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{{chembox |
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{{chembox |
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|Verifiedfields = changed |
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| verifiedrevid = 447528929 |
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|Watchedfields = changed |
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| Name = DOTA |
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|verifiedrevid = 458276313 |
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| ImageFile = Tetraxetan structure.svg |
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| ImageName = DOTA |
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|Name = DOTA |
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|ImageFile = Tetraxetan structure.svg |
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| IUPACName = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid |
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| OtherNames = DOTA, DotA, tetraxetan |
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|ImageName = DOTA |
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|PIN = 2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid |
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| Section1 = {{Chembox Identifiers |
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|OtherNames = DotA; Tetraxetan |
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| SMILES = O=C(O)CN(CC1)CCN(CC(=O)O)CCN(CC(=O)O)CCN1CC(=O)O |
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|Section1={{Chembox Identifiers |
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| CASNo = <!-- blanked - oldvalue: 60239-18-1 --> |
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|IUPHAR_ligand = 5538 |
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| CASNo_Ref = |
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|SMILES = O=C(O)CN(CC1)CCN(CC(=O)O)CCN(CC(=O)O)CCN1CC(=O)O |
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| RTECS = |
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|CASNo = 60239-18-1 |
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| PubChem = 121841 |
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|CASNo_Ref = {{cascite|correct|CAS}} |
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| InChI = 1S/C16H28N4O8/c21-13(22)9-17-1-2-18(10-14(23)24)5-6-20(12-16(27)28)8-7-19(4-3-17)11-15(25)26/h1-12H2,(H,21,22)(H,23,24)(H,25,26)(H,27,28) |
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|UNII_Ref = {{fdacite|correct|FDA}} |
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| InChIKey = WDLRUFUQRNWCPK-UHFFFAOYSA-N |
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|UNII = 1HTE449DGZ |
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}} |
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|PubChem = 121841 |
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| Section2 = {{Chembox Properties |
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|ChEBI = 61028 |
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| C = 16 | H = 28 | N = 4 | O = 8 |
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|ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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| Appearance = White crystalline solid |
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|ChemSpiderID = 108701 |
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| Density = |
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|SMILES2 = C1CN(CCN(CCN(CCN1CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O |
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| Solubility = |
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|InChI = 1/C16H28N4O8/c21-13(22)9-17-1-2-18(10-14(23)24)5-6-20(12-16(27)28)8-7-19(4-3-17)11-15(25)26/h1-12H2,(H,21,22)(H,23,24)(H,25,26)(H,27,28) |
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| MeltingPt = |
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|InChIKey = WDLRUFUQRNWCPK-UHFFFAOYAO |
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|StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| pKa = |
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|StdInChI = 1S/C16H28N4O8/c21-13(22)9-17-1-2-18(10-14(23)24)5-6-20(12-16(27)28)8-7-19(4-3-17)11-15(25)26/h1-12H2,(H,21,22)(H,23,24)(H,25,26)(H,27,28) |
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| pKb = |
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|StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| Viscosity = |
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|StdInChIKey = WDLRUFUQRNWCPK-UHFFFAOYSA-N |
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| Section3 = {{Chembox Structure |
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| Section7 = {{Chembox Hazards |
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| ExternalMSDS = |
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| FlashPt = |
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| GHSPictograms = {{GHS exclamation mark}} |
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| GHSSignalWord = '''WARNING''' |
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| HPhrases = {{H-phrases|315|319|335}} |
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| PPhrases = {{P-phrases|261|305+351+338}} |
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| RPhrases = {{R36/37/38}} |
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| SPhrases = {{S26}}, {{S36}} |
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| Section8 = {{Chembox Related |
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| OtherAnions = |
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| OtherCpds = ], ] |
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|Section2={{Chembox Properties |
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{{otheruses|DOTA (disambiguation)}} |
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|C=16 | H=28 | N=4 | O=8 |
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'''1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid''' (also known as '''DOTA''') is an organic compound with the formula (CH<sub>2</sub>CH<sub>2</sub>NCH<sub>2</sub>CO<sub>2</sub>H)<sub>4</sub>. The molecule consists of a central 12-membered tetraaza (i.e., containing four nitrogen centers) ring. DOTA is used as a complexing agent, especially for ] ions. Its complexes have medical applications as contrast agents and cancer treatments. |
