Heavy Alkaline Earth Radiometals for Cancer Theranostics: Coordination and Radiochemistry of Radium-223 and...

The possibility of pairing the α-emitter ²²³Ra for targeted α therapy with the γ-emitter ¹³¹Ba 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 (logβ = 16.6), even higher than that of Ba²⁺-macropa, the current state-of-the-art chelator for ²²³Ra/¹³¹Ba. The experimental complex stability followed the order macromal > macropa ≫ macrophospho ∼ macroHOPO > macrocat. Concentration-, temperature-, pH-, and time-dependent radiolabeling were carried out using ²²³Ra derived from Xofigo residues and cyclotron-produced ¹³¹Ba. Although quantitative ²²³Ra/¹³¹Ba incorporation was not achieved, this work expands the scarce coordination chemistry and radiochemistry of the two heaviest alkaline earth (radio)metals.