A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo
Bis-phenylamides and bis-hydroxyindolamides of diethylenetriaminepentaacetic acid-gadolinium (DTPA(Gd)) are paramagnetic reducing substrates of peroxidases that enable molecular imaging of peroxidase activity in vivo. Specifically, gadolinium chelates of bis-5-hydroxytryptamide-DTPA (bis-5HT-DTPA(Gd...
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Hindawi - SAGE Publishing
2012-09-01
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Series: | Molecular Imaging |
Online Access: | https://doi.org/10.2310/7290.2012.00006 |
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doaj-7f44fb86597542268d9623bd2a178fd82021-04-02T17:32:43ZengHindawi - SAGE PublishingMolecular Imaging1536-01212012-09-011110.2310/7290.2012.0000610.2310_7290.2012.00006A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in VivoMohammed S. ShazeebYang XieSuresh GuptaAlexei A. BogdanovBis-phenylamides and bis-hydroxyindolamides of diethylenetriaminepentaacetic acid-gadolinium (DTPA(Gd)) are paramagnetic reducing substrates of peroxidases that enable molecular imaging of peroxidase activity in vivo. Specifically, gadolinium chelates of bis-5-hydroxytryptamide-DTPA (bis-5HT-DTPA(Gd)) have been used to image localized inflammation in animal models by detecting neutrophil-derived myeloperoxidase (MPO) activity at the inflammation site. However, in other preclinical disease models, bis-5HT-DTPA(Gd) presents technical challenges due to its limited solubility in vivo. Here we report a novel MPO-sensing probe obtained by replacing the reducing substrate serotonin (5-HT) with 5-hydroxytryptophan (HTrp). Characterization of the resulting probe (bis-HTrp-DTPA(Gd)) in vitro using nuclear magnetic resonance spectroscopy and enzyme kinetic analysis showed that bis-HTrp-DTPA(Gd) (1) improves solubility in water; (2) acts as a substrate for both horseradish peroxidase and MPO enzymes; (3) induces cross-linking of proteins in the presence of MPO; (4) produces oxidation products, which bind to plasma proteins; and (5) unlike bis-5HT-DTPA(Gd), does not follow first-order reaction kinetics. In vivo magnetic resonance imaging (MR!) in mice demonstrated that bis-HTrp-DTPA(Gd) was retained for up to 5 days in MPO-containing sites and cleared faster than bis-5HT-DTPA(Gd) from MPO-negative sites. Bis-HTrp-DTPA(Gd) should offer improvements for MR! of MPO-mediated inflammation in vivo, especially in high-field MR!, which requires a higher dose of contrast agent.https://doi.org/10.2310/7290.2012.00006 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mohammed S. Shazeeb Yang Xie Suresh Gupta Alexei A. Bogdanov |
spellingShingle |
Mohammed S. Shazeeb Yang Xie Suresh Gupta Alexei A. Bogdanov A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo Molecular Imaging |
author_facet |
Mohammed S. Shazeeb Yang Xie Suresh Gupta Alexei A. Bogdanov |
author_sort |
Mohammed S. Shazeeb |
title |
A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo |
title_short |
A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo |
title_full |
A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo |
title_fullStr |
A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo |
title_full_unstemmed |
A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo |
title_sort |
novel paramagnetic substrate for detecting myeloperoxidase activity in vivo |
publisher |
Hindawi - SAGE Publishing |
series |
Molecular Imaging |
issn |
1536-0121 |
publishDate |
2012-09-01 |
description |
Bis-phenylamides and bis-hydroxyindolamides of diethylenetriaminepentaacetic acid-gadolinium (DTPA(Gd)) are paramagnetic reducing substrates of peroxidases that enable molecular imaging of peroxidase activity in vivo. Specifically, gadolinium chelates of bis-5-hydroxytryptamide-DTPA (bis-5HT-DTPA(Gd)) have been used to image localized inflammation in animal models by detecting neutrophil-derived myeloperoxidase (MPO) activity at the inflammation site. However, in other preclinical disease models, bis-5HT-DTPA(Gd) presents technical challenges due to its limited solubility in vivo. Here we report a novel MPO-sensing probe obtained by replacing the reducing substrate serotonin (5-HT) with 5-hydroxytryptophan (HTrp). Characterization of the resulting probe (bis-HTrp-DTPA(Gd)) in vitro using nuclear magnetic resonance spectroscopy and enzyme kinetic analysis showed that bis-HTrp-DTPA(Gd) (1) improves solubility in water; (2) acts as a substrate for both horseradish peroxidase and MPO enzymes; (3) induces cross-linking of proteins in the presence of MPO; (4) produces oxidation products, which bind to plasma proteins; and (5) unlike bis-5HT-DTPA(Gd), does not follow first-order reaction kinetics. In vivo magnetic resonance imaging (MR!) in mice demonstrated that bis-HTrp-DTPA(Gd) was retained for up to 5 days in MPO-containing sites and cleared faster than bis-5HT-DTPA(Gd) from MPO-negative sites. Bis-HTrp-DTPA(Gd) should offer improvements for MR! of MPO-mediated inflammation in vivo, especially in high-field MR!, which requires a higher dose of contrast agent. |
url |
https://doi.org/10.2310/7290.2012.00006 |
work_keys_str_mv |
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