DFT study of molecular probe release process of Ln-DOTA (Eu, Gd, Tb) ester complexes

Context Ln DOTA has been proven to have important application value in clinical medicine schools. Recently, there have been experimental reports on its probe hydrolysis release process. In order to clarify the specific micro reaction mechanism and the influencing factors of hydrolysis activity, this paper uses computational chemistry methods to systematically calculate and investigate the release reaction mechanism and hydrolytic activity of lanthanide ester complexes Ln-DOTA molecular probes under alkaline conditions. Different alcohol-based substituents NB, NI, Bn and lanthanide metal centers (Ln = Eu, Gd, Tb) were selected as reactants to complete the calculation research under the corresponding experimental conditions. The calculated results showed that this reaction includes three possible steps: the nucleophilic attack of the ester carbon atom, the dissociation of the alcohol group the ester bond, and the hydrogen transfer to the alcohol group, and finally the release process is completed to obtain the DOTA product. The activation energies are low (G < 5.75 kcal/mol) and the lanthanide metal center and different substituents have influence, but minor changes do not have a significant effect on the reaction mechanism and activity, indicating that it is easy to accomplish the hydrolytic release of lanthanide complexes under the existing mild experimental conditions, which is consistent with the results of experimental research. Meanwhile, the computational research also provides important basis for further exploring the mechanism of such reactions. Methods The geometry optimization and electronic properties calculations based on density functional theory were performed using the PBE1PBE method. All the theoretical calculations in this work were performed using the Gaussian 09 software. The lanthanide atoms Eu, Gd, and Tb are calculated using effective core pseudopotentials (RECPs) with 52–54 core electrons, while other atoms are selected from the 6-311G (d, p) basis group. Accurate free energy calculations were performed using the SMD solvent model at the PBE0/def2TZVP theoretical level.