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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publications
2012-09-01
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| Series: | Molecular Imaging |
| Online Access: | https://doi.org/10.2310/7290.2012.00006 |
| _version_ | 1797288974864089088 |
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| author | Mohammed S. Shazeeb Yang Xie Suresh Gupta Alexei A. Bogdanov |
| author_facet | Mohammed S. Shazeeb Yang Xie Suresh Gupta Alexei A. Bogdanov |
| author_sort | Mohammed S. Shazeeb |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-07T18:57:27Z |
| format | Article |
| id | doaj.art-7f44fb86597542268d9623bd2a178fd8 |
| institution | Directory Open Access Journal |
| issn | 1536-0121 |
| language | English |
| last_indexed | 2024-03-07T18:57:27Z |
| publishDate | 2012-09-01 |
| publisher | SAGE Publications |
| record_format | Article |
| series | Molecular Imaging |
| spelling | doaj.art-7f44fb86597542268d9623bd2a178fd82024-03-02T00:07:45ZengSAGE PublicationsMolecular 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 |
| spellingShingle | Mohammed S. Shazeeb Yang Xie Suresh Gupta Alexei A. Bogdanov A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo Molecular Imaging |
| title | 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_short | A Novel Paramagnetic Substrate for Detecting Myeloperoxidase Activity in Vivo |
| title_sort | novel paramagnetic substrate for detecting myeloperoxidase activity in vivo |
| url | https://doi.org/10.2310/7290.2012.00006 |
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