Tales of the Unexpected: The Case of Zirconium(IV) Complexes with Desferrioxamine

Abstract

The Zr4+ complexes with desferrioxamine (H3DFO) and its derivatives are the only 89Zr-based imaging agents for proton emission tomography (PET) that have been used so far in clinical trials. Nevertheless, a complete speciation of the Zr4+/H3DFO system in solution has never been performed and the stability constants of the relevant complexes are still unknown. Here we report, for the first time, the speciation of this system in water, performed by potentiometric titrations, and the determination of the stability constants of all complexes formed in the pH range 2.5–11.5. Surprisingly, although desferrioxamine gives rise to very stable 1:1 complexes with Zr4+ (logK = 36.14 for Zr4+ + DFO3− = [ZrDFO]+), 2:2 and 2:3 ones are also formed in solution. Depending on the conditions, these binuclear complexes can be main species in solution. These results were corroborated by small-angle X-ray scattering (SAXS) and MALDI mass spectrometry analyses of complex solutions. Information on complex structures was obtained by means of density functional theory (DFT) calculations.

Deferoxamine B: A Natural, Excellent and Versatile Metal Chelator

“…The calculated values of pM and K D , shown in Table 8 , are well correlated with each other, except for two specific situations: ( i ) the speciation model of DFOB complexes with Zr(IV) suggested by Savastano et al [ 12 ] contains oligomeric species and the K D value considerably decreases as the concentration of the ligand in solution increases, thus not providing an univocal value; ( ii ) in the case of the weakest complexes, pM is fixed at the value of 6, which means that, at pH 7.4, all the metal is free and no complex forms. This is the case of the alkaline earth metals.…”

“…To determine the complex-formation constants of the species that are formed at the most acidic pH values, it is necessary to use a competition method, which exploits the presence of a second ligand (or another metal) whose speciation pattern is fully known under the same experimental conditions. Savastano et al [ 12 ], after having initially explored (and then discarded) the possibility of using EDTA as a competitor, decided to revisit the hydrolysis equilibria of zirconium, in order to exploit the competition between DFOB and the hydroxyl ion. The complex-formation equilibria between Zr(IV) and DFOB were thus studied by potentiometry in the pH range 2.5–11.5, and were confirmed by spectroscopic investigations using small-angle X-ray scattering (SAXS) and MALDI mass spectrometry.…”

“… Ref. [ 12 ]: potentiometry, 25 °C, I = 0.1 mol·dm −3 (NMe 4 Cl); Ref. [ 13 ]: potentiometry/spectrophotometry, 25 °C, I = 1.0 mol·dm −3 (NaClO 4 ); Ref.…”

Predicting the Thermodynamic Stability of Zirconium Radiotracers

“…It is perhaps surprising that measurements of the thermodynamic formation constants (log b) for Zr-ligand complexation reactions are rarely performed. [8][9][10] In part this absence of thermodynamic data is explained by the challenges of measuring formation constants for Zr 4+ ions. The high charge-to-size ratio of the Zr 4+ ion means that it forms complexes with extremely high thermodynamic stability that cannot be easily (or directly) determined using standard potentiometric titrations.…”

Iron Coordination Properties of Gramibactin as Model for the New Class of Diazeniumdiolate Based Siderophores

“…[32][33][34]36] The analysiso fafull set of potentiometric data obtained on the basis of the abovementioned aspects clearly evidenced the formation of two [Fe(GBT)H r ]s pecies within the investigated pH range (2 pH 11), namely [Fe(GBT)] À and [Fe(GBT)(OH) 2 ] 3À , whose stability constantsare reported in Ta ble2.Although surprising at first glance, the lack of ad etectable stepwise deprotonation,i .e.,t he detection of a[ Fe(GBT)(OH)] 2À species, is not unexpected, as such multistep protonation processes are not uncommon for cases involving strong multifunctional ligands and/or highly hydrolysable cations. [37,38] The presence of the [Fe(GBT)] À adduct was observed in high-resolution LC-MS as a peak with m/z at 886.275, corresponding to the chemical formula of [Fe(GBT)] À (calc. for C 32 H 50 FeN 10 O 16 886.275;F igure 3), in the chromatogram of the supernatant of bacterial cultures.…”