DOTA (chelator)

Last updated
DOTA
Tetraxetan structure.svg
Names
Preferred IUPAC name
2,2′,2′′,2′′′-(1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid
Other names
DotA; Tetraxetan
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.113.833 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • 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) X mark.svgN
    Key: WDLRUFUQRNWCPK-UHFFFAOYSA-N X mark.svgN
  • 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)
    Key: WDLRUFUQRNWCPK-UHFFFAOYAO
  • O=C(O)CN(CC1)CCN(CC(=O)O)CCN(CC(=O)O)CCN1CC(=O)O
  • C1CN(CCN(CCN(CCN1CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Properties
C16H28N4O8
Molar mass 404.420 g·mol−1
AppearanceWhite crystalline solid
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H315, H319, H335
P261, P305+P351+P338
Related compounds
Related compounds
Cyclen, EDTA
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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DOTA (also known as tetraxetan) is an organic compound with the formula (CH2CH2NCH2CO2H)4. 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 lanthanide ions. Its complexes have medical applications as contrast agents and cancer treatments.

Contents

Terminology

The acronym DOTA (for dodecane tetraacetic acid) is shorthand for both the tetracarboxylic acid and its various conjugate bases. In the area of coordination chemistry, the tetraacid is called H4DOTA and its fully deprotonated derivative is DOTA4−. [1] Many related ligands are referred to using the DOTA acronym, although these derivatives are generally not tetracarboxylic acids or the conjugate bases.

Structure

DOTA is derived from the macrocycle known as cyclen. The four secondary amine groups are modified by replacement of the N-H centers with N-CH2CO2H groups. The resulting aminopolycarboxylic acid, upon ionization of the carboxylic acid groups, is a high affinity chelating agent for di- and trivalent cations. The tetracarboxylic acid was first reported in 1976. [2] At the time of its discovery DOTA exhibited the largest known formation constant for the complexation (chelating) of Ca2+ and Gd3+ ions. Modified versions of DOTA were first reported in 1988 and this area has proliferated since. [3] [4]

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. [1]

For most transition metals, DOTA functions as a hexadentate ligand, binding through the four nitrogen and two carboxylate centres. The complexes have octahedral coordination geometry, with two pendent carboxylate groups. In the case of [Fe(DOTA)], the ligand is heptadentate. [1]

Uses

Cancer treatment and diagnosis

DOTA can be conjugated to monoclonal antibodies by attachment of one of the four carboxyl groups as an amide. The remaining three carboxylate anions are available for binding to the yttrium ion. The modified antibody accumulates in the tumour cells, concentrating the effects of the radioactivity of 90Y. Drugs containing this module receive an International Nonproprietary Name ending in tetraxetan: [5]

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 positron emission tomography).

Contrast agent

The complex of Gd3+ and DOTA is used as a gadolinium-based MRI contrast agent under the name gadoteric acid. [8]

Synthesis

DOTA was first synthesized in 1976 from cyclen and bromoacetic acid. [2] This method is simple and still in use. [9]

Related Research Articles

<span class="mw-page-title-main">Ligand</span> Ion or molecule that binds to a central metal atom to form a coordination complex

In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electron pairs, often through Lewis bases. The nature of metal–ligand bonding can range from covalent to ionic. Furthermore, the metal–ligand bond order can range from one to three. Ligands are viewed as Lewis bases, although rare cases are known to involve Lewis acidic "ligands".

Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a polydentate ligand and a single central metal atom. These ligands are called chelants, chelators, chelating agents, or sequestering agents. They are usually organic compounds, but this is not a necessity, as in the case of zinc and its use as a maintenance therapy to prevent the absorption of copper in people with Wilson's disease.

<span class="mw-page-title-main">Ethylenediaminetetraacetic acid</span> Chemical compound

Ethylenediaminetetraacetic acid (EDTA) is an aminopolycarboxylic acid with the formula [CH2N(CH2CO2H)2]2. This white, water-soluble solid is widely used to bind to iron (Fe2+/Fe3+) and calcium ions (Ca2+), forming water-soluble complexes even at neutral pH. It is thus used to dissolve Fe- and Ca-containing scale as well as to deliver iron ions under conditions where its oxides are insoluble. EDTA is available as several salts, notably disodium EDTA, sodium calcium edetate, and tetrasodium EDTA, but these all function similarly.

