# Stabilities of Ac3+ Complexes Relevant as Radiopharmaceuticals

## TL;DR

This study uses computer modeling to compare the stability of Ac3+ and La3+ complexes, aiming to improve the design of radiopharmaceuticals for cancer therapy.

## Contribution

The paper introduces a DFT-based methodology to estimate Ac3+ complex stabilities using La3+ data, enabling better chelator design for radiopharmaceuticals.

## Key findings

- Ac3+ coordination bond distances are longer than La3+, suggesting a larger ionic radius of 1.275 ± 0.020 Å for Ac3+.
- Ac3+ complexes are generally less thermodynamically stable than La3+ ones, except for MACROPA2– and OCTAPA4–.
- The proposed methodology helps identify suitable chelators for Ac3+ in targeted alpha therapy.

## Abstract

We present a detailed density functional theory (DFT)
investigation
of the structural features and thermodynamic stabilities of La3+ and Ac3+ complexes relevant to develop radiopharmaceutical
agents. A total of 16 chelators were considered, covering the acyclic
and macrocyclic families functionalized with different numbers and
types of donor atoms. The bond distances of the Ac3+ coordination
environment are systematically longer than those obtained for the
La3+ analogues, which allowed us to estimate an ionic radius
for Ac3+ in coordination number 9 of 1.275 ± 0.020
Å (1.216 and 1.206 Å were proposed for La3+).
Energy decomposition analysis (EDA) provided hints into the nature
of the metal–ligand interactions and their relative weight
in La3+ and Ac3+ complexes. A thermodynamic
DFT study allowed us to estimate the stability constants of the Ac3+ complexes from those of the La3+ ones, as for
the latter experimental values are available in the literature. These
studies evidenced that Ac3+ tends to form complexes with
lower thermodynamic stability in comparison with La3+,
with the exception of one of the leading chelators for Ac3+, MACROPA2–, and the unexpected case of OCTAPA4–. Overall, the methodology reported here will allow
identifying chelators well suited for Ac3+ coordination,
thereby aiding the design of radiopharmaceuticals based on [225Ac]­Ac3+ for targeted α therapy (TAT).