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 complexes with the bifunctional DO3A-ACE ligand and its amide derivative DO3A-BACE (modelling the case where DO3A-ACE ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg and Ca complexes of DO3A-ACE and DO3A-BACE complexes are lower than for DOTA and DO3A, while the Zn and Cu complexes have similar and higher stability than for DOTA and DO3A complexes. The stability constants of the Ln(DO3A-BACE) complexes increase from Ce to Gd but remain practically constant for the late Ln ions (represented by Yb). The stability constants of the Ln(DO3A-ACE) and Ln(DO3A-BACE) complexes are several orders of magnitude lower than those of the corresponding DOTA and DO3A 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 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-() and S-(). The conformation of the C-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 in the design of GBCAs and Ln-based tags for protein structural NMR analysis.