Understanding the coordination chemistry of the heavy group 2 metal chemistry, especially of barium as surrogate for radium, is mandatory not only for adiopharmaceutical 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 calixcrowns 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 calixcrown-6 derivatives was synthesized to chelate barium, which serves as non-radioactive surrogate for radium-223/-224. These calixcrowns were functionalized with sulfonate moieties including deprotonable groups. Furthermore, the corresponding barium complexes were synthesized. Stability constants of these complexes were measured using UV/Vis titration experiments to determine logK values. Further radiolabeling and extraction studies were performed with [133Ba]Ba2+ and [124Ra]Ra2+ to further characterize the binding affinity of calixcrowns.