Radiolabeled bicyclic peptides with metal chelators as central structural scaffolds

• Applicant: Dr. Mark Bartholomä
• Subject Area: Pharmacy ; Nuclear Medicine, Radiotherapy, Radiobiology ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 529911782

The project aims to develop novel diagnostic tools and cancer therapies based on new radiopharmaceuticals for nuclear medicine. For such purpose, radiopharmaceuticals based on radiometals are nowadays the means of choice as they allow both therapeutic and diagnostic applications with the same molecular object: namely theranostics. To ensure the specific delivery of the radionuclide to the tumor(s), the radiometal must be coupled to a disease-specific targeting vector. Cyclic peptides are highly attractive as biovectors because, in addition to advantageous pharmacokinetics and high penetration into tumor tissue, they exhibit high metabolic stability and target affinity. The two partners involved in the project, previously successfully engaged in common research, have already developed peptide-based radiopharmaceuticals targeting the gastrin releasing peptide receptor (GRPr) and the CD22 cluster. Their complementary skills in radiometal chelator development and characterization, peptide synthesis and nuclear medicine allow several advances in the area based on powerful azamacrocyclic chelators involving the TACN platform cleverly functionalized for radiometal complexation and bioconjugation. The idea of this project is to use these recently described metal chelators as central structural motifs for the development of radiolabeled bicyclic peptide conjugates instead of the originally used trismethylbenzene moiety that is commonly used for such bicyclic peptides. The metal binding units will not only serve as central structural entities to create the bicyclic peptides but additionally provide the intrinsic possibility for radiolabeling without further modifications. In this study, the synthetic strategy for the preparation of bicyclic peptide conjugates will be developed using a model system of bicyclic peptides, namely RGD analogs. To obtain important insights into the interplay between the metal chelator, tether(s), and cyclic peptide(s) and their biological properties such as receptor affinity and metabolic stability, a series of conjugates will be prepared and their biological properties assessed in vitro. After further structural optimization, the biodistribution of the most promising candidates will then be assessed in small-animal experiments including PET imaging. The feasibility of this new approach will be demonstrated by following anticipated steps skillfully shared betweenthe two partners: 1) chemical modifications of metal chelators to serve as central structural entities; 2) synthesis of bicyclic peptides; 3) radiolabeling and characterization of non-radioactive metal complexes of bicyclic peptide conjugates; 4) in vitro characterization of radiopharmaceuticals; 5) preliminary in vivo evaluations of selected bicyclic peptide conjugates.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partners: Dr. Veronique Patinec; Professor Dr. Raphael Tripier