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  Dual 1H/19F MR imaging approach for detection of enzyme activity

Keliris, A., Mamedov, I., Hagberg, G., Logothetis, N., Scheffler, K., & Engelmann, J. (2012). Dual 1H/19F MR imaging approach for detection of enzyme activity. Poster presented at Fifth Annual World Molecular Imaging Congress (WMIC 2012), Dublin, Ireland.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0001-9931-B Version Permalink: http://hdl.handle.net/21.11116/0000-0001-995D-B
Genre: Poster

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 Creators:
Keliris, A1, 2, Author              
Mamedov, I2, 3, Author              
Hagberg, G1, 2, Author              
Logothetis, NK2, 3, Author              
Scheffler, K1, 2, Author              
Engelmann, J1, 2, Author              
Affiliations:
1Department High-Field Magnetic Resonance, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497796              
2Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497794              
3Department Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics, Max Planck Society, ou_1497798              

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 Abstract: Numerous processes taking place in living organism demand the action of enzymes. These catalysts serve as indicators of diseases and are used as markers of gene expression. Hence, a development of imaging probes allowing noninvasive in vivo mapping of enzyme activity by means of Magnetic Resonance Imaging (MRI) would provide a powerful means for assaying the efficacy of gene therapies and diseases diagnostics. Several mono-modal enzyme-responsive MRI probes have been reported over the years. Nevertheless, dual-modality imaging has recently attracted much attention as the way to facilitate visualization of enzyme activity in vivo by combining the benefits of different imaging techniques. In this line, we now demonstrate a smart dual-modal 1H/19F MRI probe, Gd-DOMF-Gal, sensing the activity of beta-galactosidase (marker enzyme used for revealing gene expression) as a prototype of a novel class of probes for specific detection of enzymes. In its molecular design we explored the use of a self-immolative linker that was inserted between the imaging reporters (Gd3+-chelate and a fluorine-bearing unit) and an enzyme recognizable moiety. The enzymatic activation of the probe resulted in a decomposition of the self-immolative spacer with release of imaging moieties leading to alternations in 1H/19F MRI signal intensities. Accordingly, as shown in the representative images (Fig.1, left) of phantoms filled with solutions of Gd-DOMF-Gal and samples treated with beta-galactosidase in phosphate buffer (PBS), no 19F MRI signal was detected for intact probe (intramolecular relaxation enhancement of fluorine relaxation times by paramagnetic gadolinium), whereas a 19F MRI signal of increasing intensity was observed after enzymatic conversion [1]. The corresponding proton T1 map (Fig.1, right) acquired during the same imaging session on a 7T scanner (∼25°C) prior to 19F measurements displayed a significantly longer T1 in the samples pre-incubated with beta-galactosidase. The longitudinal relaxivity (r1) of Gd-DOMF-Gal in PBS was found to be 6.7±0.6 mM-1s-1 and 5.1±0.5 mM-1s-1 for the cleaved complex (300 MHz,∼25°C), whereas at 123 MHz the r1 values were found to be 9.6±0.1 mM-1s-11 and 7.0±0.1 mM-11s-1, respectively. To explore the effect of buffer composition on relaxivity we also determined the r1 values at 123 MHz (∼25°C) in HEPES buffer (does not coordinate to gadolinium center) where the relative change in relaxivity Δr1 of 46% between Gd-DOMF-Gal and cleaved complex was higher than Δr1 obtained in PBS buffer (27%) [1]. In order to increase probe sensitivity, we have now introduced structural modifications and synthesized derivatives of Gd-DOMF-Gal with an increased number of fluorine per molecule. Here, we will present the rationale for our molecular design and MR evaluation of the enzymatic conversion of 1H/19F probes under in vitro conditions and in a cellular model. With this approach that explores the use of self-immolative spacers we will also extend in the future the application of the proposed model for the detection of other enzymes.

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 Dates: 2012-11
 Publication Status: Published in print
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 Identifiers: DOI: 10.1007/s11307-012-0598-3
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Title: Fifth Annual World Molecular Imaging Congress (WMIC 2012)
Place of Event: Dublin, Ireland
Start-/End Date: 2012-09-05 - 2012-09-08

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Title: Molecular Imaging and Biology
Source Genre: Journal
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Pages: - Volume / Issue: 14 (Supplement 2) Sequence Number: P199 Start / End Page: S1235 Identifier: -