An innovative MRI contrast agent based on the unprecedented and easily obtained ligand AAZTA is described. The simple and straightforward synthesis of the ligand, together with the potentiometric and relaxometric behavior of the corresponding Gd(III) chelate, is reported. The complex [Gd(AAZTA)]- shows outstanding magnetic properties connected with high thermodynamic stability in aqueous solution and a nearly complete inertness toward the influence of bidentate endogenous anions, placing this compound as one of the most promising candidates for the development of high performance MRI contrast agents.
A detailed study of the structures, thermodynamic stabilities and kinetics of the dissociation of Ga3+, In3+ and Cu2+ complexes formed with the heptadentate ligand AAZTA is reported. The stability constants (log KML) of the AAZTA complexes of Ga3+, In3+ and Cu2+ are 22.18, 29.58 and 22.27, respectively, which suggests that the seven‐membered‐ring skeleton is suited to the accommodation of these metal ions. The solid‐state structure of [Cu(H2AAZTA)]·H2O shows a distorted octahedral coordination. The equatorial coordination sites of Cu2+ are occupied by one of the ring N atoms, a water O atom, one of the carboxylate O atoms and the N atom of the iminodiacetate moiety. The other ring N atom and the carboxylate O atom of the iminodiacetate moiety coordinate to the Cu2+ in the axial positions. In the pH range 4.5–8.5, Ga3+ is present in the form of the highly stable [Ga(AAZTA)OH]2– (log βGaLH–1 = 17.69) The exchange reactions of [Ga(AAZTA)OH]2– with Cu2+ and transferrin are very slow and mainly occur through the spontaneous dissociation of the complex close to physiological conditions. The half‐life for the dissociation of [Ga(AAZTA)OH]2– is t1/2 = 23 h at pH = 7.5 and 25 °C in 0.025 M NaHCO3 and 0.15 M NaCl. The high conditional stability, fast formation and sufficiently slow dissociation of [Ga(AAZTA)OH]2– represent promising properties for the complexation and diagnostic applications of radioactive Ga isotopes.
The three novel pyridine-containing 12-membered macrocyclic ligands 1 ± 3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2. In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3. The relaxivities r 1p (20 MHz, 258)
The search for alternatives to Gd-containing magnetic resonance imaging (MRI) contrast agents addresses the field of Fe(III)-bearing species with the expectation that the use of an essential metal ion may avoid the issues raised by the exogenous Gd. Attention is currently devoted to highly stable Fe(III) complexes with hexacoordinating ligands, although they may lack any coordinated water molecule. We found that the hexacoordinated Fe(III) complex with two units of deferasirox, a largely used iron sequestering agent, owns properties that can make it a viable alternative to Gd-based agents. Fe(deferasirox) 2 displays an outstanding thermodynamic stability, a high binding affinity to human serum albumin (three molecules of complex are simultaneously bound to the protein), and a good relaxivity that increases in the range 20−80 MHz. The relaxation enhancement is due to second sphere water molecules likely forming H-bonds with the coordinating phenoxide oxygens. A further enhancement was observed upon the formation of the supramolecular adduct with albumin. The binding sites of Fe(deferasirox) 2 on albumin were characterized by relaxometric competitive assays. Preliminary in vivo imaging studies on a tumor-bearing mouse model indicate that, on a 3 T MRI scanner, the contrast ability of Fe(deferasirox) 2 is comparable to the one shown by the commercial Gd(DTPA) agent. ICP-MS analyses on blood samples withdrawn from healthy mice administered with a dose of 0.1 mmol/kg of Fe(deferasirox) 2 showed that the complex is completely removed in 24 h.
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