Radium-223 (Ra-223) is the first and only alpha particle-emitting radioisotope approved for therapeutic use. It is indicated for the treatment of bone metastases in men with prostate cancer. Administered as a simple chloride salt, the radioactive radium ion preferentially accumulates in bone, where its lethal cascade of alpha emissions destroys osteoblastic lesions. To expand the use of Ra-223 to soft-tissue cancers, this radiometal must be stably bound to a tumor-targeting vector via a bifunctional chelating agent. Although recent milestones in the aqueous chelation of the radium ion have been achieved, the successful delivery of Ra-223 to tumors remains elusive. This shortcoming reflects the inadequate stability of radium-ligand complexes in vivo. With the overarching goal of developing new chelators that can effectively stabilize Ra-223 in vivo, we have initiated a research program directed towards more thoroughly understanding the fundamental coordination chemistry of the radium ion, which remains underexplored in comparison to its non-radioactive alkaline earth congeners. In this presentation, we report our efforts to experimentally determine the aqueous stability constants, or log <i>K</i> values, of Ra-223 with a series of macrocyclic ligands of relevance to targeted alpha therapy. These values, which reflect the thermodynamic affinity of a chelator for a metal ion, reveal important structure-stability trends that will be leveraged to guide future ligand design efforts. Moreover, this research has led to the identification of the highest affinity chelator reported to date for the radium ion. Collectively, the stability constant data obtained from this work will provide a roadmap for the generation of novel radium-223-based targeted therapeutics to significantly expand the medicinal scope of this promising radionuclide.

Towards the development of high-affinity chelators for Ra-223 targeted alpha therapy: A stability constant roadmap

ACS Spring 2022

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