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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Gd-DOTA-G-NH(CH2)11CO-RSPAYYTAA-(CH2CH2O)8-R - Molecular Imaging and Contrast Agent Database (MICAD) - NCBI Bookshelf</title>
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<meta name="citation_author" content="Huiming Zhang">
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<meta name="og:description" content="Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases localized at the cell surface or in extracellular compartments (1). MMPs degrade all components of the extracellular matrix (ECM) and are associated with a variety of pathological conditions such as wound healing, tissue remodeling, tumor angiogenesis, and embryo development. The active site of MMPs contains a catalytic domain coordinated by zinc to recognize motifs with a consensus sequence of PXX↓XHy, where ↓ represents the cleavage point and XHy represents a large hydrophobic residue (2). Excess MMP activity has been observed in conjunction with many diseases, including rheumatoid arthritis, osteoarthritis, autoimmune diseases, cardiovascular diseases, and cancer (3). For example, an overexpression of MMP subtype-2 (MMP-2 or gelatinase A), an enzyme that degrades type IV collagen and gelatin, is present in many human tumors (4). Thus, MMP has been an important therapeutic target for many years (5).">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK22996_"><span class="title" itemprop="name">Gd-DOTA-G-NH(CH<sub>2</sub>)<sub>11</sub>CO-RSPAYYTAA-(CH<sub>2</sub>CH<sub>2</sub>O)<sub>8</sub>-R </span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">GdPCA2</div><p class="contribs">Zhang H.</p><p class="fm-aai"><a href="#_NBK22996_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figGdPCA2T1"><a href="/books/NBK22996/table/GdPCA2.T1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobGdPCA2T1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="GdPCA2.T1"><a href="/books/NBK22996/table/GdPCA2.T1/?report=objectonly" target="object" rid-ob="figobGdPCA2T1">Table</a></h4><p class="float-caption no_bottom_margin">
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<i>In vitro</i>
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Rodents
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</p></div></div><div id="GdPCA2.Background"><h2 id="_GdPCA2_Background_">Background</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=PCA2-switch" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases localized at the cell surface or in extracellular compartments (<a class="bibr" href="#GdPCA2.REF.1" rid="GdPCA2.REF.1">1</a>). MMPs degrade all components of the extracellular matrix (ECM) and are associated with a variety of pathological conditions such as wound healing, tissue remodeling, tumor angiogenesis, and embryo development. The active site of MMPs contains a catalytic domain coordinated by zinc to recognize motifs with a consensus sequence of PXX↓X<sub>Hy</sub>, where ↓ represents the cleavage point and X<sub>Hy</sub> represents a large hydrophobic residue (<a class="bibr" href="#GdPCA2.REF.2" rid="GdPCA2.REF.2">2</a>). Excess MMP activity has been observed in conjunction with many diseases, including rheumatoid arthritis, osteoarthritis, autoimmune diseases, cardiovascular diseases, and cancer (<a class="bibr" href="#GdPCA2.REF.3" rid="GdPCA2.REF.3">3</a>). For example, an overexpression of MMP subtype-2 (MMP-2 or gelatinase A), an enzyme that degrades type IV collagen and gelatin, is present in many human tumors (<a class="bibr" href="#GdPCA2.REF.4" rid="GdPCA2.REF.4">4</a>). Thus, MMP has been an important therapeutic target for many years (<a class="bibr" href="#GdPCA2.REF.5" rid="GdPCA2.REF.5">5</a>).</p><p>Gadolinium (Gd)-labeled DOTA-G-NH(CH<sub>2</sub>)<sub>11</sub>CO-RSPAYYTAA-(CH<sub>2</sub>CH<sub>2</sub>O)<sub>8</sub>-R (GdPCA2) is a proteinase-modulated contrast agent (PCA) for <i>in vivo</i> imaging of MMP-2 with magnetic resonance imaging (MRI) (<a class="bibr" href="#GdPCA2.REF.6" rid="GdPCA2.REF.6">6</a>). GdPCA2 consists of four components: a peptide substrate (RSPAY↓YTAA) specific for MMP-2, a Gd-DOTA complex as an MRI probe, an alkyl chain of 12-carbon as a hydrophilic linker between the N-terminus of the peptide and the MRI probe, and an eight-unit polyethylene glycol (PEG<sub>8</sub>) chain linked to the C-terminus of the peptide to enhance the solubility of GdPCA2. The cleavage of GdPCA2 by MMP-2 produces a less soluble Gd<sup>3+</sup>-labeled fragment. Thus, the Gd species acts as a solubility switch specific for the enzyme MMP-2. GdPCA2 may have different pharmacokinetics than its cleaved product, which can be used to evaluate MMP-2 activity <i>via</i> dynamic MRI measurement.