Polymethylated DOTA Ligands. 2. Synthesis of Rigidified Lanthanide Chelates and Studies on the Effect of Alkyl Substitution on Conformational Mobility and Relaxivity

Abstract

M4DOTA, [(2S,5S,8S,11S)-4,7,10-tris-carboxymethyl-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid (2e), and M4DOTMA, (R)-2-[(2S,5S,8S,11S)-4,7,10-tris-((R)-1-carboxyethyl)-2,5,8,11-tetramethyl-1,4,7,10-tetraazacyclododecan-1-yl]propionic acid (3e), are derivatives of ligand DOTA (1e) that form sterically crowded lanthanide chelates. M4DOTMA forms highly symmetric and totally rigid single Y(3+) and Yb(3+) species in which the ring substituents occupy corner positions in a square antiprismatic arrangement as shown by molecular mechanics calculations and by a quantitative interpretation of the relative magnitudes of the paramagnetic (1)H NMR shifts of dipolar origin. The NMR spectrum of YbM4DOTMA(-) displays two intense methyl peaks outside the 0-10 ppm range whose shift difference is strongly temperature dependent. YbM4DOTMA(-) (3d) could be a useful probe in magnetic resonance thermometric imaging. With only four methyl substituents on the tetraaza ring, M4DOTA forms three Yb(3+) species in solution. The methyl substituents prevent the inversion of configuration of the ethylenic groups but not of the acetate arms. Although the methyl groups are likely to preferably occupy ring corner positions, the dipolar equations do not allow one to distinguish with certainty between the two available corner (equatorial) orientations. Reliably applying the dipolar equations is less obvious than usually assumed. A single methyl substituent as in ligand MDOTA (5e) suffices to rigidify the tetraaza cycle but not the acetate arms. Racemic YbMDOTA(-) (5d) is present in solution as four totally asymmetric topomers with the methyl groups occupying either one of the two equatorial positions. A complete assignment of the solution structures on the basis of the dipolar equations is again uncertain. The nuclear magnetic relaxation dispersion curves of the Gd(3+) chelates of all the methylated DOTA ligands including DOTMA, (R)-2-[4,7,10-tris-((R)-carboxyethyl)- 1,4,7,10- tetraazacyclododecan-1-yl]propionic acid, are very similar, and intermolecular conformational processes appear to have no influence on the relaxivity of these small complexes for which the relaxation T(1) is mainly determined by the rotational correlation time (tau(r)). The hydration number of the Tb(3+) chelates measured by fluorescence decreases from DOTMA to M4DOTMA presumably because steric crowding leads to an increase of the metal-water distance.

Long‐Range‐Distance NMR Effects in a Protein Labeled with a Lanthanide–DOTA Chelate

“…Two sets of peaks are generally observed in NMR spectra due to slow conversion of the DOTA isomers. [67,68] In the HSQC spectra of the diamagnetic Y CLaNP-3-Paz, single peaks are observed for all residues, indicating that the protein amide groups are too far from the probe to sense possible exchange processes. In the case of the paramagnetic PazYb CLaNP-3, nearly all peaks exhibit changes in chemical shift that are of about the same size in the proton and nitrogen dimensions.…”

High‐Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

“…Gadolinium(III), with its high magnetic moment and long electron spin relaxation time, is an ideal candidate for such a proton relaxation agent and is the most widely used metal. [2,3] Free Gd III , is toxic (LD 50 of 0.2 mmol/kg in mice) [4] and must therefore be administered in the form of stable chelates that will prevent the release of the metal ion in vivo. For these reasons, the development of ligands for Gd III , suitable for production of high-relaxivity agents with favorable properties for imaging applications, remains an important goal.…”

New Insights for Pursuing High Relaxivity MRI Agents from Modelling the Binding Interaction of GdIII Chelates to HSA

“…[7,8] Therefore a primary requisite for pursuing high relaxivity for a Gd-L/HSA adduct is the occurrence of a relatively fast exchange of the inner-sphere water molecule, that is, t M has to be in the range of tens of nanoseconds at room temperature. [2,4,9] Within macrocyclic systems, Gd-DOTMA ((1R,4R,7R,10R)-a,a',a'',a'''-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,1,10-tetraacetic acid [10] satisfies this condition (t M = 68 ns). [2] On this basis, we synthesised two Gd-DOTMA-like complexes with the expectation that they would show high binding affinity to HSA, faster exchange of the coordinated water and overall rigidity of the coordination cage, a property that has been associated with a long electronic relaxation time [11] and is a further requisite for the attainment of very high relaxivity.…”

“…These values are higher than that of the parent Gd-DOTMA complex (r 1p = 3.8 mm À1 s À1 ). [10,12] Probably the hydrophobic moieties promote some kind of reversible association that causes an increase in the molecular correlation time, which in turn is responsible for yielding a r 1 value significantly larger than one would expect on the basis of M W increase alone. The t M value of Gd-L1 had been accurately determined by VT 17 O NMR T 2 measurements [13] as 65 ns at 298 K, that is, not too different from the parent Gd-DOTMA and still in the range of the optimal values for our purpose.…”