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|Appearance = White crystalline solid |
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|Section7={{Chembox Hazards |
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|GHSPictograms = {{GHS exclamation mark}} |
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|GHSSignalWord = '''WARNING''' |
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|HPhrases = {{H-phrases|315|319|335}} |
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|PPhrases = {{P-phrases|261|305+351+338}} |
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|Section8={{Chembox Related |
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|OtherCompounds = ], ] |
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'''DOTA''' (also known as '''tetraxetan''') is an organic compound with the formula (CH<sub>2</sub>CH<sub>2</sub>NCH<sub>2</sub>CO<sub>2</sub>H)<sub>4</sub>. The molecule consists of a central 12-membered tetraaza (i.e., containing four nitrogen atoms) ring. DOTA is used as a complexing agent, especially for ] ions. Its complexes have medical applications as contrast agents and cancer treatments. |
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==Terminology== |
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==Terminology== |
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The acronym DOTA is jargon for both the tetracarboxylic acid and its various conjugate bases. In the area of ], the tetraacid is called H<sub>4</sub>DOTA and its fully deprotonated derivative is DOTA<sup>4-</sup>.<ref name=Nerissa>Nerissa Viola-Villegas, Robert P. Doyle "The coordination chemistry of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (H4DOTA): Structural overview and analyses on structure–stability relationships" Coordination Chemistry Reviews Volume 253, 2009, pp1906-1925. {{DOI|10.1016/j.ccr.2009.03.013}}</ref> Many related ligands are referred to using the DOTA acronym, although these derivatives are generally not ''tetra''carboxylic acids or the conjugate bases. |
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The acronym DOTA (for dodecane tetraacetic acid) is shorthand for both the tetracarboxylic acid and its various conjugate bases. In the area of ], the tetraacid is called H<sub>4</sub>DOTA and its fully deprotonated derivative is DOTA<sup>4−</sup>.<ref name=Nerissa>{{cite journal | doi = 10.1016/j.ccr.2009.03.013| title = The coordination chemistry of 1,4,7,10-tetraazacyclododecane-N,N′,N",N′"-tetraacetic acid (H4DOTA): Structural overview and analyses on structure–stability relationships| journal = Coordination Chemistry Reviews| volume = 253| issue = 13–14| pages = 1906| year = 2009| last1 = Viola-Villegas| first1 = Nerissa| last2 = Doyle| first2 = Robert P}}</ref> Many related ligands are referred to using the DOTA acronym, although these derivatives are generally not tetracarboxylic acids or the conjugate bases. |
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==Structure== |
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==Structure== |
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DOTA is derived from the ] known as ]. The four secondary amine groups are modified by replacement of the N-H centers with N-CH<sub>2</sub>CO<sub>2</sub>H groups. The resulting ], upon ionization of the carboxylic acid groups, is a high affinity chelating agent for di- and tri] cations. The tetracarboxylic acid was first reported in 1976.<ref name="Stetter">{{Cite journal |
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DOTA is derived from the ] known as ]. The four secondary amine groups are modified by replacement of the N-H centers with N-CH<sub>2</sub>CO<sub>2</sub>H groups. The resulting ], upon ionization of the carboxylic acid groups, is a high affinity chelating agent for di- and tri] cations. The tetracarboxylic acid was first reported in 1976.<ref name="Stetter">{{Cite journal |
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| doi = 10.1002/anie.197606861 |
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| doi = 10.1002/anie.197606861 |
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| volume = 15 |
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| volume = 15 |
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| last = Stetter |
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| last = Stetter |
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| first = Hermann |
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| first = Hermann |
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| coauthors = Wolfram Frank |
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| author2=Wolfram Frank |
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| title = <nowiki>Complex Formation with Tetraazacycloalkane-N,N',N'',N''';-tetraacetic Acids as a Function of Ring Size</nowiki> |
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| title = <nowiki>Complex Formation with Tetraazacycloalkane-N,N',N'',N''';-tetraacetic Acids as a Function of Ring Size</nowiki> |
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| journal = Angewandte Chemie International Edition in English |
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| journal = Angewandte Chemie International Edition in English |
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| date = 1976 |
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| date = 1976}}</ref> |
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At the time of its discovery DOTA exhibited the largest known formation constant for the complexation (]) of ] and ] ions. Modified versions of DOTA were first reported in 1988 and this area has proliferated since.<ref>{{Cite journal |
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}}</ref> |
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At the time of its discovery DOTA exhibited the largest known formation constant for the complexation (]) of ] and ] ions. Modified versions of DOTA were first reported in 1988 and this area has proliferated since.<ref>{{Cite journal |
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| doi = 10.1021/ja00226a063 |
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| doi = 10.1021/ja00226a063 |
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| pmid = 22148823 |
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| volume = 110 |
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| volume = 110 |
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| issue = 18 |
