1361124-79-9Relevant articles and documents
Lanthanide (III) complexes that contain a self-immolative arm: Potential enzyme responsive contrast agents for magnetic resonance imaging
Chauvin, Thomas,Torres, Susana,Rosseto, Renato,Kotek, Jan,Badet, Bernard,Durand, Philippe,Toth, Eva
, p. 1408 - 1418 (2012/03/27)
Enzyme-responsive MRIcontrast agents containing a "self- immolative" benzylcarbamate moiety that links the MRI-reporter lanthanide complex to a specific enzyme substrate have been developed. The enzymatic cleavage initiates an electronic cascade reaction that leads to a structural change in the LnIII complex, with a concomitant response in its MRI-contrast- enhancing properties. We synthesized and investigated a series of Gd3+ and Yb3+ complexes, including those bearing a self-immolative arm and a sugar unit as selective substrates for bgalactosidase; we synthesized complex LnL1, its NH2 amine derivatives formed after enzymatic cleavage, LnL2, and two model compounds, LnL3 and LnL4. All of the Gd3+ complexes synthesized have a single inner-sphere water molecule. The relaxivity change upon enzymatic cleavage is limited (3.68 vs. 3.15 mm-1 s-1 for complexes GdL1 and GdL2, respectively; 37 °C, 60 MHz), which prevents application of this system as an enzyme-responsive T1 relaxation agent. Variable-temperature 17O NMR spectroscopy and 1H NMRD (nuclear magnetic relaxation dispersion) analysis were used to assess the parameters that determine proton relaxivity for the Gd 3+ complexes, including the water-exchange rate (kex 298, varies in the range 1.5-3.9×106 s -1). Following the enzymatic reaction, the chelates contain an exocyclic amine that is not protonated at physiological pH, as deduced from pH-potentiometric measurements (log KH=5.12(±0.01) and 5.99(±0.01) for GdL2 and GdL3, respectively). The Yb3+ analogues show a PARACEST effect after enzymatic cleavage that can be exploited for the specific detection of enzymatic activity. The proton-exchange rates were determined at various pH values for the amine derivatives by using the dependency of the CEST effect on concentration, saturation time, and saturation power. A concentration-independent analysis of the saturation-power-dependency data was also applied. All these different methods showed that the exchange rate of the amine protons of the Yb III complexes decreases with increasing pH value (for YbL 3, kex= 1300 s-1 at pH 8.4 vs. 6000 s -1 at pH 6.4), thereby resulting in a diminution of the observed CEST effect.
