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

Targeted radionuclide therapy (TRT) has emerged as a promising strategy for cancer treatment. While TRT offers potent therapeutic efficacy, its clinical application requires careful control due to the risk of systemic toxicity arising from off-target distribution of radionuclides. A key strategy to minimize such toxicity and enhance targeting efficiency lies in selecting an appropriate chelator that forms highly stable complexes with radionuclides and maintains their integrity under physiological conditions. This study aimed to computationally assess the chelation compatibility of four clinically relevant chelators (DOTA, NOTA, NODAGA, and TETA) with various therapeutic and diagnostic radionuclides. Chelator-radionuclide interactions were evaluated using density functional theory (DFT) computational modeling. The thermodynamic stabilities of the chelator-radionuclide complexes were evaluated using interaction energies (<i>E</i>_int), with lower values indicating stronger coordination. Coordination geometries, compatibility between internal cavity volumes of chelators and radii of radionuclides, and charge distributions upon chelation were also assessed to provide a comprehensive evaluation. Computational predictions were validated against existing literature to assess their agreement in coordination geometries and chelator-radionuclide compatibility. DOTA exhibited moderate-to-strong chelation affinity across various radionuclides, generally forming stable 8-coordinate complexes, but with a marked preference for medium-sized ions (e.g., Lu³⁺: -4.99 eV vs Ac³⁺: -2.45 eV; <i>E</i>_int). NOTA and NODAGA, which possess smaller cavity volumes (7.29 ų and 4.56 ų, respectively; vs 15.29 ų for DOTA), showed strong size-selective affinity toward smaller metal ions. TETA, structurally flexible, preferentially formed stable 6-coordinate complexes with smaller trivalent ions such as Ga³⁺ (-4.32 eV; <i>E</i>_int). Charge neutrality was identified as a critical factor for chelation, as neutral complexes exhibited more homogeneous electrostatic environments and improved stability compared to charged complexes. This computational study identifies three key factors─cavity volume compatibility, structural rigidity/flexibility, and charge neutrality─as critical determinants of chelator-radionuclide stability. By providing predictive insights into chelation behavior, our validated DFT modeling supports the rational selection and optimization of chelators, with direct implications for the development of safer and more effective theranostic radiopharmaceuticals in TRT.