecule and the metal. The ß-emitting radionuclide Re-188 is considered a very attractive candidate for the development of therapeutic radiopharmaceuticals. Studies were devoted to finding strong chelating systems capable of conferring a high in vivo stability to the resulting complexes. Our group focused on the study of five-coordinated complexes characterized by the presence of a terminal [188Re=N]2+ multiple bond. The aim of this work was to develop mixed-ligand [188Re (N)(SNS)(PCN)] complex [PCN = P(CH2CH2CN)3; SNS= 2-2’-dimercaptodiethylamine, H2SNS =NH(CH2CH2SH)2] and evaluate their stability, essential pre-requisite for the development of target-specific agents for molecular therapy. Materials and Methods. Reagents required for the preparation of mixed-ligand [188Re (N)(SNS)(PCN)] complex were provided through a two-vial freeze-dried kit formulation (vial A and B). The preparation involves two steps: (1) formation of the [188Re =N]2+ core (Vial A), (2) reaction of this "core" with the H2SNS derivative and the mono-phosphine to afford the “3+1” complex nitrido [188Re (N)(SNS)(PCN)] (vial B). Purification of the complex from excess of reagents and free ligand was carried out by passing the activity through a reversed-phase SepPak cartridge. The radiochemical yield was determined by HPLC chromatography. Results. The radiochemical yield for the complex 188Re(N)(SNS)(PCN) was found to be in the range 95.2 ± 3.0. Evaluation of stability of all complex in serum and towards transchelation with GSH and cysteine revealed no change in radiochemical purity (RCP) after 48 h of incubation at 37°C. Conclusion. The new ”3+1” chelating system studied is very stable and obtained in high yield through lyophilized formulations. The tridentate ligand (SNS) can be derivatized for developement of new therapeutic agents. --