Syntheses and Relaxation Properties of Mixed Gadolinium Hydroxypyridinonate MRI Contrast Agents
The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate as a magnetic resonance imaging (MRI) contrast agent. However, its low water solubility prevents detailed magnetic character...
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description | The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate as a magnetic resonance imaging (MRI) contrast agent. However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM-1 s-1 at 20 MHz, 25 °C, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5−4.8 mM-1 s-1). The high relaxivities of these complexes are consistent with their faster rates of water exchange (700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P1̄: Z = 4, a = 15.6963(2) Å, b = 16.9978(1) Å, c = 17.1578(2) Å, α = 61.981(1)°, β = 75.680(1)°, γ = 71.600(1)°), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths. |
doi_str_mv | 10.1021/ic000563b |
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However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM-1 s-1 at 20 MHz, 25 °C, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5−4.8 mM-1 s-1). The high relaxivities of these complexes are consistent with their faster rates of water exchange (<100 ns), higher molecular weights (>700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P1̄: Z = 4, a = 15.6963(2) Å, b = 16.9978(1) Å, c = 17.1578(2) Å, α = 61.981(1)°, β = 75.680(1)°, γ = 71.600(1)°), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths.</description><identifier>ISSN: 0020-1669</identifier><identifier>EISSN: 1520-510X</identifier><identifier>DOI: 10.1021/ic000563b</identifier><identifier>PMID: 11151375</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Contrast Media - chemical synthesis ; Contrast Media - chemistry ; Crystallography, X-Ray ; Gadolinium ; Indicators and Reagents ; Iron Chelating Agents - chemistry ; Magnetic Resonance Imaging ; Models, Molecular ; Molecular Conformation ; Molecular Structure ; Pyridones - chemistry ; Spectrophotometry, Ultraviolet</subject><ispartof>Inorganic chemistry, 2000-12, Vol.39 (25), p.5747-5756</ispartof><rights>Copyright © 2000 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a349t-ed8f286f41430b3f4ddffe4391a70bb3ee4eb342090becf3032922a85b4471dd3</citedby><cites>FETCH-LOGICAL-a349t-ed8f286f41430b3f4ddffe4391a70bb3ee4eb342090becf3032922a85b4471dd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/ic000563b$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/ic000563b$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11151375$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cohen, Seth M</creatorcontrib><creatorcontrib>Xu, Jide</creatorcontrib><creatorcontrib>Radkov, Emil</creatorcontrib><creatorcontrib>Raymond, Kenneth N</creatorcontrib><creatorcontrib>Botta, Mauro</creatorcontrib><creatorcontrib>Barge, Alessandro</creatorcontrib><creatorcontrib>Aime, Silvio</creatorcontrib><title>Syntheses and Relaxation Properties of Mixed Gadolinium Hydroxypyridinonate MRI Contrast Agents</title><title>Inorganic chemistry</title><addtitle>Inorg. Chem</addtitle><description>The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate as a magnetic resonance imaging (MRI) contrast agent. However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM-1 s-1 at 20 MHz, 25 °C, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5−4.8 mM-1 s-1). The high relaxivities of these complexes are consistent with their faster rates of water exchange (<100 ns), higher molecular weights (>700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P1̄: Z = 4, a = 15.6963(2) Å, b = 16.9978(1) Å, c = 17.1578(2) Å, α = 61.981(1)°, β = 75.680(1)°, γ = 71.600(1)°), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths.</description><subject>Contrast Media - chemical synthesis</subject><subject>Contrast Media - chemistry</subject><subject>Crystallography, X-Ray</subject><subject>Gadolinium</subject><subject>Indicators and Reagents</subject><subject>Iron Chelating Agents - chemistry</subject><subject>Magnetic Resonance Imaging</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Molecular Structure</subject><subject>Pyridones - chemistry</subject><subject>Spectrophotometry, Ultraviolet</subject><issn>0020-1669</issn><issn>1520-510X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1vEzEQBmALFdHQcuAPIF-KxGHBn7vZYxUgqUjVqi1qb5Z3PQa3GzvYXin77zFK1F44zUjz6B3pReg9JZ8pYfSL6wkhsubdKzSjkpFKUvJwhGaElJ3WdXuM3qb0WFDLRf0GHVNKJeWNnCF1O_n8GxIkrL3BNzDonc4ueHwdwxZiduUSLL50OzB4qU0YnHfjBq8mE8Nu2k7RGeeD1xnw5c0FXgSfo04Zn_8Cn9Mpem31kODdYZ6gn9-_3S1W1fpqebE4X1eaizZXYOaWzWsrqOCk41YYYy0I3lLdkK7jAAI6LhhpSQe95YSzljE9l50QDTWGn6CP-9xtDH9GSFltXOphGLSHMCbVMMmYlKzAT3vYx5BSBKu20W10nBQl6l-b6rnNYj8cQsduA-ZFHuoroNoDlzLsnu86Pqm6KUDdXd8quiY_7pvlV7Uq_mzvdZ_UYxijL5385_FfBt2LoQ</recordid><startdate>20001211</startdate><enddate>20001211</enddate><creator>Cohen, Seth