Complexes of Bifunctional DO3A-N-(α-amino)propinate Ligands with Mg(II), Ca(II), Cu(II), Zn(II), and Lanthanide(III) Ions: Thermodynamic Stability, Formation and Dissociation Kinetics, and Solution Dynamic NMR Studies

The thermodynamic, kinetic, and structural properties of Ln(3+) complexes with the bifunctional DO3A-ACE(4−) ligand and its amide derivative DO3A-BACE(4−) (modelling the case where DO3A-ACE(4−) ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd(3+) complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg(2+) and Ca(2+) complexes of DO3A-ACE(4−) and DO3A-BACE(4−) complexes are lower than for DOTA(4−) and DO3A(3−), while the Zn(2+) and Cu(2+) complexes have similar and higher stability than for DOTA(4−) and DO3A(3−) complexes. The stability constants of the Ln(DO3A-BACE)(−) complexes increase from Ce(3+) to Gd(3+) but remain practically constant for the late Ln(3+) ions (represented by Yb(3+)). The stability constants of the Ln(DO3A-ACE)(4−) and Ln(DO3A-BACE)(4−) complexes are several orders of magnitude lower than those of the corresponding DOTA(4−) and DO3A(3−) complexes. The formation rate of Eu(DO3A-ACE)(−) is one order of magnitude slower than for Eu(DOTA)(−), due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)(−) complexes to dissociate several orders of magnitude faster than Ln(DOTA)(−) and its absence in the Ln(DO3A-BACE)(−) complexes results in inertness similar to Ln(DOTA)(−) (as judged by the rate constants of acid assisted dissociation). The (1)H NMR spectra of the diamagnetic Y(DO3A-ACE)(−) and Y(DO3A-BACE)(−) reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-Λ(λλλλ) and S-Δ(δδδδ). The conformation of the C(α)-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)(−) than the amino group in Y(DO3A-ACE)(−) to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)(−), Gd(DO3A-BACE)(−) is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE(4−) in the design of GBCAs and Ln(3+)-based tags for protein structural NMR analysis.