Sulfonated calix-baskets for complexation of Barium and Radium

Understanding the coordination chemistry of heavy group 2 metals, especially of barium as surrogate for radium, is mandatory not only for radiopharmaceutical applications of radium. This is from high importance since radium-223 is the only approved therapeutic alpha-emitter (by EMA and FDA). Unfortunately, the applications are limited. To date, radium-223 is only in use as RaCl₂ for the treatment of bone cancer metastases. To overcome this limitation, which is also true for other group 2 metals, special cage-like compounds have to be developed as ligands like sulfonated calix[4]crowns to stably bind the Ba²⁺ and Ra²⁺ to avoid a release in vivo. This will be the basis for a future application of heavy group 2 metals and not only of radium to treat other cancer entities than bone metastases. Ra²⁺ can then be included in radiopharmaceuticals which contain a chelator and a biologically active molecule part to find the tumor cell.
For this purpose, a series of modified calix[4]crown-6 derivatives was synthesized to chelate barium, which serves as non-radioactive surrogate for radium-223/-224. These calixcrowns were functionalized sulfonate moieties including deprotonable groups and the corresponding barium complexes were synthesized. Stability constants of these complexes were measured using UV/Vis titration experiments to determine logK values. Further extraction studies were performed with [¹³³Ba]Ba²⁺ and [²²⁴Ra]Ra²⁺ to further characterize the binding affinity of calixcrowns.