Gd^III Complexes with Fast Water Exchange and High Thermodynamic Stability: Potential Building Blocks for High‐Relaxivity MRI Contrast Agents

Abstract

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(ex)298=150x10(6), 330x10(6), and 3.3x10(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-) (DeltaV(not equal sign)=(+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)](-) (DeltaV (not equal sign)=(-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(ex)298=31x10(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.

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

“…For example, Merbach and coworkers have reported numerous studies that probe the factors influencing the water exchange rate of aminocarboxylate Gd III complexes. [30][31][32][33][34] The main explanation for increased water exchange rates is steric crowding at the water binding sites, a property that favors the release of the coordinated water molecule in a dissociative exchange process. Derivatives of DTPA, shown in Figure 3, have been synthesized with varying numbers of carbon atoms in the ligand scaffold.…”

“…The DTPA ligand and two of its representative derivatives prepared for water exchange rate studies. [31,32] Increased water exchange rates for macrocyclic complexes based on [Gd-DOTA(H 2 O)]…”

Study of Thermodynamic and Kinetic Stability of Transition Metal and Lanthanide Complexes of DTPA Analogues with a Phosphorus Acid Pendant Arm

“…The steric strain was usually reached by introduction of one extra methylene group into the backbone (propylene group instead of ethylene bridge) or in one of the pendant arms (i.e. with propionate pendant instead of acetate), [8][9][10][11] or by substitution of ligand backbone by alkyl/aryl group. [12,13] The complexes formed with these new ligands are thermodynamically usually slightly less stable than those of H 4 dota and H 5 dtpa.…”

“…[12,13] The complexes formed with these new ligands are thermodynamically usually slightly less stable than those of H 4 dota and H 5 dtpa. [9,10,14,15] Unfortunately, no detailed kinetic studies are available in the literature for these complexes. To contribute to this field, we prepared several analogues of H 4 dota and H 5 dtpa having a bulkier phosphorus acid pendant moiety instead of the carboxylate group.…”

Dendrimer-based magnetic resonance imaging agents for brain cancer

“…Nevertheless, conjugation of the Gd 3+ -chelate to a large dendrimer does not significantly affect the water exchange rate at the metal center, and the constants for the water exchange rate remain almost similar for all the dendrimer agents studied [57]. Also, protonated dendrimers often generate a more rigid and open structure, and hence a further increase in relaxivity [58,59]. Moreover, Ali and colleagues [60] reported a pHsensitive agent based on a PAMAM dendrimer of generation 5 which bears a DOTA-derived chelating ligand, DOTA-4AmP, at the dendrimer surface.…”