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Gd III Complexes with Fast Water Exchange and High Thermodynamic Stability: Potential Building Blocks for High‐Relaxivity MRI Contrast Agents
Author(s) -
Laus Sabrina,
Ruloff Robert,
Tóth Éva,
Merbach André E.
Publication year - 2003
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200204612
Subject(s) - steric effects , chemistry , ligand (biochemistry) , gadolinium , crystallography , diethylenetriamine , electron paramagnetic resonance , nuclear magnetic resonance spectroscopy , stereochemistry , nuclear magnetic resonance , organic chemistry , biochemistry , physics , receptor
On the basis of structural considerations in the inner sphere of nine‐coordinate, monohydrated Gd III poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA 5− ligand (DTPA=(diethylenetriamine‐ N , N , N′ , N″ , N″ ‐pentaacetic acid) by replacing one (EPTPA 5− ) or two (DPTPA 5− ) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA‐prop 5− ). The ligand EPTPA 5− was additionally functionalized with a nitrobenzyl linker group (EPTPA‐bz‐NO 2 5− ) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable‐temperature 17 O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa‐bz‐NO 2 )(H 2 O)] 2− and [Gd(eptpa)(H 2 O)] 2− than on [Gd(dtpa)(H 2 O)] 2− ( k ${_{{\rm ex}}^{\,298}}$ =150×10 6 , 330×10 6 , and 3.3×10 6 s −1 , respectively). This is optimal for attaining maximum proton relaxivities for Gd III ‐based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable‐pressure 17 O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H 2 O)] 2− (Δ V ≠ =(+6.6±1.0) cm 3 mol −1 ). In contrast to [Gd(eptpa)(H 2 O)] 2− , an interchange mechanism is proved for the macrocyclic [Gd(trita)(H 2 O)] − (Δ V ≠ =(−1.5±1.0) cm 3 mol −1 ), which has one more CH 2 group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H 2 O)] − , and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA 5− is substituted by a propionate, the water exchange rate on the Gd III complex increases by a factor of 10 ( k ${_{{\rm ex}}^{\,298}}$ =31×10 6 s −1 ). The [Gd(dptpa)] 2− chelate has no inner‐sphere water molecule. The protonation constants of the EPTPA‐bz‐NO 2 5− and DPTPA 5− ligands and the stability constants of their complexes with Gd III , Zn II , Cu II and Ca II were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa‐bz‐NO 2 )(H 2 O)] 2− is reduced to a slight extent in comparison with [Gd(dtpa)(H 2 O)] 2− , it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H 2 O)] − are potential building blocks for the development of high‐relaxivity macromolecular agents.