</p></div><div id="GdPCA2.Synthesis"><h2 id="_GdPCA2_Synthesis_">Synthesis</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=(%20PCA2-switch)+AND+synthesis%0D%0A" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Lebel et al. briefly described the preparation of GdPCA2 (<a class="bibr" href="#GdPCA2.REF.6" rid="GdPCA2.REF.6">6</a>). With standard protocols of solid-phase peptide synthesis, the N-terminus of the PCA2 peptide (RSPAYYTAA) was linked to the Gd-DOTA <i>via</i> a 12-carbon alkyl chain, and the C-terminus of the peptide was linked to an amino PEG<sub>8</sub>-Arg to yield GdPCA2.</p></div><div id="GdPCA2.In_Vitro_Studies_Tes"><h2 id="_GdPCA2_In_Vitro_Studies_Tes_"><i>In Vitro</i> Studies: Testing in Cells and Tissues</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=(%20PCA2-switch)+AND+%22in+vitro%22" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>The cleavage efficacy (<i>k</i><sub><i>cat</i></sub><i>/K</i><sub><i>m</i></sub>) of GdPCA2 was measured <i>in vitro</i> (<a class="bibr" href="#GdPCA2.REF.6" rid="GdPCA2.REF.6">6</a>). Cleavage of GdPCA2 by MMP-2 produced a free amino group that was detectable with the addition of fluorescamine. The <i>k</i><sub><i>cat</i></sub><i>/K</i><sub><i>m</i></sub> was 1.2 × 10<sup>5</sup> M<sup>-1</sup>s<sup>-1</sup> for GdPCA2, which was slightly lower than the <i>k</i><sub><i>cat</i></sub><i>/K</i><sub><i>m</i></sub> of 3.1 × 10<sup>5</sup> M<sup>-1</sup>s<sup>-1</sup> for the PCA2 peptide but 37.5 times higher than the <i>k</i><sub><i>cat</i></sub><i>/K</i><sub><i>m</i></sub> of 3.1 × 10<sup>5</sup> M<sup>-1</sup>s<sup>-1</sup> for a scrambled GdPCA2 (GdPCA2-scrambled) that contained a scrambled peptide (SYPATAYA). The cleaved products were further examined with high-performance liquid chromatography and mass spectrometry; two fragments were found for GdPCA2 (specific cleavage) and four fragments for GdPCA2-scrambled (non-specific cleavage).</p><p>The T<sub>1</sub> relaxivity of GdPCA2 and its cleaved product (cleaved-GdPCA2) was measured at 7 T (<a class="bibr" href="#GdPCA2.REF.6" rid="GdPCA2.REF.6">6</a>). The value for the GdPCA2 was 2.06 ± 0.03 mM<sup>-1</sup>s<sup>-1</sup> in H<sub>2</sub>O and 2.03 ± 0.03 mM<sup>-1</sup>s<sup>-1</sup> in aqueous bovine albumin (BSA) (14 mg/ml), respectively. The values for the cleaved-GdPCA2 were slightly higher: 2.18 ± 0.03 mM<sup>-1</sup>s<sup>-1</sup> in H<sub>2</sub>O and 2.19 ± 0.02 mM<sup>-1</sup>s<sup>-1</sup> in aqueous BSA. In comparison, the T<sub>1</sub> relaxivity of GdDTPA was 3.58 ± 0.10 mM<sup>-1</sup>s<sup>-1</sup>.</p></div><div id="GdPCA2.Animal_Studies"><h2 id="_GdPCA2_Animal_Studies_">Animal Studies</h2><div id="GdPCA2.Rodents"><h3>Rodents</h3><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=(%20PCA2-switch)%20+AND++rodentia" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>Lebel et al. used GdPCA2 with dynamic contrast-enhanced MRI to examine the MMP-2 activity as a function of time (the pharmacokinetics) <i>in vivo</i> (<a class="bibr" href="#GdPCA2.REF.6" rid="GdPCA2.REF.6">6</a>). Balb/c mice were implanted with two types of mammary carcinomas ~310 mm<sup>3</sup> in volume: a wild-type MC7-L1 (WT) tumor that had overexpressed MMP-2 at the left hind limb and a knockdown MC7-L1 (KD) tumor that had suppressed MMP-2 (~51% lower) at the right hind limb. The tumor-bearing mice (<i>n</i> = 8) were injected with 2 μmol GdPCA2 <i>via</i> the caudal vein, and sequential T<sub>1</sub>-weighted images were collected at 7 T at a temporal resolution of 51 s. The signal in each voxel was converted into the relaxation rate difference (ΔR<sub>1</sub>) between the relaxation rate R<sub>1</sub> and the precontrast relaxation rate R<sub>1,0</sub>. A rapid increase in ΔR<sub>1</sub> was observed in the WT and KD tumors after the injection of GdPCA2, but the subsequent pharmacokinetics were different in the two types of tumors. In the WT tumor, ΔR<sub>1</sub> remained constant 5–20 min after injection, then exhibited a second increase with a maximum at ~40 min. In the KD tumor, ΔR<sub>1</sub> continued to decrease 5 min after injection. As a control, the tumor-bearing mice (<i>n</i> = 2) were injected with 2 μmol GdPCA2-scrambled and imaged with the same MRI protocols. A pharmacokinetics similar to that of the KD tumor after injection of GdPCA2 was observed in both the WT tumor and the KD tumor after injection of GdPCA2-scrambled. This result suggests that the GdPCA2 in WT tumors is different from the GdPCA2-scrambled in both tumors. In the WT tumor, the first increase in ΔR<sub>1</sub> after injection of GdPCA2 was caused by the perfusion of GdPCA2 from the blood to the ECM, as seen in all tumors and/or injection with GdPCA2-scrambled; the second increase was attributed to the activation of enzyme MMP-2, which was only present in tumors overexpressing MMP-2 (WT type).