Heavy Alkaline Earth Radiometals for Cancer Theranostics: Coordination and Radiochemistry of Radium-223 and Barium-131 with Kryptofix 22-Based Chelators

The possibility of pairing the alpha-emitter Ra-223 for targeted alpha therapy with the gamma-emitter Ba-131 for SPECT imaging could unlock novel theranostic options in cancer management. However, the lack of stable in vivo chelation for Ra2+/Ba2+ 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 Ra2+/Ba2+: 2-pyridylphosphonic acid (macrophospho), malonic acid (macromal), catechol (macrocat), and 1,2-HOPO (macroHOPO). The thermodynamic and structural properties of their Ba2+ and Ra2+ 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 Ba2+-to-ligand fully deprotonated complex (log beta = 16.6), even higher than that of Ba2+-macropa, the current state-of-the-art chelator for Ra-223/Ba-131. The experimental complex stability followed the order macromal > macropa >> macrophospho similar to macroHOPO > macrocat. Concentration-, temperature-, pH-, and time-dependent radiolabeling were carried out using Ra-223 derived from Xofigo residues and cyclotron-produced Ba-131. Although quantitative Ra-223/Ba-131 incorporation was not achieved, this work expands the scarce coordination chemistry and radiochemistry of the two heaviest alkaline earth (radio)metals.