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 The lanthanide () or lanthanoid () series of chemical elements comprises the 15 metallic chemical elements with atomic numbers 57–71, from lanthanum through lutetium. These elements, along with the chemically similar elements scandium and yttr ...

ions. Its complexes have medical applications as contrast agents and cancer treatments.

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 A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many ...

, the tetraacid is called H₄DOTA and its fully deprotonated derivative is DOTA⁴⁻. Many related ligands are referred to using the DOTA acronym, although these derivatives are generally not ''tetra''carboxylic acids or the conjugate bases.

Structure

DOTA is derived from the

macrocycle Macrocycles are often described as molecules and ions containing a ring of twelve or more atoms. Classical examples include the crown ethers, calixarenes, porphyrins, and cyclodextrins. Macrocycles describe a large, mature area of chemistry. ...

known as

cyclen Cyclen (1,4,7,10-tetraazacyclododecane) is a aza-crown ether with the formula (CH2CH2NH)4. It is a white solid. Synthesis Some syntheses exploit the Thorpe-Ingold effect to facilitate ring-formation. Illustrative is the reaction of the depro ...

. The four secondary amine groups are modified by replacement of the N-H centers with N-CH₂CO₂H groups. The resulting

aminopolycarboxylic acid left, 120px, a metal complex with the EDTA anion 120px, Aspartic acid is an aminodicarboxylic acid and precursor to other ligands. An aminopolycarboxylic acid (sometimes abbreviated APCA) is a chemical compound containing one or more nitrogen at ...

, upon ionization of the carboxylic acid groups, is a high affinity chelating agent for di- and tri valent cations. The tetracarboxylic acid was first reported in 1976. At the time of its discovery DOTA exhibited the largest known formation constant for the complexation (

chelating 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 Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...

) of Ca²⁺ and Gd³⁺ ions. Modified versions of DOTA were first reported in 1988 and this area has proliferated since. 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. For most transition metals, DOTA functions as a

hexadentate ligand A hexadentate ligand in coordination chemistry is a ligand that combines with a central metal atom with six bonds. One example of a hexadentate ligand that can form complexes with soft metal ions is TPEN. A commercially important hexadentate ligan ...

, binding through the four nitrogen and two carboxylate centres. The complexes have

octahedral coordination geometry In chemistry, octahedral molecular geometry, also called square bipyramidal, describes the shape of compounds with six atoms or groups of atoms or ligands symmetrically arranged around a central atom, defining the vertices of an octahedron. The oc ...

, with two pendent carboxylate groups. In the case of e(DOTA)sup>−, the ligand is heptadentate.

Uses

Cancer treatment and diagnosis

DOTA can be conjugated to

monoclonal antibodies A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...

by attachment of one of the four carboxyl groups as an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

. The remaining three

carboxylate anion In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...

s 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'': * Yttrium (⁹⁰Y) clivatuzumab tetraxetan * Yttrium (⁹⁰Y) tacatuzumab tetraxetan 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 Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bl ...

). * Affinity for

somatostatin receptor Somatostatin receptors are receptors for the ligand somatostatin, a small neuropeptide associated with neural signaling, particularly in the post-synaptic response to NMDA receptor co-stimulation/activation. Somatostatin is encoded by a CRE ...

s, which are found on

neuroendocrine tumour Neuroendocrine tumors (NETs) are neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of t ...

s: **

DOTATOC Edotreotide (USAN, also known as (DOTA0- Phe1- Tyr3) octreotide, DOTA-TOC, DOTATOC) is a substance which, when bound to various radionuclides, is used in the treatment and diagnosis of certain types of cancer. When used therapeutically it is an e ...

, DOTA-(Tyr³)-octreotide or edotreotide **

DOTA-TATE DOTA-TATE (DOTATATE, DOTA-octreotate, oxodotreotide, DOTA-(Tyr3)-octreotate, and DOTA-0-Tyr3-Octreotate) is an eight amino acid long peptide, with a covalently bonded DOTA bifunctional chelator. DOTA-TATE can be reacted with the radionuclides ...

or DOTA-(Tyr³)-octreotate * Affinity for the proteins

streptavidin Streptavidin is a 66.0 (tetramer) kDa protein purified from the bacterium '' Streptomyces avidinii''. Streptavidin homo-tetramers have an extraordinarily high affinity for biotin (also known as vitamin B7 or vitamin H). With a dissociation co ...

and

avidin 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 ...

, which can be targeted at tumours by aid of monoclonal antibodies: **

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 studi ...

File:Y-90 tacatuzumab tetraxetan structure.svg, DOTA linked to the monoclonal antibody

tacatuzumab Yttrium (90Y) tacatuzumab tetraxetan (trade name AFP-Cide) is a humanized monoclonal antibody intended for the treatment of cancer. The antibody itself, tacatuzumab, is conjugated with tetraxetan, a chelator for yttrium-90, a radioisotope A ra ...

and chelating

yttrium-90 Yttrium-90 () is an isotope of yttrium. Yttrium-90 has found a wide range of uses in radiation therapy to treat some forms of cancer. Decay undergoes β− decay to zirconium-90 with a half-life of 64.1 hours and a decay energy of 2.28 ...

File:Yttrium-90 edotreotide.svg,

chelating yttrium-90 File:DOTATATE.svg,

Contrast agent

The complex of Gd³⁺ and DOTA is used as a

gadolinium-based MRI contrast agent MRI contrast agents are contrast agents used to improve the visibility of internal body structures in magnetic resonance imaging (MRI). The most commonly used compounds for contrast enhancement are gadolinium-based. Such MRI contrast agents shorten ...

under the name

gadoteric acid Gadoteric acid, sold under the brand name Dotarem among others, is a macrocycle-structured gadolinium-based MRI contrast agent (GBCA). It consists of the organic acid DOTA as a chelating agent, and gadolinium (Gd3+), and is used in form of the ...

Synthesis

DOTA was first synthesized in 1976 from

and

bromoacetic acid Bromoacetic acid is the chemical compound with the formula CH2BrCO2H. This colorless solid is a relatively strong alkylating agent. Bromoacetic acid and its esters are widely used building blocks in organic synthesis, for example, in pharmaceuti ...

. This method is simple and still in use.

References

{{reflist, 30em Carboxylic acids Macrocycles Chelating agents Octadentate ligands Substances discovered in the 1970s