A rigidified AAZTA-like ligand as efficient chelator for ⁶⁸Ga radiopharmaceuticals

The new cyclohexane-fused CyAAZTA ligand was synthesized to increase the structural rigidity of the heptadentate chelator AAZTA with the aim of improving the overall stability of its Ga^III complex. The stability constant of Ga(CyAAZTA)⁻, determined both by pH-potentiometry (logK_GaL=21.39) and by ⁷¹Ga NMR (logK_GaL=21.92), was found similar to that of GaAAZTA (logK_GaL=22.18). The kinetic inertness of Ga(CyAAZTA)⁻ was investigated by following its transmetallation and ligand exchange reactions with Cu²⁺ and human serum transferrin, respectively. The formation of a hydroxido-complex near pH 7 decreases the half-life (t_1/2) of the dissociation reactions for Ga(CyAAZTA)⁻ compared to Ga(AAZTA)⁻ (8.5 h vs 21 h, pH 7.4). However, at pH < 7 the t_1/2 of Ga(CyAAZTA)⁻ is much longer (234 h at pH 6). Finally, CyAAZTA was successfully radiolabelled with ⁶⁸Ga in acetate buffer at pH 3.8, in 15 minutes at room temperature at [CyAAZTA]=10 μM, with a labelling yield higher than 80 %. A 1 μM solution of CyAAZTA was successfully labelled (L.Y.: 97.4 %) in 5 minutes at 90 °C. Stability tests in human serum and in the presence of 50 mM DTPA showed no significant decomposition of ⁶⁸GaCyAAZTA over 90 minutes.