Tools for peptide radiolabeling

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Tools for peptide radiolabeling The tremendous interest of peptides for positron emission tomography (PET) imaging and tumour targeting is due to the many advantages including small size, easy preparation, low toxicity and low immunogenicity. Among others, the ability to attach bifunctional chelates (BFC) to peptides can extremely simplify their labeling with radiometal to the point where kit formulations are possible. With the goal of identifying improved BFC for the labeling of peptides with positron emitting radiometals such as Cu-64, Ga-68 and Zr-89, we propose to develop a series of cyclic BFC derived from polyazacycles and acyclic BFC derived from amino acids and bearing various donor groups. As well, 18F-labeling of peptides by direct labeling is almost not possible. Since peptide 18F-labeling includes multistep procedures, there is still the need for 18F-labeling methods suitable for faster peptide labeling. Based on encouraging preliminary results, we propose to investigate thioester ligation chemistry to label peptide with F-18. Although this reaction was developed some time ago, its application to F-18 radiochemistry has never been studied. Our approach focuses on the development of cleavable thiol auxiliaries using simple reaction and purification conditions to give the desired peptides in high yields, specific activities and short reaction times (minutes instead of hours). We also propose to investigate the thioester ligation chemistry for the preparation of peptide dimers and cyclic peptides. These peptide constructs are more stable and may present many advantages over the corresponding acyclic peptide monomer such as a superior tumor uptake and longer tumor retention. The current research program advances the development of novel BFC for peptide-labeling with positron emitting radiometals, a new synthetic approach based on thioester ligation chemistry for an improved 18F-labeling procedure and the development of diverse peptide constructs. The long term objective of this program is: To develop novel tools—BFC, chemoselective conjugation methods, peptide dimers and cyclic peptides—that will improve the labeling and/or stability of peptide-based tracers. In addition to developing alternative synthetic procedures for the preparation and the radiolabeling of peptide analogs, our program will provide a base for the design of new radiopeptides that will enlarge the number of medical conditions that can benefit from diagnostic PET imaging. The research proposed herein will also permit the training of HQP in an important field of research that will possess a unique combination of skills from synthetic chemistry, radiolabelling and biomedical imaging.