Gd-Complexes of 1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-1,4,7,10-tetraacetic Acid (DOTA) Conjugates of Tranexamates as a New Class of Blood-Pool Magnetic Resonance Imaging Contrast Agents
Gd-complexes of the type [Gd(L)(H2O)]·xH2O (5a−c), where L is DOTA conjugates of tranexamic acid (4a) and tranexamic esters (4b,c), have been prepared as a new class of MRI blood-pool contrast agents (BPCAs). Thermodynamic stability (K GdL) and pharmacokinetic inertness of 5 compare well with or bet...
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| Veröffentlicht in: | Journal of medicinal chemistry 2011-01, Vol.54 (1), p.143-152 |
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| creator | Gu, Sungwook Kim, Hee-Kyung Lee, Gang Ho Kang, Bong-Seok Chang, Yongmin Kim, Tae-Jeong |
| description | Gd-complexes of the type [Gd(L)(H2O)]·xH2O (5a−c), where L is DOTA conjugates of tranexamic acid (4a) and tranexamic esters (4b,c), have been prepared as a new class of MRI blood-pool contrast agents (BPCAs). Thermodynamic stability (K GdL) and pharmacokinetic inertness of 5 compare well with or better than those of analogous MRI contrasting agents (CAs) such as Gd-DOTA and Gd-DTPA-BMA. Their R 1-relaxivities are significantly higher than those of any of the clinically used MRI CAs. T 1-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver. The structural uniqueness of 5c lies in the fact that it adopts macrocyclic DOTA instead of acyclic DTPA. In addition, 5c is nonionic and makes no resort to aromatic substituent(s) in the chelate backbone for the blood-pool enhancement. The nature of hepatobiliary uptake demonstrated by 5c may be explained in terms of lipophilicity of tranexamate in the chelate (4c). The cell cytotoxicity test shows no toxicity found with 5, suggesting their use as a practical MRI BPCAs. |
| doi_str_mv | 10.1021/jm100966t |
| format | Article |
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Thermodynamic stability (K GdL) and pharmacokinetic inertness of 5 compare well with or better than those of analogous MRI contrasting agents (CAs) such as Gd-DOTA and Gd-DTPA-BMA. Their R 1-relaxivities are significantly higher than those of any of the clinically used MRI CAs. T 1-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver. The structural uniqueness of 5c lies in the fact that it adopts macrocyclic DOTA instead of acyclic DTPA. In addition, 5c is nonionic and makes no resort to aromatic substituent(s) in the chelate backbone for the blood-pool enhancement. The nature of hepatobiliary uptake demonstrated by 5c may be explained in terms of lipophilicity of tranexamate in the chelate (4c). The cell cytotoxicity test shows no toxicity found with 5, suggesting their use as a practical MRI BPCAs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm100966t</identifier><identifier>PMID: 21141934</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Blood ; Cell Line ; Contrast Media - chemical synthesis ; Contrast Media - chemistry ; Contrast Media - pharmacokinetics ; Coordination Complexes - chemical synthesis ; Coordination Complexes - chemistry ; Coordination Complexes - pharmacokinetics ; Esters ; Gadolinium ; Heterocyclic Compounds, 1-Ring - chemical synthesis ; Heterocyclic Compounds, 1-Ring - chemistry ; Heterocyclic Compounds, 1-Ring - pharmacokinetics ; Humans ; Liver - metabolism ; Magnetic Resonance Imaging ; Male ; Mice ; Mice, Inbred ICR ; Organ Specificity ; Structure-Activity Relationship ; Tranexamic Acid - chemical synthesis ; Tranexamic Acid - chemistry ; Tranexamic Acid - pharmacokinetics</subject><ispartof>Journal of medicinal chemistry, 2011-01, Vol.54 (1), p.143-152</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a314t-7d8e225e7ec5f820bf6d05342e3c9d8a458bc368e72d098d34a555154c35d0083</citedby><cites>FETCH-LOGICAL-a314t-7d8e225e7ec5f820bf6d05342e3c9d8a458bc368e72d098d34a555154c35d0083</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/jm100966t$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm100966t$$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/21141934$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gu, Sungwook</creatorcontrib><creatorcontrib>Kim, Hee-Kyung</creatorcontrib><creatorcontrib>Lee, Gang