| Three new methods were developed that allow for the labeling of peptides with rhenium and technetium. These methods were designed to facilitate the use of modern drug discovery strategies for the preparation of libraries of novel radiopharmaceuticals. The first approach was based on a simple post-labeling strategy. As a model compound, the chelate-peptide complex DMG-ser-cys-TKPPR was directly labeled with rhenium and technetium in solution. The labeling of DMG-ser-cys-TKPPR with Re(V) and Tc(V) was carried out in 50% and 65% yield respectively and the products were characterized in detail by 1H and 13C NMR spectroscopy. Despite the fact that the desired products were obtained, the low yields and complex purification protocols suggest that a post-labeling solution-phase approach is not a viable means of preparing libraries of radiopharmaceuticals.; In an attempt to overcome the limitation of the solution-phase, direct-labeling method, an alternate synthetic strategy based on a pre-labeling method was developed. In this approach a metal-chelate active ester (3.8) was first synthesized and purified in solution. The chelate-metal complex was subsequently linked to a resin-bound targeting agent. Using a model compound derived from bombesin, labeling was successful and went in reasonably high yield, based on HPLC data. Unfortunately, HPLC purification was required to isolate a pure product, which was further complicated by the poor solubility of the complex. As a result, the isolated yield of 3.11a was quite low (18%). The need to use HPLC to purify the products suggested that an alternative strategy was needed.; The third, and ultimately the most successful, methodology involved the use of a different chelate system and a novel post labeling strategy. Monoamide monoamine (MAMA) chelates were attached to functionalized polystyrene beads through a thioether linkage. When the resin bound ligands were treated with Re(V) the sulphur-carbon bond was weakened and the Re-MAMA complex was cleaved from the support. The yield of the un-functionalized MAMA-rhenium complex, which was purified by simple solid phase extraction, was 80%. Methods were subsequently developed to prepare functionalized Re-MAMA complexes including benzyl (70%), N-acetyl (70%), N-acetyl-O-Bn-Gly (68%) and N-acetyl-(ethylene diamine)-Phe-Leu-Nle-NBu (28%) derivatives, which demonstrated the flexibility and utility of the system. (Abstract shortened by UMI.)... |
