Heavy Alkaline Earth Radiometals for Cancer Theranostics: Coordination and Radiochemistry of Radium-223 and Barium-131 with Kryptofix 22-Based Chelators
Sara Franchi, Mattia Asti, Magdalena Blei, Silvia Pozzo, Andrea Madabeni, Claudia Graiff, Ileana Menegazzo, Francesca Volpato, Silvia Gentile, Laura Orian, Fabrizio Mancin, Sven Stadlbauer, Klaus Kopka, Constantin Mamat, Valerio Di Marco, Marianna Tosato
Abstract
The possibility of pairing the α-emitter 223 Ra for targeted α therapy with the γ-emitter 131 Ba for SPECT imaging could unlock novel theranostic options in cancer management. However, the lack of stable in vivo chelation for Ra 2+ /Ba 2+ remains a key barrier to clinical use. Four macrocyclic chelators were herein developed by functionalizing 1,10-diaza-18-crown-6 (Kryptofix 22) with donor groups tailored to Ra 2+ /Ba 2+: 2-pyridylphosphonic acid (macrophospho), malonic acid (macromal), catechol (macrocat), and 1,2-HOPO (macroHOPO). The thermodynamic and structural properties of their Ba 2+ and Ra 2+ complexes were explored in aqueous solution through potentiometry, NMR spectroscopy, X-ray crystallography and DFT calculations. Macromal gave the highest stability constant known so far for a 1:1 Ba 2+ -to-ligand fully deprotonated complex (logβ = 16.6), even higher than that of Ba 2+ -macropa, the current state-of-the-art chelator for 223 Ra/ 131 Ba. The experimental complex stability followed the order macromal > macropa ≫ macrophospho ∼ macroHOPO > macrocat. Concentration-, temperature-, pH-, and time-dependent radiolabeling were carried out using 223 Ra derived from Xofigo residues and cyclotron-produced 131 Ba. Although quantitative 223 Ra/ 131 Ba incorporation was not achieved, this work expands the scarce coordination chemistry and radiochemistry of the two heaviest alkaline earth (radio)metals.