Ph.D. topics

Design of high-affinity ligands for chelation of f-elements

Ph. D. student

Rodrigo Castro Biondo

Supervisor

Dr. Jérôme Kretzschmar

Department

Actinide thermodynamics department

Period

11/2023 - 10/2026

Desription

Radiometals and the design of chelating ligands to create stable complexes is an important element in radiopharmaceutical and radioecological research. From the application’s perspective, complexes must carry the radiometal to the target in the human body or capture radiometals in living beings for removal or excretion. From a fundamental research perspective, it is of pivotal interest to elucidate structure–property correlations as inferred from HSAB-related donor–acceptor relationships as well as coordination number and geometry, especially for complexes of f-elements but also of some main group metal ions.

Essential for the design of these ligands is their stability – in terms of both thermodynamics and kinetics – whether it is in vivo, for instance as radiopharmaceuticals or decorporation agents, or in the biogeosphere as with radio-ecological applications such as remediation. Release of the radiometal should be avoided to prevent accumulation in non-desired biological targets, leading to off-target effects or, in the case of plants or animals, leading to accumulation or distribution along the food chain. As there is no chelator known to be active and stable with all metals and conditions, finding the best-suited metal–ligand pairs is of high interest. To determine the stability of the chelator, a crucial parameter is the association constant (log K). Stability in vivo is also influenced by charge and hydrophilicity, as they have a direct impact on biodistribution and renal clearance.

To overcome the disadvantages of the DOTA ligand (i.e., suitability for ions of small radius, high reaction temperatures to facilitate complexation), the macropa ligand (cf. Figure 1) is a promising alternative suited particularly for metal ions of larger radius.

Regarding synthesis of new ligands, two strategies will be pursued. That is, primarily, the functionalization of macropa’s aromatic rings, as introduction of acceptors or donors could modulate electron density distribution in the aromatic ring, leading to a hardening or softening of the ligands’ HSAB donor properties. Additionally, perdeuteration of macropa’s diazacrown ether, as it is hypothesized that due to steric deuterium isotope effect the stability of the complex might increase.

All ligands will be fully characterized in terms of their structure and their pKa values, utilizing nuclear magnetic resonance (NMR) spectroscopy. Complexation studies focus especially on f-elements (lanthanides and actinides) but also of some main group metal ions (Ba, Ra, Pb), and comprise radiolabeling experiments in the tracer concentration range as well as complexation studies applying a multi-method approach. The latter include various spectroscopic techniques (NMR, time-resolved Laser-induced fluorescence spectroscopy (TRLFS), X-ray absorption fine-structure spectroscopy (EXAFS)), calorimetry, and where applicable, also diffractometry. Quantum chemical calculations may complement experimental data.