Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion

Targeted α therapy (TAT) of soft-tissue cancers using the α particle-emitting radionuclide ²²³Ra holds great potential because of its favorable nuclear properties, adequate availability, and established clinical use for treating metastatic prostate cancer of the bone. Despite these advantages, the use of ²²³Ra has been largely overshadowed by other α emitters due to its challenging chelation chemistry. A key criterion that needs to be met for a radionuclide to be used in TAT is its stable attachment to a targeting vector via a bifunctional chelator. The low charge density of Ra²⁺ arising from its large ionic radius weakens its electrostatic binding interactions with chelators, leading to insufficient complex stability in vivo. In this study, we synthesized and evaluated macropa-XL as a novel chelator for ²²³Ra. It bears a large 21-crown-7 macrocyclic core and two picolinate pendent groups, which we hypothesized would effectively saturate the large coordination sphere of the Ra²⁺ ion. The structural chemistry of macropa-XL was first established with the nonradioactive Ba²⁺ ion using X-ray diffraction and X-ray absorption spectroscopy, which revealed the formation of an 11-coordinate complex in a rare anti pendent-arm configuration. Subsequently, the stability constant of the [Ra(macropa-XL)] complex was determined via competitive cation exchange with ²²³Ra and ²²⁴Ra radiotracers and compared with that of macropa, the current state-of-the-art chelator for Ra²⁺. A moderate log K_ML value of 8.12 was measured for [Ra(macropa-XL)], which is approximately 1.5 log K units lower than the stability constant of [Ra(macropa)]. This relative decrease in Ra²⁺ complex stability for macropa-XL versus macropa was further probed using density functional theory calculations. Additionally, macropa-XL was radiolabeled with ²²³Ra, and the kinetic stability of the resulting complex was evaluated in human serum. Although macropa-XL could effectively bind ²²³Ra under mild conditions, the complex appeared to be unstable to transchelation. Collectively, this study sheds additional light on the chelation chemistry of the exotic Ra²⁺ ion and contributes to the small, but growing, number of chelator development efforts for ²²³Ra-based TAT.