Optimizing the efficiency of complex formation with highly substituted bispidines

• Applicant: Professor Dr. Peter Comba
• Subject Area: Inorganic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551508622

In this project we will apply Density Functional Theory (DFT) calculations to determine the mechanism of complex formation with hepta- to nonadentate bispidine-based ligands and metal ions of relevance for theranostic radiopharmaceutical applications as well as contrast agents for magnetic resonance imaging (MRI) (La3+, Lu3+, Ac3+, Bi3+, Pb2+, Mn2+, Zn2+). For both applications, there is a range of published experimental studies, which indicate that with certain metal-ligand combinations, complex formation can be very sluggish or even impossible, while, in general, the complexation with bispidine ligands is fast and efficient. Moreover, with some metal-ligand combinations stability constants, complex inertness as well as other important properties such as the relaxivity, an important property for MRI contrast agents, are much lower than usual. We have indications that this is due to the formation of an inactive “out-of-cage” complex that only can be transformed to the final complex with difficulty, if at all. Therefore, the complex formation pathway, which supposedly involves around one dozen intermediates, needs to be studied in detail in order to be optimize the ligand structures for specific metal ions to prevent species that are not efficiently converted to the final product. The computational approach proposed will involve (i) the optimization of all intermediates in order to accurately compute the thermodynamics, i.e., all coupled equilibria; (ii) the computation of molecular properties of all intermediates, which then can be compared with available experimental data of these species; (iii) the computation of important transition states that may be involved in making some of the complexation steps inefficient. With the knowledge of the mechanistic details, ligands for specific metal ions will then be optimized such that complex formation, thermodynamic stability and inertness will allow to improve the quality of these applications.

• DFG Programme: Research Grants