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-ACE4− ligand and its amide derivative DO3A-BACE4− (modelling the case where DO3A-ACE4− 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-ACE4− and DO3A-BACE4− complexes are lower than for DOTA4− and DO3A3−, while the Zn2+ and Cu2+ complexes have similar and higher stability than for DOTA4− and DO3A3− 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 DOTA4− and DO3A3− 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 Cα-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-ACE4− in the design of GBCAs and Ln3+-based tags for protein structural NMR analysis.This research was funded by the Hungarian National Research, Development and Innovation Office (Projects NKFIH K-128201, K-134694, and FK-134551)

Analysis of the Conformational Behavior and Stability of the SAP and TSAP Isomers of Lanthanide(III) NB-DOTA-Type Chelates

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Properties, Solution State Behavior, and Crystal Structures of Chelates of DOTMA

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Stable and inert macrocyclic cobalt(II) and nickel(II) complexes with paraCEST response

We report the synthesis of the macrocyclic ligands 3,9-PC2AMH (2,2'-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)diacetamide) and 3,9-PC2AMtBu (2,2'-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)bis(N-tert-butyl)acetamide) which contain a pyclen platform functionalized with acetamide or tert-butylacetamide pendant arms at positions 3 and 9 of the macrocyclic unit. The corresponding Co(II) and Ni(II) complexes were prepared, isolated and characterised as potential paramagnetic chemical exchange saturation transfer (paraCEST) agents. The X-ray structures of the Ni(II) complexes reveal six-coordination of the ligands to the metal ion. The Co(II) complex with 3,9-PC2AMtBu shows a similar six-coordinate structure in the solid state, while the Co(II) complex with 3,9-PC2AMH contains a seven-coordinate metal ion, seventh coordination being completed by the presence of an inner-sphere water molecule. The structure of the Co(II) complexes was investigated using 1H NMR spectroscopy and computational methods. The complexes present a seven-coordinate structure in solution, as demonstrated by the analysis of the paramagnetic shifts using density functional theory. Ligand protonation constants and stability constants of the complexes with 3,9-PC2AMH were determined using potentiometric titrations (I = 0,15 M NaCl). The Co(II) complex was found to be more stable than the Ni(II) analogue (log KCoL = 14.46(5) and log KNiL = 13.15(3)). However, the Ni(II) and Co(II) complexes display similar rate constants characterizing the proton-assisted dissociation mechanism. The presence of highly shifted 1H NMR signals due to the amide protons in slow exchange with bulk water results in sizeable CEST signals, which are observed at +67 and +15 ppm for the Co(II) complex with 3,9-PC2AMH and +42 and +7 ppm for the Ni(II) analogue at 25 °C

A Bridge to Coordination Isomer Selection in Lanthanide(III) DOTA-tetraamide Complexes

Interest in macrocyclic lanthanide complexes such as DOTA is driven largely through interest in their use as contrast agents for MRI. The lanthanide tetraamide derivatives of DOTA have shown considerable promise as PARACEST agents, taking advantage of the slow water exchange kinetics of this class of complex. We postulated that water exchange in these tetraamide complexes could be slowed even further by introducing a group to sterically encumber the space above the water coordination site, thereby hindering the departure and approach of water molecules to the complex. The ligand 8O2-bridged-DOTAM was synthesized in a 34% yield from cyclen. It was found that the lanthanide complexes of this ligand did not possess a water molecule in the inner coordination sphere of the bound lanthanide. The crystal structure of the ytterbium complex revealed that distortions to the coordination sphere were induced by the steric constraints imposed on the complex by the bridging unit. The extent of the distortion was found to increase with increasing ionic radius of the lanthanide ion, eventually resulting in a complete loss of symmetry in the complex. Because this ligand system is bicyclic, the conformation of each ring in the system is constrained by that of the other, in consequence inclusion of the bridging unit in the complexes means only a twisted square antiprismatic coordination geometry is observed for complexes of 8O2-bridged-DOTAM

A bridge to coordination isomer selection in lanthanide(III) DOTA-tetraamide complexes

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A Bridge to Coordination Isomer Selection in Lanthanide(III) DOTA-tetraamide Complexes

Interest in macrocyclic lanthanide complexes such as DOTA is driven largely through interest in their use as contrast agents for MRI. The lanthanide tetraamide derivatives of DOTA have shown considerable promise as PARACEST agents, taking advantage of the slow water exchange kinetics of this class of complex. We postulated that water exchange in these tetraamide complexes could be slowed even further by introducing a group to sterically encumber the space above the water coordination site, thereby hindering the departure and approach of water molecules to the complex. The ligand 8O2-bridged-DOTAM was synthesized in a 34% yield from cyclen. It was found that the lanthanide complexes of this ligand did not possess a water molecule in the inner coordination sphere of the bound lanthanide. The crystal structure of the ytterbium complex revealed that distortions to the coordination sphere were induced by the steric constraints imposed on the complex by the bridging unit. The extent of the distortion was found to increase with increasing ionic radius of the lanthanide ion, eventually resulting in a complete loss of symmetry in the complex. Because this ligand system is bicyclic, the conformation of each ring in the system is constrained by that of the other, in consequence inclusion of the bridging unit in the complexes means only a twisted square antiprismatic coordination geometry is observed for complexes of 8O2-bridged-DOTAM