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Reining in Radium for Nuclear Medicine: Extra-Large Chelator Development for an Extra-Large Ion
Megan E Simms1, Megan M Sibley1, Darren M Driscoll1
1Chemical Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
Inorganic Chemistry
|October 9, 2023
Summary
Researchers developed macropa-XL, a novel chelator for radium-223 (223Ra) in targeted alpha therapy (TAT). While macropa-XL binds 223Ra, its complex stability is lower than current standards, limiting its therapeutic potential.
Area of Science:
- Radiochemistry
- Nuclear Medicine
- Materials Science
Background:
- Targeted alpha therapy (TAT) using 223Ra shows promise for soft-tissue cancers.
- Challenges in chelating 223Ra due to the Ra2+ ion's properties hinder its clinical application.
- Stable attachment of radionuclides to targeting vectors is crucial for TAT efficacy.
Purpose of the Study:
- To synthesize and evaluate macropa-XL, a novel chelator designed for radium-223 (223Ra).
- To assess the complex stability and radiolabeling efficiency of macropa-XL with 223Ra.
- To investigate the chelation chemistry of the Ra2+ ion.
Main Methods:
- Synthesis and structural characterization of macropa-XL using Ba2+ with X-ray diffraction and X-ray absorption spectroscopy.
- Determination of the stability constant of the [Ra(macropa-XL)] complex via competitive cation exchange with 223Ra and 224Ra.
- Radiolabeling of macropa-XL with 223Ra and evaluation of kinetic stability in human serum.
Main Results:
- Macropa-XL formed an 11-coordinate complex with Ba2+ in an anti pendent-arm configuration.
- The stability constant (log KM L) for [Ra(macropa-XL)] was determined to be 8.12, which is 1.5 log K units lower than that of macropa.
- The [Ra(macropa-XL)] complex showed instability to transchelation in human serum, despite effective radiolabeling under mild conditions.
Conclusions:
- Macropa-XL demonstrates potential for chelating Ra2+ but exhibits reduced complex stability compared to existing chelators.
- The findings provide insights into the chelation chemistry of Ra2+ and inform future chelator development for 223Ra-based TAT.
- Further research is needed to overcome the stability limitations for clinical translation.
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