Mixed-Ligand Rhenium-188 Complexes with Tetradentate/Monodentate NS3/P ('4 + 1') Coordination: Relation of Structure with Antioxidation Stability

Development of new radiopharmaceuticals based on Rhenium-188 depends on finding appropriate ligands able to give complexes with high in vivo stability. The ‘4+1’ mixed ligand system appears to be among the promising tools to achieve this goal. According to this approach we have synthesized rhenium model complexes with tris-(2-mercaptoethyl)amine (NS3) and derivatives thereof and various monodentate phosphorus(III) ligands (Re1-8). In vitro stabilities of the corresponding rhenium-188 complexes 188Re1-8 were determined by incubating 2-3 MBq or alternatively 37 MBq of the complex in phosphate buffer, human plasma and rat plasma, respectively, at 22 °C or 37 °C, followed by checking the amount of 188ReO4- formed after 1 h , 24 h and 48 h by thin layer chromatography. The rate of perrhenate formation varied over a wide range, depending primarily on the nature of the phosphorus(III) ligand. Physico-chemical parameters of the corresponding non-radioactive rhenium complexes Re1-8 were analyzed in detail to find out the factors influencing their different stability and furthermore to design new substitution-inert ‘4+1’ complexes. Tolman’s cone angle of phosphorus(III) ligands and the lipophilic character of the inner coordination sphere were found to be crucial factors to build up stable rhenium ‘4+1’ complexes. Additional information useful to describe electronic and steric properties of these compounds were selected from electronic spectra (wavelength l of the Re’S charge transfer band), cyclovoltammetric measurements (E° of the ReIII/ReIV couple) and NMR investigations (31P chemical shift of coordinated P(III) ligands).