</p></div><div id="GdPCA2.Other_NonPrimate_Mam"><h3>Other Non-Primate Mammals</h3><p>[<a href="/entrez/query.fcgi?cmd=PureSearch&db=pubmed&details_term=%22%20SUBSTANCENAME%22%5BSubstance%20Name%5D%20AND%20%28dog%20OR%20rabbit%20OR%20pig%20OR%20sheep%29" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No publication is currently available.</p></div><div id="GdPCA2.NonHuman_Primates"><h3>Non-Human Primates</h3><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=(%20PCA2-switch)%20+AND+(primate+non+human)" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No publication is currently available.</p></div></div><div id="GdPCA2.Human_Studies"><h2 id="_GdPCA2_Human_Studies_">Human Studies</h2><p>[<a href="/sites/entrez?Db=pubmed&Cmd=DetailsSearch&Term=(%20PCA2-switch)%20+AND+human" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubMed</a>]</p><p>No publication is currently available.</p></div><div id="GdPCA2.references"><h2 id="_GdPCA2_references_">References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="GdPCA2.REF.1">Lepage M. , Dow W.C. , Melchior M. , You Y. , Fingleton B. , Quarles C.C. , Pepin C. , Gore J.C. , Matrisian L.M. , McIntyre J.O. Noninvasive detection of matrix metalloproteinase activity in vivo using a novel magnetic resonance imaging contrast agent with a solubility switch. <span><span class="ref-journal">Mol Imaging. </span>2007;<span class="ref-vol">
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<strong>6</strong>
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</span>(6):393–403.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18053410" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18053410</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="GdPCA2.REF.2">Chen E.I. , Kridel S.J. , Howard E.W. , Li W. , Godzik A. , Smith J.W. A unique substrate recognition profile for matrix metalloproteinase-2. <span><span class="ref-journal">J Biol Chem. </span>2002;<span class="ref-vol">
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<strong>277</strong>
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</span>(6):4485–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11694539" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11694539</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="GdPCA2.REF.3">Yan C. , Boyd D.D. Regulation of matrix metalloproteinase gene expression. <span><span class="ref-journal">J Cell Physiol. </span>2007;<span class="ref-vol">
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<strong>211</strong>
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</span>(1):19–26.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17167774" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17167774</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="GdPCA2.REF.4">Klein G. , Vellenga E. , Fraaije M.W. , Kamps W.A. , de Bont E.S. The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia. <span><span class="ref-journal">Crit Rev Oncol Hematol. </span>2004;<span class="ref-vol">
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<strong>50</strong>
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</span>(2):87–100.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15157658" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15157658</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="GdPCA2.REF.5">Overall C.M. , Kleifeld O. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. <span><span class="ref-journal">Nat Rev Cancer. </span>2006;<span class="ref-vol">
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<strong>6</strong>