Ho</creatorcontrib><creatorcontrib>Kang, Bong-Seok</creatorcontrib><creatorcontrib>Chang, Yongmin</creatorcontrib><creatorcontrib>Kim, Tae-Jeong</creatorcontrib><title>Gd-Complexes of 1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-1,4,7,10-tetraacetic Acid (DOTA) Conjugates of Tranexamates as a New Class of Blood-Pool Magnetic Resonance Imaging Contrast Agents</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Gd-complexes of the type [Gd(L)(H2O)]·xH2O (5a−c), where L is DOTA conjugates of tranexamic acid (4a) and tranexamic esters (4b,c), have been prepared as a new class of MRI blood-pool contrast agents (BPCAs). Thermodynamic stability (K GdL) and pharmacokinetic inertness of 5 compare well with or better than those of analogous MRI contrasting agents (CAs) such as Gd-DOTA and Gd-DTPA-BMA. Their R 1-relaxivities are significantly higher than those of any of the clinically used MRI CAs. T 1-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver. The structural uniqueness of 5c lies in the fact that it adopts macrocyclic DOTA instead of acyclic DTPA. In addition, 5c is nonionic and makes no resort to aromatic substituent(s) in the chelate backbone for the blood-pool enhancement. The nature of hepatobiliary uptake demonstrated by 5c may be explained in terms of lipophilicity of tranexamate in the chelate (4c). The cell cytotoxicity test shows no toxicity found with 5, suggesting their use as a practical MRI BPCAs.</description><subject>Animals</subject><subject>Blood</subject><subject>Cell Line</subject><subject>Contrast Media - chemical synthesis</subject><subject>Contrast Media - chemistry</subject><subject>Contrast Media - pharmacokinetics</subject><subject>Coordination Complexes - chemical synthesis</subject><subject>Coordination Complexes - chemistry</subject><subject>Coordination Complexes - pharmacokinetics</subject><subject>Esters</subject><subject>Gadolinium</subject><subject>Heterocyclic Compounds, 1-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, 1-Ring - chemistry</subject><subject>Heterocyclic Compounds, 1-Ring - pharmacokinetics</subject><subject>Humans</subject><subject>Liver - metabolism</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Organ Specificity</subject><subject>Structure-Activity Relationship</subject><subject>Tranexamic Acid - chemical synthesis</subject><subject>Tranexamic Acid - chemistry</subject><subject>Tranexamic Acid - pharmacokinetics</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1u1DAQgC0EokvhwAsgXxBUWsP4Lz_HJUCpVLYILefIa0-irJJ4iR3RcuKZeA6egichzZYVB6SRRyN_841GQ8hTDq84CP5613GAPEniPbLgWgBTGaj7ZAEgBBOJkCfkUQg7AJBcyIfkRHCueC7Vgvw6d6zw3b7FawzUV5Qv1TJdcmAbjIMx3429sa133qE1PbL1cv37x8_5-SdPwY6NcW60GBtLV7Zx9OXbq83qjBa-3421iYc5m2HSXZturs0UdI3faNGaMH-_ab137JP3Lf1o6n6Wfcbge9NbpBedqZu-vlVOs0Kkqxr7GB6TB5VpAz65y6fky_t3m-IDu7w6vyhWl8xIriJLXYZCaEzR6ioTsK0SB1oqgdLmLjNKZ1srkwxT4SDPnFRGa821slI7gEyekhcH737wX0cMseyaYLFtp5X8GMoshyRVSuqJPDuQdvAhDFiV-6HpzHBTcihvb1cebzexz-6s47ZDdyT_HmsCnh8AY0O58-PQT0v-R_QHMTCkHw</recordid><startdate>20110113</startdate><enddate>20110113</enddate><creator>Gu, Sungwook</creator><creator>Kim, Hee-Kyung</creator><creator>Lee, Gang Ho</creator><creator>Kang, Bong-Seok</creator><creator>Chang, Yongmin</creator><creator>Kim, Tae-Jeong</creator><general>American Chemical Society</general><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>20110113</creationdate><title>Gd-Complexes of 1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-1,4,7,10-tetraacetic Acid (DOTA) Conjugates of Tranexamates as a New Class of Blood-Pool Magnetic Resonance Imaging Contrast Agents</title><author>Gu, Sungwook ; Kim, Hee-Kyung ; Lee, Gang Ho ; Kang, Bong-Seok ; Chang, Yongmin ; Kim, Tae-Jeong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-7d8e225e7ec5f820bf6d05342e3c9d8a458bc368e72d098d34a555154c35d0083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Blood</topic><topic>Cell Line</topic><topic>Contrast Media - chemical