Synthesis of Rhenium-Centric Reverse Turn Mimics

Abstract

Molecular scaffolds have been shown to facilitate and stabilise secondary structural turn elements, with a central core-arranging functionality in a defined three-dimensional orientation. In a peptide-based molecular imaging probe, this approach is of particular value as it would essentially "hide" a metal radioisotope within the ligand framework, making the labelling element a critical component of the receptor-bound structure. Starting from a 1,2-diaminoethane loaded 2-chlorotrityl resin, a versatile set of triamine ligand systems were synthesised by using solid-phase Fmoc-based peptide chemistry. The resultant resin-bound peptides then underwent amide reduction by treatment with borane-THF at 65 °C. This provided complete conversion to the corresponding polyamine entities in high purity for the majority of the amino acids utilised. The triamines were then coordinated on solid support by using [NEt(4)](2)[Re(CO)(3)(Br)(3)] followed by resin cleavage and HPLC purification, to give the desired rhenium coordinated species. We have shown that amino acid sequences can be assembled, reduced and coordinated on-resin, resulting in a versatile set of metal-ligand constructs. These studies could be expanded to generate libraries of turn-based peptidomimetics containing Re/Tc(I) organometallic scaffolds, with the intention of developing an improved approach for finding new diagnostic and therapeutic radiopharmaceutical entities.