M</creator><creator>Xu, Jide</creator><creator>Radkov, Emil</creator><creator>Raymond, Kenneth N</creator><creator>Botta, Mauro</creator><creator>Barge, Alessandro</creator><creator>Aime, Silvio</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20001211</creationdate><title>Syntheses and Relaxation Properties of Mixed Gadolinium Hydroxypyridinonate MRI Contrast Agents</title><author>Cohen, Seth M ; Xu, Jide ; Radkov, Emil ; Raymond, Kenneth N ; Botta, Mauro ; Barge, Alessandro ; Aime, Silvio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a349t-ed8f286f41430b3f4ddffe4391a70bb3ee4eb342090becf3032922a85b4471dd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Contrast Media - chemical synthesis</topic><topic>Contrast Media - chemistry</topic><topic>Crystallography, X-Ray</topic><topic>Gadolinium</topic><topic>Indicators and Reagents</topic><topic>Iron Chelating Agents - chemistry</topic><topic>Magnetic Resonance Imaging</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Molecular Structure</topic><topic>Pyridones - chemistry</topic><topic>Spectrophotometry, Ultraviolet</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cohen, Seth M</creatorcontrib><creatorcontrib>Xu, Jide</creatorcontrib><creatorcontrib>Radkov, Emil</creatorcontrib><creatorcontrib>Raymond, Kenneth N</creatorcontrib><creatorcontrib>Botta, Mauro</creatorcontrib><creatorcontrib>Barge, Alessandro</creatorcontrib><creatorcontrib>Aime, Silvio</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Inorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cohen, Seth M</au><au>Xu, Jide</au><au>Radkov, Emil</au><au>Raymond, Kenneth N</au><au>Botta, Mauro</au><au>Barge, Alessandro</au><au>Aime, Silvio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Syntheses and Relaxation Properties of Mixed Gadolinium Hydroxypyridinonate MRI Contrast Agents</atitle><jtitle>Inorganic chemistry</jtitle><addtitle>Inorg. Chem</addtitle><date>2000-12-11</date><risdate>2000</risdate><volume>39</volume><issue>25</issue><spage>5747</spage><epage>5756</epage><pages>5747-5756</pages><issn>0020-1669</issn><eissn>1520-510X</eissn><abstract>The tripodal ligand tris[(3-hydroxy-1-methyl-2-oxo-1,2-didehydropyridine-4-carboxamido)ethyl]amine (TREN-Me-3,2-HOPO) forms a stable Gd3+ complex that is a promising candidate as a magnetic resonance imaging (MRI) contrast agent. However, its low water solubility prevents detailed magnetic characterization and practical applicability. Presented here are a series of novel mixed ligand systems that are based on the TREN-Me-3,2-HOPO platform. These new ligands possess two hydroxypyridinone (HOPO) chelators and one other chelator, the latter of which can be easily functionalized. The ligands described use salicylamide, 2-hydroxyisophthalamide, 2,3-dihydroxyterephthalamide, and bis(acetate) as the derivatizable chelators. The solution thermodynamics and relaxivity properties of these new systems are presented. Three of the four complexes (salicylamide-, 2-hydroxyisophthalamide-, and 2,3-dihydroxyterephthalamide-based ligands) possess sufficient thermodynamic stability for in vivo applications. The relaxivities of the three corresponding Gd3+ complexes range from 7.2 to 8.8 mM-1 s-1 at 20 MHz, 25 °C, and pH 8.5, significantly higher than the values for the clinically employed polyaminocarboxylate complexes (3.5−4.8 mM-1 s-1). The high relaxivities of these complexes are consistent with their faster rates of water exchange (<100 ns), higher molecular weights (>700), and greater numbers of inner-sphere coordinated water molecules (q = 2) relative to those of polyaminocarboxylate complexes. A mechanism for the rapid rates of water exchange is proposed involving a low energy barrier between the 8- and 9-coordinate geometries for lanthanide complexes of HOPO-based ligands. The pathway is supported by the crystal structure of La[TREN-Me-3,2-HOPO] (triclinic P1̄: Z = 4, a = 15.6963(2) Å, b = 16.9978(1) Å, c = 17.1578(2) Å, α = 61.981(1)°, β = 75.680(1)°, γ = 71.600(1)°), which shows both 8- and 9-coordinate metal centers in the asymmetric unit, demonstrating that these structures are very close in energy. These properties make heteropodate Gd3+ complexes promising candidates for use in macromolecular contrast media, particularly at higher magnetic field strengths.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>11151375</pmid><doi>10.1021/ic000563b</doi><tpages>10</tpages></addata></record> |
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subjects | Contrast Media - chemical synthesis Contrast Media - chemistry Crystallography, X-Ray Gadolinium Indicators and Reagents Iron Chelating Agents - chemistry Magnetic Resonance Imaging Models, Molecular Molecular Conformation Molecular Structure Pyridones - chemistry Spectrophotometry, Ultraviolet |
title | Syntheses and Relaxation Properties of Mixed Gadolinium Hydroxypyridinonate MRI Contrast Agents |
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