Introduction:
The strategies used to develop molecular imaging and therapy agents have not kept pace with the technologies used in modern drug discovery programs. This is due in large part to the costs associated with high throughput discovery strategies and the lack of synthetic methods that are suited for working with radionuclides. This is particularly true in the case of radiometals where chelate complexes are not often amenable to multi-step or solid-phase synthetic protocols that are common to most drug discovery methods.
To facilitate the use of modern drug discovery techniques in Tc-radiopharmaceutical development our group created a novel series of organometalic complexes of Tc(I) and Re(I). The single amino acid chelate (SAAC) system is an amino acid analogue that can be incorporated into peptides at any position as if it were a natural amino acid. This affords the opportunity to create libraries of potential imaging agents by using a chelate scan similar to the alanine scan used in HTS.
Experimental: Using the one-bead one-compound approach, libraries of peptide-ligand derivatives that are as large as 64 million compounds were prepared by one person in under 48 hours. The Re(SAAC) complex was incorporated into a hexapeptide library for example using a mix-and-split approach with the efficiency of each coupling step monitored to ensure equimolar mixture of peptides. Protecting groups were removed using standard protocols.
Results and Discussion: By employing validated peptide synthesis methods, libraries of peptides containing the SAAC ligand were prepared. What is particularly unique about the approach is that the peptide derivatives were prepared using the Re complex of the ligand. As a result, the library constituents are exact mimics of the target Tc (and radio-Re) products so that the impact of the metal on target affinity and specificity is taken into account while screening for leads. The methodology is highly efficient and amenable to the preparation of complex peptide structures including cyclic peptides.
Conclusion:
A new technique for producing libraries of peptide-based radiopharmaceuticals was developed. The methodology is designed to accelerate the process of producing novel technetium and rhenium-based molecular imaging and therapy agents.