<sup>90</sup>Y-DOTA-biotin

90Y-DOTA-biotin consists of a radioactive substance (yttrium-90) complexed by a chelating agent (DOTA), which in turn is attached to the vitamin biotin via a chemical linker. It is used experimentally in pretargeted radioimmunotherapy. Animal studies have been conducted as well as clinical studies in humans.

<span class="mw-page-title-main">Streptavidin</span> Protein in Streptomyces avidinii

Streptavidin is a 66.0 (tetramer) kDa protein purified from the bacterium Streptomyces avidinii. Streptavidin homo-tetramers have an extraordinarily high affinity for biotin. With a dissociation constant (Kd) on the order of ≈10−14 mol/L, the binding of biotin to streptavidin is one of the strongest non-covalent interactions known in nature. Streptavidin is used extensively in molecular biology and bionanotechnology due to the streptavidin-biotin complex's resistance to organic solvents, denaturants, detergents, proteolytic enzymes, and extremes of temperature and pH.

Protein tags are peptide sequences genetically grafted onto a recombinant protein. Tags are attached to proteins for various purposes. They can be added to either end of the target protein, so they are either C-terminus or N-terminus specific or are both C-terminus and N-terminus specific. Some tags are also inserted at sites within the protein of interest; they are known as internal tags.

<span class="mw-page-title-main">Gadolinium(III) chloride</span> Chemical compound

Gadolinium(III) chloride, also known as gadolinium trichloride, is GdCl3. It is a colorless, hygroscopic, water-soluble solid. The hexahydrate GdCl3∙6H2O is commonly encountered and is sometimes also called gadolinium trichloride. Gd3+ species are of special interest because the ion has the maximum number of unpaired spins possible, at least for known elements. With seven valence electrons and seven available f-orbitals, all seven electrons are unpaired and symmetrically arranged around the metal. The high magnetism and high symmetry combine to make Gd3+ a useful component in NMR spectroscopy and MRI.

<span class="mw-page-title-main">Avidin</span> Type of protein

Avidin is a tetrameric biotin-binding protein produced in the oviducts of birds, reptiles and amphibians and deposited in the whites of their eggs. Dimeric members of the avidin family are also found in some bacteria. In chicken egg white, avidin makes up approximately 0.05% of total protein (approximately 1800 μg per egg). The tetrameric protein contains four identical subunits (homotetramer), each of which can bind to biotin (Vitamin B7, vitamin H) with a high degree of affinity and specificity. The dissociation constant of the avidin-biotin complex is measured to be KD ≈ 10−15 M, making it one of the strongest known non-covalent bonds.

<span class="mw-page-title-main">Nitrilotriacetic acid</span> Chemical compound

Nitrilotriacetic acid (NTA) is the aminopolycarboxylic acid with the formula N(CH2CO2H)3. It is a colourless solid that is used as a chelating agent, which forms coordination compounds with metal ions (chelates) such as Ca2+, Co2+, Cu2+, and Fe3+.

<span class="mw-page-title-main">Pentetic acid</span> DTPA: aminopolycarboxylic acid

Pentetic acid or diethylenetriaminepentaacetic acid (DTPA) is an aminopolycarboxylic acid consisting of a diethylenetriamine backbone with five carboxymethyl groups. The molecule can be viewed as an expanded version of EDTA and is used similarly. It is a white solid with limited solubility in water.

Molecular binding is an attractive interaction between two molecules that results in a stable association in which the molecules are in close proximity to each other. It is formed when atoms or molecules bind together by sharing of electrons. It often, but not always, involves some chemical bonding.

<span class="mw-page-title-main">EDDHA</span> Chemical compound

EDDHA or ethylenediamine-N,N′-bis(2-hydroxyphenylacetic acid) is a chelating agent. Like EDTA, it binds metal ions as a hexadentate ligand, using two amines, two phenolate centers, and two carboxylates as the six binding sites. The complexes are typically anionic. The ligand itself is a white, water soluble powder. Both the free ligand and its tetraanionic chelating agent are abbreviated EDDHA. In contrast to EDDHA, most related aminopolycarboxylic acid chelating agents feature tertiary amines and few have phenolate groups.

<span class="mw-page-title-main">Ferrichrome</span> Chemical compound

Ferrichrome is a cyclic hexa-peptide that forms a complex with iron atoms. It is a siderophore composed of three glycine and three modified ornithine residues with hydroxamate groups [-N(OH)C(=O)C-]. The 6 oxygen atoms from the three hydroxamate groups bind Fe(III) in near perfect octahedral coordination.

