Efficient chelating agents for Zr(IV) ions: design, synthesis and thermodynamic properties

Current directions in radiochemistry and nuclear medicine highlight the importance of Positron Emission Tomography (PET) imaging. PET is one of the molecular imaging modalities that probes physiological changes noninvasively. A fundamental critical component of PET radiometal-based radiopharmaceutical is a chelator - the ligand system that binds the radiometal ion in a tight, stable, kinetically inert coordination complex so that it can be properly directed to a desirable molecular target in vivo. Currently, the most successfully used 89Zr(IV) chelator is desferrioxamine B (DFOB) but some decomposition can be observed over time in vivo, as 89Zr slowly accumulates in bones. Nevertheless, the thermodynamic studies for Zr(IV) - DFOB system have not been performed till this work. Therefore, the solution chemistry of Zr(IV) - DFOB (here (Zr(IV) - H4L1+ ) has been investigated as the first step of the thesis. The obtained data are in line with the problems with the full effectiveness of DFOB as a zirconium chelator. Even if there are many other highly competent zirconium chelators described in the literature up to now, DFOB still remains the best choice for 89Zr. This allows recognizing the challenges to be addressed by inorganic chemistry directing to the development of new scaffolds. In order to develop novel chelators for non-invasive in vivo imaging agents and understand the influence of ligands’ structure, size or flexibility on the stability of Zr(IV) complexes, a series of tri- and tetra-hydroxamic (or mixed donor) ligands with linear, cyclic and pendant arrangements have been designed, synthesized and fully characterized. To get a deep insight into the thermodynamic stability and binding aspects of Zr(IV) complexes, several techniques including electrospray ionization mass spectrometry, potentiometry, UV–Vis spectroscopy and isothermal titration calorimetry were used to determine the stoichiometry and thermodynamic stability of complexes formed in solution over pH range 1 - 11, overcoming all the difficulties with the characterisation of the aqueous solution chemistry of Zr(IV) complexes, like strong hydrolysis and lack of spectral information. Overall, the results obtained for the whole series of compounds bring very important information on parameters that can influence the thermodynamic stability of the complexes formed in solution. The comparison of cyclic versus linear/tripodal trihydroxamate chelators did not show any significant differences, with all of them being in the range of good Zr(IV) chelators, close to the affinity of DFOB. The pM for cyclic tetrahydroxamate chelator H4L3 (pM = 37.0) is in the same range as the most stable tetrapodal compound of this work, H4L6 (pM = 37.5). The comparison of the results obtained for tetrapodal chelators (H4L6, H4L7 and H4L8) clearly shows the importance of the ligand flexibility as well as its high symmetry in order to improve the complex stability. Among investigated ligands, the highest stability was observed for Zr(IV) complexes of mixed donors, trihydroxamate-catecholate H6L9 ligand. Importantly, participation in the International Joint Doctoral Study Programme in Chemistry between University of Wroclaw and Ferrara University, and Short Term Scientific Missions to Ferrara University funded by Erasmus+ and COST (European Cooperation in Science and Technology), Action CA18202, NECTAR – Network for Equilibria and Chemical Thermodynamics Advanced Research, allowed me to profit from the expertise and knowledge of prof. Remo Guerrini’s research group to design and perform the synthesis of very efficient, tetrapodal hydroxamate Zr(IV) chelator - H4L3. Understanding the thermodynamic stability and structural properties of the Zr(IV) complexes formed by the studied ligands opens the possibility of further design of ligands with improved properties and the potential to be used in the field of 89Zr - PET

Thermodynamic Stability and Speciation of Ga(III) and Zr(IV) Complexes with High-Denticity Hydroxamate Chelators

Increasing attention has been recently devoted to 89Zr(IV) and 68Ga(III) radionuclides, due to their favorable decay characteristics for positron emission tomography (PET). In the present paper, a deep investigation is presented on Ga(III) and Zr(IV) complexes with a series of tri-(H3L1, H3L3, H3L4 and desferrioxamine E, DFOE) and tetrahydroxamate (H4L2) ligands. Herein, we describe the rational design and synthesis of two cyclic complexing agents (H3L1 and H4L2) bearing three and four hydroxamate chelating groups, respectively. The ligand structures allow us to take advantage of the macrocyclic effect; the H4L2 chelator contains an additional side amino group available for a possible further conjugation with a biomolecule. The thermodynamic stability of Ga(III) and Zr(IV) complexes in solution has been measured using a combination of potentiometric and pH-dependent UV-vis titrations, on the basis of metal-metal competition. The Zr(IV)-H4L2 complex is characterized by one of the highest formation constants reported to date for a tetrahydroxamate zirconium chelate (log β = 45.9, pZr = 37.0), although the complex-stability increase derived from the introduction of the fourth hydroxamate binding unit is lower than that predicted by theoretical calculations. Solution studies on Ga(III) complexes revealed that H3L1 and H4L2 are stronger chelators in comparison to DFOB. The complex stability obtained with the new ligands is also compared with that previously reported for other hydroxamate ligands. In addition to increasing the library of the thermodynamic stability data of Ga(III) and Zr(IV) complexes, the present work allows new insights into Ga(III) and Zr(IV) coordination chemistry and thermodynamics and broadens the selection of available chelators for 68Ga(III) and 89Zr(IV)