Calix[4]crown-6 scaffold for the complexation of barium and radium

Radium is the heaviest known member of the alkaline earth metals and all 33 of its isotopes are radioactive. Two of these, radium-223 and radium-224, have suitable half-lives with 11.4 d and 3.6 d, respectively, and nuclear decay properties that make them useful tools for alpha particle therapy. Unfortunately, no suitable chelating agents are available for a stable complexation. Thus, radium-223 is only in use as radium chloride to treat bone metastases. For this purpose, a series of modified calix[4]crown-6 derivatives was synthesized to chelate heavy group 2 metal ions like barium, which serves as a non-radioactive surrogate for radium-223/-224.
The calix[4]arene framework can be seen as an ideal platform to build an optimized chelator. Two of the four hydroxy groups of the lower rim can be functionalized as deprotonizable groups to form a neutral complex with barium or radium; the remaining two are bridged by a crown ether moiety. With this concept, the advantages of the electrostatic, macrocyclic, and cryptate effect are combined. Another benefit of the calixcrowns is their easy access.
As a result, our calix[4]crowns were functionalized with either cyclic amide moieties or with deprotonizable groups like carboxylic acids or hydroxyl amines, and the corresponding barium complexes were synthesized.
To prove the ability of these chelators for a further usage in radiopharmacy, stability constants of the corresponding barium complexes were determined by using NMR and UV/Vis titration to determine logK values. Further extraction studies were performed to characterize the binding affinity of calixcrowns to barium-133 and radium-224.