Lanthanide(III) Complexes That Contain a Self-Immolative Arm: Potential Enzyme Responsive Contrast Agents for Magnetic Resonance Imaging

Enzyme‐responsive MRI‐contrast 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 LnII...

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Published in:Chemistry : a European journal 2012-01, Vol.18 (5), p.1408-1418
Main Authors: Chauvin, Thomas, Torres, Susana, Rosseto, Renato, Kotek, Jan, Badet, Bernard, Durand, Philippe, Tóth, Éva
Format: Article
Language:English
Subjects:
Chemical Sciences
Chemistry
Contrast Media - chemistry
enzymatic detection
Gadolinium - chemistry
lanthanides
Lanthanoid Series Elements - chemistry
Magnetic Resonance Imaging - methods
Magnetic Resonance Spectroscopy
Models, Chemical
Molecular Structure
MRI contrast agents
Organic chemistry
Organometallic Compounds - chemical synthesis
Organometallic Compounds - chemistry
PARACEST
Water - chemistry
water exchange
Ytterbium - chemistry
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Summary:Enzyme‐responsive MRI‐contrast 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 β‐galactosidase; 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 Gd3+ complexes, including the water‐exchange rate (kex298, 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 YbIII complexes decreases with increasing pH value (for YbL3, 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. Trial by fire: Enzyme‐responsive contrast agents for MRI studies have been designed based on a “self‐immolative” mechanism. Enzymatic cleavage of the appropriate substrate moiety on the contrast agent initiates a cascade reaction that is expected to result in structural changes of the LnIII complex with a
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201101779