Abstract
The stability constant (logK1) and reactivity are ultimately the most crucial components to consider during the evaluation and selection of chelators to match with a specific radiometal ion for usage in radiopharmaceutical applications. These components evaluate the thermodynamic stability of the radiometal-chelator complex. Additionally, the effectiveness of chelator in binding with radiometal ions with relatively large atomic radii (e.g., 213Bi3+ and 225Ac3+) coupled with charge-diffuse properties result in weaker metal-ligand interactions, and this poses challenges in chelator development. The (2-[(carboxymethyl)]5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tPentan-2-yl) amino] acetic acid (3p-C-DEPA) is a new hybrid chelator designed for potential radio-complexation applications in radio-theranostics and preclinical data has shown great promise for this chelating ligand. Hence, this study investigates the stability constant and chemical reactivity descriptors of the complex generated between 3p-C-DEPA and the α-emitting radioisotopes 213Bi3+ and 225Ac3+ as well as the β-emitting particle 177Lu3+ for the first-time using density functional theory (DFT) calculations. The method employs two functional densities, MO6-HF and B3LYP, using the basis set 6-311G(d)/SDD, alongside the continuous solvation models SMD (solvation model density) and COSMO (conductor-like screening model). The interactions of all radiometals with the hybrid chelator 3p-C-DEPA are compared to the benchmark chelator, 1,4,7,10-tetrazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), yielding comprehensive data on the stability constants and based structural features of radiometal-chelator complexes. DFT analysis has shown that the stability of the 3p-C-DEPA chelator complex formation is influenced by the atomic radius of the radiometal and the number of nitrogen and oxygen donors, proving to be effective for Ac3+ and Bi3+, in contrast to Lu3+, which shows lower stability constant values.
Data availability
The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files. Should any raw data files be needed in another format they are available from the corresponding author upon reasonable request. Source data are provided with this paper. Additional data can be obtained by contacting the corresponding author: d.ramdhani@unpad.ac.id.
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Open access funding provided by University of Padjadjaran. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Danni Ramdhani: Writing – review & editing, Writing – original draft, Visualization, Resources, Methodology, Formal analysis, Data curation, Conceptualization. Hiroshi Watabe: Writing – review & editing, Supervision. Stephen Ahenkorah: Writing – review & editing. Rina F. Nuwarda: Writing – review & editing. Ari Hardianto: Writing – review & editing, Supervision. Regaputra S. Janitra: Writing – review & editing, Validation, Supervision, Investigation, Formal analysis.
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The Supporting Information is available free of charge. Calculated energies from the optimized structures of complex compiled ΔG°g, ΔGaq, and log K1 calculated in this work; DFT-optimized structure and cartesian coordinate of [Lu(DOTA)(H2O)]-, and [Lu(3p-C-DEPA)]2- complex; DFT-optimized structure and cartesian coordinate of [Bi(DOTA)(H2O)]-, and [Bi(3p-C-DEPA)]2- complex; DFT-optimized structure and cartesian coordinate of [Ac(DOTA)(H2O)]-, and [Ac(3p-C-DEPA)]2-complex (PDF).
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Ramdhani, D., Watabe, H., Ahenkorah, S. et al. DFT calculation of Ac3+ and Bi3+ complexation with hybrid chelator 3p-C-DEPA for targeted alpha therapy. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35633-z
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DOI: https://doi.org/10.1038/s41598-026-35633-z
