Synthesis, in vitro stability studies, and bioconjugation of Rhenium-188 complexes with tetradentate/monodentate NS₃/P ('4+1')coordination

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’’ = tertiary phosphine) are promising candidates for the development of rhenium-188 complexes for radiotherapeutic applications. In order to understand relationships between the structure of ¹⁸⁸Re ‘4+1’ complexes and their in vitro stability we synthesized a series of rhenium model complexes using various combinations of NS₃ derivatives and monodentate phosphorus(III) ligands and determined their stability at MBq activity level in human plasma. As an outcome of these investigations we are able to roughly estimate which ligands are suitable for a rational complex design with regard to high in vitro and in vivo stability. Subsequently, the most stable representative was investigated at GBq activity level showing no detectable degradation of the rhenium-188 complex in pharmaceutical preparation up to 2 hours after preparation. This stable ¹⁸⁸Re ‘4+1’ complex was furthermore successfully conjugated to the model peptide arginine-tyrosine using the water-soluble N-hydroxy-sulfosuccinimidyl activated ester of the monodentate phosphine ligand. In summary, our results show the great potential of ¹⁸⁸Re ‘4+1’ complexes for labelling biomolecules for therapeutic purposes.