Synthesis of new contrast agents for biomedical applications

Several different metal complexes are currently used in diagnostics and therapy (MRI, PET, SPECT, OI, TAT etc.). For their preparation a chelating agent (CA) is mandatory to hold the metal ion, to reduce its toxicity and to target its activity. Polyaminocarboxylates and polyaminophosphonates represent the best choice of CAs for the preparation of metal complexes exploited as imaging probes. These scaffolds ensure high thermodynamic and kinetic stability of the corresponding metal complex. However, their preparation is not always straightforward. During this PhD the research work was focused on the following three main objectives: 1) A strategy for the 1,7-heterodiprotection of cyclen with orthogonal protecting groups have been realised. This protection method is based on the control of pH to implant two different and orthogonal protecting groups in the cyclen scaffold. 2) This protection method has been exploited to prepare two novel bifunctional chelating agents (BFCAs) bearing a phosphonic functionality (DO2AP(tBu)4 and DO3AP(tBu)4). These two novel BFCAs have been designed to prepare innovative and stable metal complexes conjugated with vectors such as antibodies, peptides, nucleotides etc. 3) Three innovative CAs have been prepared and characterised: - TRASUTA is a hexadentate mesocyclic chelating agent and a rigidified AAZTA-like ligand for the coordination of Ga(III). - Cb-tebpm is a cyclam-based chelating agent, designed to prepare stable complexes with gadolinium or in general with lanthanides. - HB-DO3A is an HP-DO3A homologue, optimised to be a strong Gd(III) chelator. HBDO3A has been investigated in its safety profile. In vitro data have shown that, if compared to clinically approved MRI CAs, HB-DO3A presents low affinity to collagen. This characteristic could confer HB-DO3A the advantage of a faster and complete clearance after administration to the patient, with less release of toxic Gd(III) and less side effects.