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

Abstract

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 8O 2 -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 8O 2 -bridged-DOTAM.

Nano assembly and encapsulation; a versatile platform for slowing the rotation of polyanionic Gd3+‐based MRI contrast agents

“…All four chelates have an outer-sphere contribution to relaxivity ( r 1 os ) which contributes about 1.8 mM −1 s −1 to the overall discrete chelate’s relaxivity. (1,2,15) But, for GdTTHA 3− this contribution makes up almost the entire relaxivity of the chelate. (16) In every case this is expected to disappear once the chelate is encapsulated and no longer diffusing close to solvent water.…”

“…(17–19) Phosphonates are effective groups for generating second sphere relaxivity, carboxylates less so. (17,19) Although almost(15) every chelate has some second sphere relaxivity ( r 1 ss ), it is typically only about 0.8 mM −1 s −1 (20 MHz, 25 °C)(15,17) for the carboxylate-based chelates, but rises to about 2.9 mM −1 s −1 (20 MHz, 25 °C) for GdDOTP 5− . (1,2) GdDOTA − and GdDTPA 2− are “inner-sphere chelates” – relaxivity arises through exchange of water between the inner coordination sphere of Gd 3+ and the bulk solvent.…”

Structure, Dynamics, and Computational Studies of Lanthanide‐Based Contrast Agents

“…In order to try to further slow down the coordinated water exchange process through steric hindrance of its dissociation, a new DOTAM derivative ligand was prepared (8O 2 -bridged DOTAM, 38) containing a bridged substituent forming a cycle by joining two trans-amide moieties [431]. However, it was found that the Ln 3+ complexes of this ligand lack an inner-sphere water molecule.…”

“…A bridged DOTAM chelate(38) [431] was also studied.The crystal structures of several tetramide complexes studied show variability in their Ln 3+ coordination. The [La(21)(H 2 O)(Tf)] 2+ species with the meta-pyridyl substituents has a 10-coordinate structure [425], like for the DOTAM complexes [394], the [Eu(21)(H 2 O)] 3+ (meta-pyridyl) [425], [Eu(26)(H 2 O)] 3+ (glycine ethyl ester) [421] and the [Tb(32)(H 2 O)] 3+ ketone [428] have nine-coordinate SA geometries, and the [Eu(16)(CH 3 OH)] 3+ (p-NO 2 -Ph) [422] and [Eu(15)(H 2 O)] 3+ (phenyl)…”

Unexpected Changes in the Population of Coordination Isomers for the Lanthanide Ion Complexes of DOTMA–Tetraglycinate

“…Published data for LnDOTA (brown) and LnDOTA–(gly) 4 (green) (right graph) are also shown for comparative purposes. 2,11,18 …”