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| issue = 18 |
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| last = Moi |
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| last = Moi |
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| first = Min K. |
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| first = Min K. |
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| coauthors = Claude F. Meares, Sally J. DeNardo |
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| author2=Claude F. Meares|author3=Sally J. DeNardo |
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| title = <nowiki>The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid and study of its yttrium(III) complex</nowiki> |
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| title = <nowiki>The peptide way to macrocyclic bifunctional chelating agents: synthesis of 2-(p-nitrobenzyl)-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid and study of its yttrium(III) complex</nowiki> |
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| journal = Journal of the American Chemical Society |
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| journal = Journal of the American Chemical Society |
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| date = 1988 |
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| date = 1988}}</ref><ref>{{Cite journal |
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}}</ref><ref>{{Cite journal |
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| doi = 10.1021/cr9804386 |
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| doi = 10.1021/cr9804386 |
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| volume = 99 |
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| volume = 99 |
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| last = Volkert |
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| last = Volkert |
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| first = Wynn A. |
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| first = Wynn A. |
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| coauthors = Timothy J. Hoffman |
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| author2=Timothy J. Hoffman |
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| title = Therapeutic Radiopharmaceuticals |
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| title = Therapeutic Radiopharmaceuticals |
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| journal = Chemical Reviews |
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| journal = Chemical Reviews |
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| date = 1999 |
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| date = 1999 |
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| pmid = 11749482 |
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| pmid = 11749482}}</ref> |
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}}</ref> |
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As a polydentate ligand, DOTA envelops metal cations, but the denticity of the ligand depends on the geometric tendencies of the metal cation. The main applications involve the lanthanides and in such complexes DOTA functions as an octadentate ligand, binding the metal through four amine and four carboxylate groups. Most such complexes feature an additional water ligand, giving an overall coordination number of nine.<ref name=Nerissa/> |
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As a polydentate ligand, DOTA envelops metal cations, but the denticity of the ligand depends on the geometric tendencies of the metal cation. The main applications involve the lanthanides and in such complexes DOTA functions as an octadentate ligand, binding the metal through four amine and four carboxylate groups. Most such complexes feature an additional water ligand, giving an overall coordination number of nine.<ref name=Nerissa/> |
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For most transition metals, DOTA functions as a hexadentate ligand, binding through the four nitrogen and two carboxylate centres. The complexes have ], with two pendent carboxylate groups. In the case of <sup>-</sup>, the ligand is heptadentate.<ref name=Nerissa/> |
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For most transition metals, DOTA functions as a ], binding through the four nitrogen and two carboxylate centres. The complexes have ], with two pendent carboxylate groups. In the case of <sup>−</sup>, the ligand is heptadentate.<ref name=Nerissa/> |
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==Uses== |
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==Uses== |
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===Cancer treatment and diagnosis=== |
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===Cancer treatment and diagnosis=== |
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DOTA is used as part of some ] therapies, where it functions as a chelating agent for the ] ]. DOTA can be conjugated to ] by attachment of one of the four carboxyl groups as an ]. The remaining three ]s are available for binding to the yttrium ion. The modified anitibody accumulates in the tumour cells, concentrating the effects of the radioactivity of <sup>90</sup>Y. Drugs containing this module receive an ] ending in ''tetraxetan'':<ref>{{cite web|title=Statement On A Nonproprietary Name Adopted By The USAN Council: Yttrium Y90 clivatuzumab tetraxetan|publisher=]|url=http://www.ama-assn.org/ama1/pub/upload/mm/365/yttrium-Y-90-clivatuzumab-tetraxetan.pdf}}</ref> |
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DOTA can be conjugated to ] by attachment of one of the four carboxyl groups as an ]. The remaining three ]s are available for binding to the yttrium ion. The modified antibody accumulates in the tumour cells, concentrating the effects of the radioactivity of <sup>90</sup>Y. Drugs containing this module receive an ] ending in ''tetraxetan'':<ref>{{cite web|title=Statement On A Nonproprietary Name Adopted By The USAN Council: Yttrium Y90 clivatuzumab tetraxetan|publisher=]|url=http://www.ama-assn.org/ama1/pub/upload/mm/365/yttrium-Y-90-clivatuzumab-tetraxetan.pdf}}</ref> |
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DOTA can also be linked to molecules that have affinity for various structures. The resulting compounds are used with a number of radioisotopes in cancer therapy and diagnosis (for example in ]). |