synthesis</topic><topic>Contrast Media - chemistry</topic><topic>Contrast Media - pharmacokinetics</topic><topic>Coordination Complexes - chemical synthesis</topic><topic>Coordination Complexes - chemistry</topic><topic>Coordination Complexes - pharmacokinetics</topic><topic>Esters</topic><topic>Gadolinium</topic><topic>Heterocyclic Compounds, 1-Ring - chemical synthesis</topic><topic>Heterocyclic Compounds, 1-Ring - chemistry</topic><topic>Heterocyclic Compounds, 1-Ring - pharmacokinetics</topic><topic>Humans</topic><topic>Liver - metabolism</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Organ Specificity</topic><topic>Structure-Activity Relationship</topic><topic>Tranexamic Acid - chemical synthesis</topic><topic>Tranexamic Acid - chemistry</topic><topic>Tranexamic Acid - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gu, Sungwook</creatorcontrib><creatorcontrib>Kim, Hee-Kyung</creatorcontrib><creatorcontrib>Lee, Gang Ho</creatorcontrib><creatorcontrib>Kang, Bong-Seok</creatorcontrib><creatorcontrib>Chang, Yongmin</creatorcontrib><creatorcontrib>Kim, Tae-Jeong</creatorcontrib><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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gu, Sungwook</au><au>Kim, Hee-Kyung</au><au>Lee, Gang Ho</au><au>Kang, Bong-Seok</au><au>Chang, Yongmin</au><au>Kim, Tae-Jeong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gd-Complexes of 1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-1,4,7,10-tetraacetic Acid (DOTA) Conjugates of Tranexamates as a New Class of Blood-Pool Magnetic Resonance Imaging Contrast Agents</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-01-13</date><risdate>2011</risdate><volume>54</volume><issue>1</issue><spage>143</spage><epage>152</epage><pages>143-152</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Gd-complexes of the type [Gd(L)(H2O)]·xH2O (5a−c), where L is DOTA conjugates of tranexamic acid (4a) and tranexamic esters (4b,c), have been prepared as a new class of MRI blood-pool contrast agents (BPCAs). Thermodynamic stability (K GdL) and pharmacokinetic inertness of 5 compare well with or better than those of analogous MRI contrasting agents (CAs) such as Gd-DOTA and Gd-DTPA-BMA. Their R 1-relaxivities are significantly higher than those of any of the clinically used MRI CAs. T 1-weighted MR images of mice administered by 5c demonstrate high blood-pool effect with simultaneous contrast enhancement in liver. The structural uniqueness of 5c lies in the fact that it adopts macrocyclic DOTA instead of acyclic DTPA. In addition, 5c is nonionic and makes no resort to aromatic substituent(s) in the chelate backbone for the blood-pool enhancement. The nature of hepatobiliary uptake demonstrated by 5c may be explained in terms of lipophilicity of tranexamate in the chelate (4c). The cell cytotoxicity test shows no toxicity found with 5, suggesting their use as a practical MRI BPCAs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21141934</pmid><doi>10.1021/jm100966t</doi><tpages>10</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2011-01, Vol.54 (1), p.143-152 |
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| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Blood Cell Line Contrast Media - chemical synthesis Contrast Media - chemistry Contrast Media - pharmacokinetics Coordination Complexes - chemical synthesis Coordination Complexes - chemistry Coordination Complexes - pharmacokinetics Esters Gadolinium Heterocyclic Compounds, 1-Ring - chemical synthesis Heterocyclic Compounds, 1-Ring - chemistry Heterocyclic Compounds, 1-Ring - pharmacokinetics Humans Liver - metabolism Magnetic Resonance Imaging Male Mice Mice, Inbred ICR Organ Specificity Structure-Activity Relationship Tranexamic Acid - chemical synthesis Tranexamic Acid - chemistry Tranexamic Acid - pharmacokinetics |
| title | Gd-Complexes of 1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-1,4,7,10-tetraacetic Acid (DOTA) Conjugates of Tranexamates as a New Class of Blood-Pool Magnetic Resonance Imaging Contrast Agents |
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