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 Ln³⁺ 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 Gd³⁺ complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg²⁺ and Ca²⁺ complexes of DO3A-ACE^4- and DO3A-BACE^4- complexes are lower than for DOTA^4- and DO3A^3-, while the Zn²⁺ and Cu²⁺ 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 Ce³⁺ to Gd³⁺ but remain practically constant for the late Ln³⁺ ions (represented by Yb³⁺). 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 ¹H 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 Ln³⁺-based tags for protein structural NMR analysis.