Abstract
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).
Highlights
Recent research confirms an increasing interest in the use of gallium and zirconium radioiosotopes for medical diagnostic techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT).[1−8]The interest in the use of 68Ga (t1/2 = 1.13 h, Eβ+avg = 830 keV, 89%) for clinical PET comes from the accessibility of its production via an portable and long-lived 68Ge/68Ga generator system.[9]
The synthetic approaches for the preparation of H3L1 and H4L2 are depicted in Schemes 2 and 3, respectively
Assuming the domination of the [GaHL1]+ complex below pH 2, its stability was determined by metal−metal competition titrations, (i) Fe(III)-H3L1 + Ga(III) and (ii) Ga(III)-H3L1 + Fe(III), both performed at pH 1.5
Summary
Recent research confirms an increasing interest in the use of gallium and zirconium radioiosotopes for medical diagnostic techniques such as PET or single-photon emission computed tomography (SPECT).[1−8]. Assuming the domination of the [GaHL1]+ complex below pH 2, its stability was determined by metal−metal competition titrations, (i) Fe(III)-H3L1 + Ga(III) and (ii) Ga(III)-H3L1 + Fe(III), both performed at pH 1.5 This pH was chosen in order to prevent the hydrolysis of the free metal ions and decomposition of the ligand, which is common for hydroxamic acids at a very acidic pH.[37,51] Upon addition of Ga(III) (up to 600 equiv) to the Fe(III)-H3L1 solution, the UV−vis band of [FeHL1]+ (λmax = 470 nm, Figure 2a) slowly disappeared as a result of the [GaHL1]+ complex formation. For the Zr(IV) complexes of trihydroxamate H3L1, H3L3, and H3L4 systems, the pZr value is on the same order as those for DFOB24 and DTPA25 chelators The reason could be the type of chelating groups present in the ligands and the ligand architecture and dimensions
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