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. Rhenium(III) mixed-ligand complexes with tetradentate/monodentate ('4 + 1') coordination of the general formula [Re(NS3)(PRR'R '')] (NS3 = tris-(2-mercaptoethyl)amine and derivatives thereof, PRR'R '' = phosphorus(III) ligands) appear to be among the promising tools to achieve this goal. According to this approach, we synthesized and characterized a series of rhenium model complexes. In vitro stabilities of the corresponding rhenium-188 complexes were determined by incubating 2-3 MBq or alternatively 37 MBq of the complexes in phosphate buffer, human plasma, and rat plasma, respectively, at 22 degrees C or 37 degrees C, followed by checking the amount of (ReO4-)-Re-188 formed after 1 h, 24, 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. Physicochemical parameters of the corresponding nonradioactive rhenium complexes 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 of the Re -> S charge-transfer band), cyclovoltammetric measurements (E degrees of the Re-III/Re-IV couple), and NMR investigations (P-31 chemical shift of coordinated P(III) ligands).

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).