Density Functional Theory Study on the Complexation of NOTA as a Bifunctional Chelator with Radiometal Ions

Area of Science:

• Computational Chemistry
• Radiopharmaceutical Science
• Coordination Chemistry

Background:

• 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) is a crucial bifunctional chelator for radiometal complexation in radiopharmaceuticals.
• Chelator efficacy is determined by the strength of metal ion binding.
• Understanding solution-phase interactions is vital for optimizing radiopharmaceutical design.

Purpose of the Study:

• To computationally evaluate the complexation of Cu²⁺, Ga³⁺, Sc³⁺, and In³⁺ with the NOTA chelator.
• To investigate the role of ion-water interactions in the chelation process.
• To determine the most stable NOTA-radiometal complex for potential radiopharmaceutical use.

Main Methods:

• Density Functional Theory (DFT) with the B3LYP functional and 6-311+G(2d,2p)/DGDZVP basis sets was employed.
• Calculations included interaction energies, Gibbs free energies, entropies, and natural atomic charges.
• Theoretical ¹H NMR chemical shifts and global scalar properties (HOMO/LUMO energies, hardness, softness) were analyzed.

Main Results:

• NOTA-Ga³⁺ exhibited the most stable complexation, while NOTA-Cu²⁺ was the least stable.
• Theoretical binding constants, geometries, and ¹H NMR chemical shifts showed good agreement with experimental data.
• Charge transfer was observed between NOTA and the radiometal ions, with significant variations in hardness and ΔE_LUMO-HOMO.

Conclusions:

• Gallium-68 (Ga³⁺) is the most suitable radiometal ion for stable complexation with NOTA for radiopharmaceutical applications.
• DFT calculations provide reliable insights into chelator-metal interactions and can guide radiopharmaceutical development.
• The study highlights the importance of considering ion-water competition and electronic properties in chelator design.