Chelation of radium with double-armed benzo-rigidified macrocycles for radiopharmaceutical purposes

Abstract

Radium-223 is a promising alpha-emitter for targeted alpha therapy (TAT), yet its clinical application is limited by the lack of chelating agents capable of forming stable and kinetically inert complexes under physiological conditions. In this work, we investigated the coordination chemistry of Ra2+, Ba2+, and Ca2+ with a series of rigidified diazacrown ethers featuring acetate (BADA-18/21) and picolinate (BADPA-18/21) pendant arms. The central design strategy utilized an annelated benzene ring to enhance the structural rigidity of the macrocyclic framework and promote effective preorganization of the donor atoms. We demonstrate that picolinate derivatives significantly outperform acetate ones in their affinity for heavy alkaline earth metals. A key finding of this study is that thermodynamic stability constants of Ba2+ complexes are not absolute predictors of radiolabeling efficiency or biological stability for Ra2+ complexes. Despite the high affinity of the 18-membered macrocycle (BADPA-18) for the surrogate Ba2+ ion, only the expanded 21-membered chelator (BADPA-21) provided near-quantitative radiochemical yields (99 ± 6%) with [226Ra]Ra2+ within 1 minute at room temperature. The [226Ra]Ra(BADPA-21) complex exhibited high kinetic inertness in fetal bovine serum for 48 h and in the presence of biologically relevant metal ions. In vivo biodistribution studies in mice showed that BADPA-21 can at least partially redirect radium from bone and spleen tissues, although its biological stability was found to be moderate compared to macropa. Nevertheless, the combination of exceptionally rapid labeling kinetics under mild conditions and high synthetic accessibility establishes BADPA-21 as a valuable structural lead for the development of improved chelators for TAT.