Rational Selection of Chelators for Theranostic Radionuclides: Insights from Ab Initio Computational Modeling

Area of Science:

• Radiochemistry
• Computational Chemistry
• Oncology

Background:

• Targeted radionuclide therapy (TRT) shows promise for cancer treatment but requires precise control to avoid systemic toxicity from off-target radionuclide distribution.
• Selecting appropriate chelators is crucial for forming stable radionuclide complexes, minimizing toxicity and enhancing therapeutic efficacy.

Purpose of the Study:

• To computationally evaluate the chelation compatibility of four clinically relevant chelators (DOTA, NOTA, NODAGA, TETA) with various therapeutic and diagnostic radionuclides.
• To identify key factors governing chelator-radionuclide complex stability for optimizing radiopharmaceutical design.

Main Methods:

• Density Functional Theory (DFT) was employed to model chelator-radionuclide interactions and calculate thermodynamic stabilities (interaction energies).
• Evaluated coordination geometries, chelator cavity volume compatibility with radionuclide radii, and charge distributions.
• Validated computational predictions against existing literature data for accuracy.

Main Results:

• DOTA showed moderate-to-strong affinity, preferring medium-sized ions and forming stable 8-coordinate complexes.
• NOTA and NODAGA, with smaller cavities, exhibited size-selective affinity for smaller metal ions.
• TETA preferentially formed stable 6-coordinate complexes with smaller trivalent ions; charge neutrality was critical for complex stability.

Conclusions:

• Chelator-radionuclide stability is determined by cavity volume compatibility, structural rigidity/flexibility, and charge neutrality.
• Validated DFT modeling provides predictive insights for rational chelator selection and optimization.
• This work supports the development of safer and more effective theranostic radiopharmaceuticals for TRT.