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</span>(3):227–39.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16498445" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16498445</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="GdPCA2.REF.6">Lebel R. , Jastrzebska B. , Therriault H. , Cournoyer M.M. , McIntyre J.O. , Escher E. , Neugebauer W. , Paquette B. , Lepage M. Novel solubility-switchable MRI agent allows the noninvasive detection of matrix metalloproteinase-2 activity in vivo in a mouse model. <span><span class="ref-journal">Magn Reson Med. </span>2008;<span class="ref-vol">
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<strong>60</strong>
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</span>(5):1056–65.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18956456" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18956456</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK22996_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Huiming Zhang</span>, PhD<div class="affiliation small">
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National Center for Biotechnology Information, NLM, NIH, Bethesda, MD,
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.mln.ibcn@dacim" class="oemail">vog.hin.mln.ibcn@dacim</a>
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</div></div><h3>Publication History</h3><p class="small">Created: <span itemprop="datePublished">December 22, 2008</span>; Last Update: <span itemprop="dateModified">January 14, 2009</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p><a href="http://www.ncbi.nlm.nih.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Center for Biotechnology Information (US)</a>, Bethesda (MD)</p><h3>NLM Citation</h3><p>Zhang H. Gd-DOTA-G-NH(CH2)11CO-RSPAYYTAA-(CH2CH2O)8-R. 2008 Dec 22 [Updated 2009 Jan 14]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/micad/P975/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/micad/GdLPG/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobGdPCA2T1"><div id="GdPCA2.T1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK22996/table/GdPCA2.T1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__GdPCA2.T1_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Chemical name:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gd-DOTA-G-NH(CH<sub>2</sub>)<sub>11</sub>CO-RSPAYYTAA-(CH<sub>2</sub>CH<sub>2</sub>O)<sub>8</sub>-R</td><td rowspan="9" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Abbreviated name:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GdPCA2</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Synonym:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PCA2-switch</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Agent category:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Peptide</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Target:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Matrix metalloprotein-2 (MMP-2)</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Target category:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Enzyme</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Method of detection:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Magnetic Resonance Imaging (MRI)</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Source of signal/contrast:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Gadolinium</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Activation:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Yes</td></tr><tr><td rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">
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<b>Studies:</b>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<ul class="simple-list"><li class="half_rhythm"><div>
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<img alt="Checkbox" src="/corehtml/pmc/css/bookshelf/2.26/img/studies.checkbox.png" />
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<i>In vitro</i>
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</div></li></ul>
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<ul class="simple-list"><li class="half_rhythm"><div>
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<img alt="Checkbox" src="/corehtml/pmc/css/bookshelf/2.26/img/studies.checkbox.png" /> Rodents
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</div></li></ul>
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</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">No structure is current available in <a href="http://pubchem.ncbi.nlm.nih.gov" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubChem</a>.</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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