Synthesis and characterization of a Gd(III) based contrast agent responsive to thiol containing compounds.
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.
Carrera
Carla
C
Department of Chemistry IFM, University of Torino, Via Pietro Giuria 7, I-10125, Torino, Italy.
Digilio
Giuseppe
G
Baroni
Simona
S
Burgio
Daniela
D
Consol
Simona
S
Fedeli
Franco
F
Longo
Dario
D
Mortillaro
Armando
A
Aime
Silvio
S
D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014867:Water / Q000737:chemistry
D003287:Contrast Media; D013438:Sulfhydryl Compounds; D014867:Water; D005682:Gadolinium