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DOTA can also be linked to molecules that have affinity for various structures. The resulting compounds are used with a number of radioisotopes in cancer therapy and diagnosis (for example in ]). |
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* Affinity for ]s, which are found on ]s:<ref>{{pmid|21624565}}</ref> |
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* Affinity for ]s, which are found on ]s:<ref>{{Cite journal | last1 = Breeman | first1 = W. A. P. |
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| last2 = De Blois | first2 = E. |
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| last3 = Sze Chan | first3 = H. |
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| last4 = Konijnenberg | first4 = M. |
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| last5 = Kwekkeboom | first5 = D. J. |
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| last6 = Krenning | first6 = E. P. |
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| doi = 10.1053/j.semnuclmed.2011.02.001 |
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| title = 68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives |
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| journal = Seminars in Nuclear Medicine |
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| volume = 41 |
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| issue = 4 |
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| pages = 314–321 |
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| year = 2011 |
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| pmid = 21624565}}</ref> |
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** ], DOTA-(Tyr<sup>3</sup>)-octreotide or edotreotide |
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** ], DOTA-(Tyr<sup>3</sup>)-octreotide or edotreotide |
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** ] or DOTA-(Tyr<sup>3</sup>)-octreotate |
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** ] or DOTA-(Tyr<sup>3</sup>)-octreotate |
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* Affinity for the proteins ] and ], which can be targeted at tumours by aid of monoclonal antibodies:<ref>{{pmid|10717908}}</ref> |
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* Affinity for the proteins ] and ], which can be targeted at tumours by aid of monoclonal antibodies:<ref>{{Cite journal |
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| last1 = Domingo | first1 = R. J. |
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| last2 = Reilly | first2 = R. M. |
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| title = Pre-targeted radioimmunotherapy of human colon cancer xenografts in athymic mice using streptavidin-CC49 monoclonal antibody and 90Y-DOTA-biotin |
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| journal = Nuclear Medicine Communications |
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| volume = 21 |
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| issue = 1 |
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| pages = 89–96 |
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| year = 2000 |
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| pmid = 10717908 |
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| doi=10.1097/00006231-200001000-00015}}</ref> |
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<gallery widths="180px" heights="180px"> |
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<gallery widths="180px" heights="180px"> |
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File:Y-90 tacatuzumab tetraxetan structure.svg|DOTA linked to the monoclonal antibody ] and chelating ] |
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File:Y-90 tacatuzumab tetraxetan structure.svg|DOTA linked to the monoclonal antibody ] and chelating ] |
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File:90Y-DOTATOC.png|] chelating yttrium-90 |
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File:Yttrium-90 edotreotide.svg|] chelating yttrium-90 |
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File:DOTATATE.svg|] |
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File:DOTATATE.svg|] |
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</gallery> |
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</gallery> |
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===Contrast agent=== |
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===Contrast agent=== |
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The complex of ]<sup>3+</sup> and DOTA is used as a ] under the name ].<ref>{{cite |url=http://clinicaltrials.gov/ct2/show/NCT00447889 |title=A Clinical Study of Gadoteric Acid in Non-Coronary Magnetic Resonance (MR) Angiography }}</ref> |
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The complex of ] and DOTA is used as a ] under the name ].<ref>{{citation |url=http://clinicaltrials.gov/ct2/show/NCT00447889 |title=A Clinical Study of Gadoteric Acid in Non-Coronary Magnetic Resonance (MR) Angiography |date=25 November 2008 }}</ref> |
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==Synthesis== |
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==Synthesis== |
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DOTA was first synthesized in 1976 from cyclen and ].<ref name="Stetter" /> This method is simple and still in use.<ref>{{cite journal|pmid=17503419|year=2007|last1=Knör|first1=S|last2=Modlinger|first2=A|last3=Poethko|first3=T|last4=Schottelius|first4=M|last5=Wester|first5=HJ|last6=Kessler|first6=H|title=Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds|volume=13|issue=21|pages=6082–90|doi=10.1002/chem.200700231|journal=Chemistry (Weinheim an der Bergstrasse, Germany)}}</ref> |
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DOTA was first synthesized in 1976 from ] and ].<ref name="Stetter" /> This method is simple and still in use.<ref>{{cite journal|pmid=17503419|year=2007|last1=Knör|first1=S|last2=Modlinger|first2=A|last3=Poethko|first3=T|last4=Schottelius|first4=M|last5=Wester|first5=HJ|last6=Kessler|first6=H|title=Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds|volume=13|issue=21|pages=6082–90|doi=10.1002/chem.200700231|journal=Chemistry: A European Journal}}</ref> |
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== References == |
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== References == |
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