Premium
MD Simulations of Acyclic and Macrocyclic Gd 3+ ‐Based MRI Contrast Agents: Influence of the Internal Mobility on Water Proton Relaxivity
Author(s) -
Yerly Fabrice,
Borel Alain,
Helm Lothar,
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.200305175
Subject(s) - chemistry , dota , crystallography , square antiprism , chelation , molecular dynamics , gadolinium , aqueous solution , coordination sphere , ligand (biochemistry) , ion , stereochemistry , lanthanide , crystal structure , computational chemistry , inorganic chemistry , biochemistry , receptor , organic chemistry
Classical molecular dynamics simulations with a force field adapted to the family of Gd 3+ polyaminocarboxylate complexes have been successfully applied on two macrocyclic ([Gd(DOTA)(H 2 O)] − and [Gd(DO3A)(H 2 O) 2 ]) and two acyclic ([Gd(DTPA)(H 2 O)] 2− and [Gd(EGTA)(H 2 O)] − ) complexes in aqueous solution (DOTA=1,4,7,10‐tetrakis(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane, DO3A=1,4,6‐tris(carboxymethyl)‐1,4,7,10‐tetraazacyclododecane, DTPA=1,1,4,7,7‐pentakis(carboxymethyl)‐1,4,7‐triazaheptane, EGTA=1,1,10,10‐tetrakis(carboxymethyl)‐1,10‐diaza‐4,7‐dioxadecane). In both macrocylic complexes the Gd 3+ coordination polyhedron remains close to a monocapped square antiprism (MSA) during the entire simulation time. For the stereolabile acyclic complexes different interconverting sets of geometries are observed: three sets close to tricapped trigonal prisms (TTP) for [Gd(EGTA)(H 2 O)] − and three sets intermediate between MSA and TTP (distorted C 2 v symmetry) for [Gd(DTPA)(H 2 O)] 2− . The fast conformational changes observed in the acyclic complexes might weaken the hydration of the second water shell and therefore disfavour the outer‐sphere relaxivity. Moreover, the motions of the chelate observed in both acyclic complexes involve the reorientation of the symmetry elements over time. This reorientation, occurring on a picosecond timescale, can be associated with the correlation time for modulation of the zero field splitting and might participate in the electron spin relaxation mechanisms of the Gd 3+ ion. The internal motion of the inner‐sphere water molecule can be quantified by the ratio τ R (GDHW)/ τ R (GDOW) which increases slightly from 0.7 for the acyclic to 0.8 for the macrocyclic complexes. This increase for the macrocylic chelates is favourable for a higher relaxivity and can be related to their rigidity. The water exchange rate on the four complexes has been related to the steric constraint of the ligand on the inner‐sphere water molecule(s), which is inversely proportional to a geometrical descriptor, the solid angle ψ . A range of ψ values is given (2≪ ψ <3.3) where the exchange should be optimal. The observations made on the picosecond timescale give general directions for the design of more efficient magnetic resonance imaging contrast agents.