The Population of SAP and TSAP Isomers in Cyclen-Based Lanthanide(III) Chelates Is Substantially Affected by Solvent

Abstract

The square antiprism/twisted square antiprism ratio in LnDOTA-tetraamide chelates is a critical parameter in governing water-exchange kinetics and ultimately the utility of a chelate as a PARACEST MRI contrast agent. In LnDOTA-tetraamide chelates with tertiary amides, this ratio and the rate of interconversion between these two structural isomers are found to be dramatically dependent upon the solvent and possibly other local environmental factors.The realization that Ln 3+ chelates with slowly exchanging inner-sphere water molecules could induce magnetic resonance imaging (MRI) contrast through a paramagnetic chemical exchange saturation transfer (PARACEST) mechanism has given rise to a recent upsurge in interest in LnDOTA-tetraamide chelates. 1,2 The large paramagnetic hyperfine chemical shifts induced by anisotropic 4f electrons effectively shift the resonance of the inner-sphere water far from that of solvent water. However, because unchelated Ln 3+ ions are toxic, suitable chelating ligands must be employed that both eliminate the toxic effects 3 of these ions and appropriately slow water exchange. 1,2,4,5 Ligands derived from cyclen have been widely accepted in the development of MRI contrast agents, 3 and the related DOTAtetraamide ligands (Chart 1) are now widely studied as PARACEST agents. Although DOTA-tetraamide chelates are kinetically inert, retaining the Ln 3+ ion throughout the in vivo residence of the chelate, 6,7 the use of DOTA-tetraamide ligands in vivo can be problematic. It has been shown that only when the cationic nature of these chelates is offset by anionic substituents, such as carboxylates, can the severe toxic effects intrinsic to cationic chelates be avoided at the relatively high dosing levels required for MRI. 6 A chelate incorporating four glycinateamide substituents has been shown to be safe for in vivo use. 6,7 The unique water-exchange characteristics of these chelates make them attractive as MRI sensors of various biological species such as glucose, Zn 2+ , or protons (pH), [8][9][10][11] species. In such situations, it may be desirable to incorporate the offsetting negative charges as tertiary amide substituents, leaving the sensing secondary amide substituents in place.However, DOTA-tetraamides with tertiary amide pendant arms have not been widely studied as PARACEST agents. Of particular relevance is the coordination chemistry of these chelates. LnDOTA-tetraamide chelates can adopt both a monocapped square antiprismatic (SAP) and a monocapped twisted square antiprismatic (TSAP) coordination geometry, 4,5 and it has been shown that water exchange in complexes that form a TSAP isomer is 1-2 orders of magnitude faster than that in complexes that form a SAP isomer. 4,5,12 Given the requirement for slow exchange kinetics in putative PARACEST agents, it is clearly preferable for the SAP coordination geometry to predominate. Indeed, to our knowledge, the rate of exchange observed in the TSAP isomers of these complexes is so fast that CEST arising from this species has not...

Electrochemical Investigation of the Eu3+/2+ Redox Couple in Complexes with Variable Numbers of Glycinamide and Acetate Pendant Arms

“…Typically, Eu 3+ -complexes of DOTA-tetraamide ligand systems adopt two coordination geometries in solution, which are distinguishable by high-resolution 1 H-NMR spectroscopy. [2, 19] Accordingly, we acquired 1 H-NMR spectra of the Eu 3+ complexes Eu( 1 ) and Eu( 2 ) (D 2 O, 9.4 T, and 25 °C, Figures S1 and S2). Ligand 2 has C 2 symmetry; therefore, Eu( 2 ) is expected to have a relatively simplified 1 H-NMR spectrum compared to Eu( 1 ) because ligand ( 1 ) has only C 1 symmetry.…”

The effect of regioisomerism on the coordination chemistry and CEST properties of lanthanide(III) NB-DOTA-tetraamide chelates

“…This was not a consideration during the preparation of the Ln 1 − chelates since the chelate itself was the anion and the acidic eluent afforded the chelate as the conjugate acid. In previous studies on tricationic DOTA-tetraamides we tried to restrict the counterion to the convenient triflate anion for reasons of consistency [32–34]. However, triflic acid is not a good additive to an HPLC eluent because excess acid is not readily removed under a vacuum.…”

“…In common with other DOTA-tetraamides bearing bulky aromatic amide substituents, these chelates exhibit a marked preference for the square antiprismatic (SAP) coordination geometry [14, 32, 39]. DOTA-type ligands will sandwich an Ln 3+ ion between the four coplanar nitrogen atoms of the macrocyclic ring and four coplanar oxygen atoms from the pendant arms (carboxylates, amides, phosphonates, phosphinates, etc.).…”

Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation

“…The ratio between the τ M Actually, effects of the characteristics of the local microenvironment on the isomer distribution in DOTA-amide complexes have been already reported. 42 It is interesting to note that, unlike other macrocyclic complexes, the SAP/TSAP ratio for Gd-DOTAMA(C 18 ) 2 in micelles is lower than 1.…”