Thermodynamic and Kinetic Stabilities of Al(III) Complexes with N(2)O(3) Pentadentate Ligands

Al(III) complexes have been recently investigated for their potential use in imaging with positron emission tomography (PET) by formation of ternary complexes with the radioisotope fluorine-18 ((18)F). Although the derivatives of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) are the most applied chelators for [Al(18)F](2+) labelling and (pre)clinical PET imaging, non-macrocyclic, semi-rigid pentadentate chelators having two N- and three O-donor atoms such as RESCA1 and AMPDA-HB have been proposed with the aim to allow room temperature labelling of temperature-sensitive biomolecules. The paucity of stability data on Al(III) complexes used for PET imaging instigated a complete thermodynamic and kinetic solution study on Al(III) complexes with aminomethylpiperidine (AMP) derivatives AMPTA and AMPDA-HB and the comparison with a RESCA1-like chelator CD3A-Bn (trans-1,2-diaminocyclohexane-N-benzyl-N,N′,N′-triacetic acid). The stability constant of [Al(AMPDA-HB)] is about four orders of magnitude higher than that of [Al(AMPTA)] and [Al(CD3A-Bn)], highlighting the greater affinity of phenolates with respect to acetate O-donors. On the other hand, the kinetic inertness of the complexes, determined by following the Cu(2+)-mediated transmetallation reactions in the 7.5–10.5 pH range, resulted in a spontaneous and hydroxide-assisted dissociation slightly faster for [Al(AMPTA)] than for the other two complexes (t(1/2) = 4.5 h for [Al(AMPTA)], 12.4 h for [Al(AMPDA-HB)], and 24.1 h for [Al(CD3A-Bn)] at pH 7.4 and 25 °C). Finally, the [AlF](2+) ternary complexes were prepared and their stability in reconstituted human serum was determined by (19)F NMR experiments.