Separation and Characterization of the Two Diastereomers for [Gd(DTPA-bz-NH₂)(H₂O)]^2-, a Common Synthon in Macromolecular MRI Contrast Agents:  Their Water Exchange and Isomerization Kinetics

Abstract

Chiral, bifunctional poly(amino carboxylate) ligands are commonly used for the synthesis of macromolecular, Gd(III)-based MRI contrast agents, prepared in the objective of increasing relaxivity or delivering the paramagnetic Gd(III) to a specific site (targeting). Complex formation with such ligands results in two diastereomeric forms for the complex which can be separated by HPLC. We demonstrated that the diastereomer ratio for Ln(III) DTPA derivatives (approximately 60:40) remains constant throughout the lanthanide series, in contrast to Ln(III) EPTPA derivatives, where it varies as a function of the cation size with a maximum for the middle lanthanides (DTPA(5-) = diethylenetriaminepentaacetate; EPTPA(5-) = ethylenepropylenetriaminepentaacetate). The interconversion of the two diastereomers, studied by HPLC, is a proton-catalyzed process (k(obs) = k(1)[H(+)]). It is relatively fast for [Gd(EPTPA-bz-NH(2))(H(2)O)](2-) but slow enough for [Gd(DTPA-bz-NH(2))(H(2)O)](2-) to allow investigation of pure individual isomers (isomerization rate constants are k(1) = (3.03 +/- 0.07) x 10(4) and 11.6 +/- 0.5 s(-1) M(-1) for [Gd(EPTPA-bz-NH(2))(H(2)O)](2)(-) and [Gd(DTPA-bz-NH(2))(H(2)O)](2-), respectively). Individual water exchange rates have been determined for both diastereomers of [Gd(DTPA-bz-NH(2))(H(2)O)](2-) by a variable-temperature (17)O NMR study. Similarly to Ln(III) EPTPA derivatives, k(ex) values differ by a factor of 2 (k(ex)(298) = (5.7 +/- 0.2) x 10(6) and (3.1 +/- 0.1) x 10(6) s(-1)). This variance in the exchange rate has no consequence on the proton relaxivity of the two diastereomers, since it is solely limited by fast rotation. However, such difference in k(ex) will affect proton relaxivity when these diastereomers are linked to a slowly rotating macromolecule. Once the rotation is optimized, slow water exchange will limit relaxivity; thus, a factor of 2 in the exchange rate can lead to a remarkably different relaxivity for the diastereomer complexes. These results have implications for future development of Gd(III)-based, macromolecular MRI contrast agents, since the use of chiral bifunctional ligands in their synthesis inevitably generates diastereomeric complexes.

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

“…The EPTPA-bz-NCS ligand was prepared from (dl)-p-nitrophenylalanine in a multistep synthesis with an overall yield of 39 %. In the last step, EPTPA-bz-NH 2 [41,44,45] was reacted with CSCl 2 by using a standard two-phase methodology to give EPTPA-bz-NCS. The isothiocyanates are known to react very slowly with water, but are very reactive to amine groups.…”

“…EPTPA-bz-NH 2 was obtained as described in the literature. [41,45] The ethylenediamine core PAMAM dendrimers with primary amines on the surface G5-(NH 2 ) 128 , G7-(NH 2 ) 512 and G9-(NH 2 ) 2048 were purchased as aqueous solutions from Dendritech Inc. (Midland, MI). Ultrafiltration membranes YM10 and YM30 were obtained from Amicon, (Bedford, MA).…”

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

“…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. [9,10,14,15] Unfortunately, no detailed kinetic studies are available in the literature for these complexes.…”

Helicity Inversion in Lanthanide(III) Complexes with Chiral Nonaaza Macrocyclic Ligands

“…In favorable cases, these chiral compounds can be separated into enantiopure forms 2c. 5 Alternatively, the enantiopure supramolecular assemblies and metal complexes can be obtained by diastereoselective synthesis from nonracemic chiral organic building blocks, which may determine the chirality of the assembly or complex (for example, the handedness of a helical structure). Generally, this strategy is successful when one of the possible diastereoisomers is thermodynamically favored 6.…”