Complexation of Hard Radiometals with Macrocyclic Chelators for Targeted Therapy and Imaging

Radioactivity is employed in nuclear medicine to provide precise and personalized diagnosis and therapy of various diseases, especially cancer at different progression stages. Radiometals offer a plethora of decay properties suitable for these applications and a relatively easy way of incorporation into radiopharmaceuticals through coordination chemistry. Indeed, a suitable chelator usually tethers the radiometal cation, to avoid its uncontrolled distribution in the body, and is covalently linked to a biologically active targeting molecule, to selectively deliver radioactivity to the desired site. Therefore, chelators play a paramount role in radiopharmaceuticals and must be designed to fit the coordination requirements of the radiometal of interest. In this thesis, a family of high-denticity oxygen-rich chelators was designed to complex hard radiometals that favor high coordination numbers, in particular the α emitters radium-223, actinium-225, and thorium-227 for targeted alpha therapy, together with the respective diagnostic counterparts, i.e. barium-131, lanthanum-133, and zirconium-89, and the practical imaging surrogate gallium-68. Additionally, two nitrogen-rich chelators were considered to optimize the complexation of copper-61/64/67. All the chelators were synthesized by attaching different functional groups to the amines of appropriate macrocyclic scaffolds, and their acid-base properties were studied in aqueous solution. Thermodynamic, kinetic, and structural features of the metal complexes were investigated with the non-radioactive cations by combining several experimental techniques, including electrochemistry (potentiometry, cyclic voltammetry), spectroscopy (NMR, UV-Vis, EPR) and X-ray diffraction, with computational methods (DFT). The ability of the chelators to incorporate the corresponding radioactive isotopes under radiochemical conditions was assessed in radiolabeling studies. Finally, the biological stability of the radioactive complexes was assayed both in vitro and in vivo. Interesting correlations between the structures in water and the radiochemical properties of the complexes emerged upon comparison of the various (radio)metal-chelator pairs considered in this work.