Synthesis and physicochemical characterization of a novel precursor for covalently bound macromolecular MRI contrast agents

Abstract

The ligand DOTASA was designed and synthesized in the aim of obtaining a kinetically and thermodynamically stable Gd(III) chelate which, through its uncoordinated carboxylate function, will provide an efficient pathway to couple the complex to bio- or macromolecules without affecting the coordination pattern of DOTA. Furthermore, it allows us to study the influence of an extra carboxylate arm on the parameters determining proton relaxivity in comparison to the commercial agent [Gd(DOTA)(H2O)]-. A combined variable-temperature 17O NMR, EPR and nuclear magnetic relaxation dispersion study on the Gd(III) chelate resulted in kex298 = (6.3 +/- 0.2) x 10(6) s-1 for the water exchange rate and tau R298 = 125 +/- 2 ps for the rotational correlation time. The slight increase in both kex298 and tau R298, as compared to those for [Gd(DOTA)(H2O)]-, is attributed to the presence of the extra negative charge. The longer rotational correlation time results in a proton relaxivity of 5.03 mM-1 s-1 for [Gd(DOTASA)(H2O)]2-, which is approximately 30% higher than that for [Gd(DOTA)(H2O)]-. The increased water exchange rate of [Gd(DOTASA)(H2O)]2- has no consequence for proton relaxivity since this latter is exclusively limited by fast rotation for both complexes. However, for slowly rotating macromolecular agents, which contain a covalently coupled DOTASA unit instead of a coupled DOTA, this increased exchange rate will have a significant positive effect.

Spectroscopic Study of the Hydration Equilibria and Water Exchange Dynamics of Lanthanide(III) Complexes of 1,7-Bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (DO2A)

“…[19] A similar effect was observed upon substitution of one carboxylate of DOTA 4-or DTPA 5-by noncharged amide groups. In both systems, the water exchange rate diminished by a factor of 3-4.…”

High Relaxivity for Monomeric Gd(DOTA)-Based MRI Contrast Agents, Thanks to Micellar Self-Organization

“…Synthesis of NaH[Gd(DOTASA)´H 2 O]: The ligand DOTASA was synthesized according to a procedure published elsewhere [11] (H 5 DOTASA 1,4,7,10-tetraazacyclododecane-1-succinic-4,7,10-triacetic acid). The NaH[Gd(DOTASA)´H 2 275 mg, 7.2 Â 10 À4 mol, 3 equiv] were incubated for 10 minutes (the pH was checked with pH paper and it showed to be 7 ± 8) prior to the addition of Nmethyldodecylamine (180 mL; 7.2 Â 10 À4 mol, 3 equiv; Scheme 2).…”

“…Since the micelles formed are expected to have slow rotation, the treatment we use also includes non-extreme narrowing conditions. The dipolar contribution is given by Equations (11). [37] The quadrupolar contributions is given by Equation (12).…”

“…Recently we published the synthesis of a new DOTA derivative that offers the possibility to easily couple the intact [Gd(DOTA)(H 2 O)] À unit to other molecules without any decrease in the stability and in the water exchange rate. [11] Here we report the synthesis and physicochemical characterization of a new potential MRI contrast agent whose design was based on the following concepts: i) maintenance the thermodynamic and kinetic stability as well as the relatively fast water exchange of the [Gd(DOTA)(H 2 O)]…”

Towards Binuclear Polyaminocarboxylate MRI Contrast Agents? Spectroscopic and MD Study of the Peculiar Aqueous Behavior of the LnIII Chelates of OHEC (Ln=Eu, Gd, and Tb): Implications for Relaxivity

“…[1] In order to enhance r 1 , it has been found that: 1) tumbling has to be slowed down by attaching the chelate to macromolecular assemblies, such as proteins, [2,3] dendrimers, [4,5] micellar aggregates [6,7] or polymers; [8] 2) the water-exchange rate has to be increased by promotion of the departure of a coordinated water molecule; this is achieved by the design of optimized chelates such as Gd III complexes of TRITA (1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid), [9] EPTPA (ethylenepropylenetriaminepentaacetic Abstract: We report the study of binuclear Ln III chelates of OHEC (OHEC = octaazacyclohexacosane-1, 4,7,10,14,17,20,23-octaacetate). The interconversion between two isomeric forms, which occurs in aqueous solution, has been studied by NMR, UV/ Vis, EPR, and luminescence spectroscopy, as well as by classical molecular dynamics (MD) simulations.…”