<span class="mw-page-title-main">Cyclam</span> Chemical compound

Cyclam (1,4,8,11-tetraazacyclotetradecane) is an organic compound with the formula (NHCH2CH2NHCH2CH2CH2)2. Classified as an aza-crown ether, it is a white solid that is soluble in water. As a macrocyclic ligand, it binds strongly to many transition metal cations. The compound was first prepared by the reaction of 1,3-dibromopropane and ethylenediamine.

In coordination chemistry, a macrocyclic ligand is a macrocyclic ring having at least nine atoms and three or more donor sites that serve as ligands that can bind to a central metal ion. Crown ethers and porphyrins are prominent examples. Macrocyclic ligands exhibit high affinity for metal ions.

<span class="mw-page-title-main">Peptide receptor radionuclide therapy</span> Type of radiotherapy

Peptide receptor radionuclide therapy (PRRT) is a type of radionuclide therapy, using a radiopharmaceutical that targets peptide receptors to deliver localised treatment, typically for neuroendocrine tumours (NETs).

Transition metal amino acid complexes are a large family of coordination complexes containing the conjugate bases of the amino acids, the 2-aminocarboxylates. Amino acids are prevalent in nature, and all of them function as ligands toward the transition metals. Not included in this article are complexes of the amides and ester derivatives of amino acids. Also excluded are the polyamino acids including the chelating agents EDTA and NTA.

<span class="mw-page-title-main">Kinetic exclusion assay</span>

A kinetic exclusion assay (KinExA) is a type of bioassay in which a solution containing receptor, ligand, and receptor-ligand complex is briefly exposed to additional ligand immobilized on a solid phase.

<span class="mw-page-title-main">Pretargeting (imaging)</span>

Pretargeting (imaging) is a tool for nuclear medicine and radiotherapy. Imaging studies require a high contrast of target to background. This can be provided by using a biomarker which has a high affinity and specificity for its target.

<span class="mw-page-title-main">Transition metal carboxylate complex</span>

Transition metal carboxylate complexes are coordination complexes with carboxylate (RCO2) ligands. Reflecting the diversity of carboxylic acids, the inventory of metal carboxylates is large. Many are useful commercially, and many have attracted intense scholarly scrutiny. Carboxylates exhibit a variety of coordination modes, most common are κ1- (O-monodentate), κ2 (O,O-bidentate), and bridging.

References

  1. 1 2 3 Viola-Villegas, Nerissa; Doyle, Robert P (2009). "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. 253 (13–14): 1906. doi:10.1016/j.ccr.2009.03.013.
  2. 1 2 Stetter, Hermann; Wolfram Frank (1976). "Complex Formation with Tetraazacycloalkane-N,N',N'',N''';-tetraacetic Acids as a Function of Ring Size". Angewandte Chemie International Edition in English. 15 (11): 686. doi:10.1002/anie.197606861.
  3. Moi, Min K.; Claude F. Meares; Sally J. DeNardo (1988). "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". Journal of the American Chemical Society. 110 (18): 6266–6267. doi:10.1021/ja00226a063. PMID   22148823.
  4. Volkert, Wynn A.; Timothy J. Hoffman (1999). "Therapeutic Radiopharmaceuticals". Chemical Reviews. 99 (9): 2269–2292. doi:10.1021/cr9804386. PMID   11749482.
  5. "Statement On A Nonproprietary Name Adopted By The USAN Council: Yttrium Y90 clivatuzumab tetraxetan" (PDF). American Medical Association.
  6. Breeman, W. A. P.; De Blois, E.; Sze Chan, H.; Konijnenberg, M.; Kwekkeboom, D. J.; Krenning, E. P. (2011). "68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives". Seminars in Nuclear Medicine. 41 (4): 314–321. doi:10.1053/j.semnuclmed.2011.02.001. PMID   21624565.
  7. Domingo, R. J.; Reilly, R. M. (2000). "Pre-targeted radioimmunotherapy of human colon cancer xenografts in athymic mice using streptavidin-CC49 monoclonal antibody and 90Y-DOTA-biotin". Nuclear Medicine Communications. 21 (1): 89–96. doi:10.1097/00006231-200001000-00015. PMID   10717908.
  8. A Clinical Study of Gadoteric Acid in Non-Coronary Magnetic Resonance (MR) Angiography, 25 November 2008
  9. Knör, S; Modlinger, A; Poethko, T; Schottelius, M; Wester, HJ; Kessler, H (2007). "Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds". Chemistry: A European Journal. 13 (21): 6082–90. doi:10.1002/chem.200700231. PMID   17503419.