Synthesis and characterization of a Gd(iii) based contrast agent responsive to thiol containing compounds

Abstract

A novel Gd(III) complex with a modified DO3A-like chelating cage has been synthesized and characterized as a candidate contrast agent responsive to the concentration of free thiols in tissues (essentially represented by reduced glutathione, GSH). The novel compound (called Gd-DO3AS-Act) bears a flexible linker ending with a 2-pyridyl-dithio group, that can promptly react with free thiols (XSH) to form mixed disulfides of the form Gd-DO3AS-SX. Compound Gd-DO3AS-Act is characterized by a millimolar relaxivity as high as 8.1 mM(-1) s(-1) (at 20 MHz, 25 degrees C and pH 7.4). Upon reaction with GSH, the Gd-DO3AS-SG covalent adduct is formed and the millimolar relaxivity drops to 4.1 mM(-1) s(-1). Such a decrease in relaxivity is explained on the basis of the formation of an intramolecular coordinative bond between one of the glutathionyl carboxyl groups and the Gd(III) centre, lowering the hydration state of the paramagnetic centre. (1)H-NMR dispersion profiles together with (17)O-NMR transverse relaxation time versus temperature profiles confirm that the hydration of the Gd(III) centre is strongly reduced ongoing from Gd-DO3AS-Act to the Gd-DO3AS-SG adduct. The relaxivity difference brought about by the reaction of Gd-DO3AS-Act with GSH can be enhanced up to 60% in the presence of poly-beta-cyclodextrin.

Redox-Triggered Self-Assembly of Gadolinium-Based MRI Probes for Sensing Reducing Environment

“…28−34 These probes typically have a small value of r 1 relaxivity (2.77 mM –1 s –1 ) 31 or show a decrease in r 1 relaxivity after thiol-activation that leads to a darker contrast. 28,29,31 Here we report MR probes that give an increasing, high value (>10 mM –1 s –1 ) of r 1 relaxivity upon biothiol activation, resulting in a brighter contrast.…”

Redox‐ and Hypoxia‐Responsive MRI Contrast Agents

“…The 2-pyridyldithio function of the Gd 3+ complexes reacts with free thiol groups to form an -S–S- bond. [34, 38–40] …”

“…[34] Gd 3+ - 4 contains a thiol-reactive 2-pyridyldithio functionality and when the complex reacts with a thiol that has a carboxyl group such as glutathione, L-cysteine, or β-mercaptopropionic acid, the resulting product was found to have about half of the relaxivity of the starting Gd 3+ complex (Figure 5). This has been explained by the decrease of the Gd 3+ -bound water molecules from q =2 of the Gd 3+ -DO3A system to q =1 due to coordination of the carboxylate group present in the thiol.…”

“…Larger relaxivity differences could be achieved by forming an inclusion complex between Gd 3+ - 4 and β-cyclodextrin (β-CD) or poly-β-CD. [34] …”

Metal Complexes as MRI Contrast Enhancement Agents

“…In a reducing environment, GSH is released and the system becomes bishydrated, with a concomitant increase in relaxivity. 276 In a macromolecular approach, perthiolated b-cyclodextrin nanocapsules were synthesized that can incorporate Gd 3+ complexes via host-guest interaction. The particles were efficiently loaded with bishydrated GdAAZTA-benzyl complexes to yield a very high-relaxivity (per Gd and per particle) system.…”