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 (logKGaL= 21.39) and by Ga-71 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 Ga-68 in acetate buffer at pH 3.8, in 15 minutes at room temperature at [CyAAZTA]= 10 mu M, with a labelling yield higher than 80%. A 1 mu M solution of CyAAZTA was successfully labelled (L. Y.: 97.4%) in 5 minutes at 90 degrees C. Stability tests in human serum and in the presence of 50 mM DTPA showed no significant decomposition of (68)GaCyAAZTA over 90 minutes.