DOTA-TATE (DOTATATE, DOTA-octreotate, oxodotreotide, DOTA-(Tyr³)-octreotate, and DOTA-0-Tyr3-Octreotate) is an eight

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

long

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

, with a

covalently A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

bonded

DOTA ''Dota'' is a series of strategy video games by Valve. The series began in 2003 with the release of ''Defense of the Ancients'' (''DotA''), a fan-developed multiplayer online battle arena (MOBA) mod for the video game '' Warcraft III: Reign of ...

bifunctional chelator. DOTA-TATE can be reacted with the

radionuclide A radionuclide (radioactive nuclide, radioisotope or radioactive isotope) is a nuclide that has excess nuclear energy, making it unstable. This excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transfer ...

gallium-68 Natural gallium (31Ga) consists of a mixture of two stable isotopes: gallium-69 and gallium-71. The most commercially important radioisotopes are gallium-67 and gallium-68. Gallium-67 (half-life 3.3 days) is a gamma-emitting isotope (the gamma r ...

(T_1/2 = 68 min),

lutetium-177 Naturally occurring lutetium (71Lu) is composed of one stable isotope 175Lu (97.41% natural abundance) and one long-lived radioisotope, 176Lu with a half-life of 3.78 × 1010 years (2.59% natural abundance). Thirty-five radioisotopes have been ch ...

(T_1/2 = 6.65 d) and

copper-64 Copper-64 (64Cu) is a positron and beta emitting isotope of copper, with applications for molecular radiotherapy and positron emission tomography. Its unusually long half-life (12.7-hours) for a positron-emitting isotope makes it increasingly us ...

(T_1/2 = 12.7 h) to form

radiopharmaceutical Radiopharmaceuticals, or medicinal radiocompounds, are a group of pharmaceutical drugs containing radioactive isotopes. Radiopharmaceuticals can be used as diagnostic and therapeutic agents. Radiopharmaceuticals emit radiation themselves, which is ...

s for

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 ...

(PET) imaging or

radionuclide therapy Radionuclide therapy (RNT, also known as unsealed source radiotherapy or molecular radiotherapy) uses radioactive substances called radiopharmaceuticals to treat medical conditions, particularly cancer. These are introduced into the body by vario ...

. ¹⁷⁷Lu DOTA-TATE therapy is a form of

peptide receptor radionuclide therapy 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). Mechanism A key advantage of ...

(PRRT) which targets

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 (SSR). In that form of application it is a form of

targeted drug delivery Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. This means of delivery is la ...

Chemistry and mechanism of action

DOTA-TATE is a compound containing tyrosine³-octreotate, an SSR agonist, and the bifunctional chelator

(tetraxetan). SSRs are found with high density in numerous

malignancies Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

, including CNS,

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...

lung The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

, and

lymphatics The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph vessel ...

. The role of SSR agonists (i.e. somatostatin and its analogs such as

octreotide Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was ...

somatuline Lanreotide, sold under the brand name Somatuline among others, is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, li ...

and

vapreotide Vapreotide (Sanvar) is a synthetic somatostatin analog. It is used in the treatment of esophageal variceal bleeding in patients with cirrhotic liver disease and AIDS-related diarrhea Diarrhea, also spelled diarrhoea, is the condition of ...

) in

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 (NETs) is well established, and massive SSR overexpression is present in several NETs. ( Tyr³)-octreotate binds the

transmembrane receptors Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

of NETs with highest activity for

SSR2 Translocon-associated protein subunit beta also known as TRAP-beta is a protein that in humans is encoded by the ''SSR2'' gene. Function The signal sequence receptor (SSR) is a glycosylated endoplasmic reticulum (ER) membrane receptor associ ...

and is actively transported into the cell via

endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...

, allowing trapping of the radioactivity and increasing the probability of the desired double-strand DNA breakage (for tumour control). Trapping improves the probability of this kind of effect due to the relatively short range of the

beta particles A beta particle, also called beta ray or beta radiation (symbol β), is a high-energy, high-speed electron or positron emitted by the radioactive decay of an atomic nucleus during the process of beta decay. There are two forms of beta decay, β� ...

emitted by ¹⁷⁷Lu, which have a maximum range in tissue of <2 mm. Bystander effects include cellular damage by

free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Ailments of unknown cause Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabo ...

formation.

Clinical applications

Gallium-68 DOTA-TATE

⁶⁸Ga DOTA-TATE (gallium-68 dotatate, GaTate) is used to measure tumor SSR density and wholebody bio-distribution via PET imaging. ⁶⁸Ga DOTA-TATE imagery has a much higher sensitivity and resolution compared to ¹¹¹In octreotide gamma camera or

SPECT Single-photon emission computed tomography (SPECT, or less commonly, SPET) is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera (that is, ...

scans, due to intrinsic modality differences.

Copper-64 DOTA-TATE

Copper (⁶⁴Cu) oxodotreotide or copper Cu 64 dotatate, sold under the brand name

Detectnet Copper (64Cu) oxodotreotide or Copper Cu 64 dotatate, sold under the brand name Detectnet, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroe ...

, is a radioactive diagnostic agent indicated for use with

(PET) for localization of somatostatin receptor positive

neuroendocrine tumors Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung ...

(NETs) in adults. It was FDA approved in September 2020. These are the same indications for as the gallium DOTA-TATE scans, but Cu-64 has advantages over Ga-68 in having a 12-hour half life rather than the much shorter one-hour half life of Ga-68, making it easier to transport from central production locations.

Lutetium-177 DOTA-TATE

The combination of the

beta emitter In nuclear physics, beta decay (β-decay) is a type of radioactive decay in which a beta particle (fast energetic electron or positron) is emitted from an atomic nucleus, transforming the original nuclide to an isobar of that nuclide. For exam ...

¹⁷⁷Lu with DOTA-TATE can be used in the treatment of

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

s expressing the relevant somatostatin receptors. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) considers ¹⁷⁷Lu-dotatate to be a

first-in-class medication A first-in-class medication is a pharmaceutical that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medicat ...

. Alternatives to ¹⁷⁷Lu-DOTA-TATE include ⁹⁰Y (T_1/2 = 64.6 h) DOTA-TATE. The longer penetration range in the target tissues of the more energetic

beta particle A beta particle, also called beta ray or beta radiation (symbol β), is a high-energy, high-speed electron or positron emitted by the radioactive decay of an atomic nucleus during the process of beta decay. There are two forms of beta decay, β� ...

s emitted by ⁹⁰Y (high average beta energy of 0.9336 MeV) could make it more suitable for large tumors while ¹⁷⁷Lu would be preferred for smaller volume tumors.

References