DOTA-TATE

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DOTA-TATE
DOTATATE.svg
Names
Other names
DOTA-(Tyr3)-octreotate
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C65H90N14O19S2/c1-38(80)56-64(96)73-51(63(95)75-57(39(2)81)65(97)98)37-100-99-36-50(72-59(91)47(28-40-10-4-3-5-11-40)68-52(83)32-76-20-22-77(33-53(84)85)24-26-79(35-55(88)89)27-25-78(23-21-76)34-54(86)87)62(94)70-48(29-41-15-17-43(82)18-16-41)60(92)71-49(30-42-31-67-45-13-7-6-12-44(42)45)61(93)69-46(58(90)74-56)14-8-9-19-66/h3-7,10-13,15-18,31,38-39,46-51,56-57,67,80-82H,8-9,14,19-30,32-37,66H2,1-2H3,(H,68,83)(H,69,93)(H,70,94)(H,71,92)(H,72,91)(H,73,96)(H,74,90)(H,75,95)(H,84,85)(H,86,87)(H,88,89)(H,97,98)/t38-,39-,46+,47-,48+,49-,50+,51+,56+,57+/m1/s1
    Key: QVFLVLMYXXNJDT-CSBVGUNJSA-N
  • InChI=1/C65H90N14O19S2/c1-38(80)56-64(96)73-51(63(95)75-57(39(2)81)65(97)98)37-100-99-36-50(72-59(91)47(28-40-10-4-3-5-11-40)68-52(83)32-76-20-22-77(33-53(84)85)24-26-79(35-55(88)89)27-25-78(23-21-76)34-54(86)87)62(94)70-48(29-41-15-17-43(82)18-16-41)60(92)71-49(30-42-31-67-45-13-7-6-12-44(42)45)61(93)69-46(58(90)74-56)14-8-9-19-66/h3-7,10-13,15-18,31,38-39,46-51,56-57,67,80-82H,8-9,14,19-30,32-37,66H2,1-2H3,(H,68,83)(H,69,93)(H,70,94)(H,71,92)(H,72,91)(H,73,96)(H,74,90)(H,75,95)(H,84,85)(H,86,87)(H,88,89)(H,97,98)/t38-,39-,46+,47-,48+,49-,50+,51+,56+,57+/m1/s1
    Key: QVFLVLMYXXNJDT-CSBVGUNJBN
  • C[C@H]([C@H]1C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N[C@H](C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)[C@@H](CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)O)CC(=O)O)CC(=O)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)O
Properties
C65H90N14O19S2
Molar mass 1435.63 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

DOTA-TATE (DOTATATE, [1] DOTA-octreotate, oxodotreotide, DOTA-(Tyr3)-octreotate, [2] 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 gallium-68 (T1/2 = 68 min), lutetium-177 (T1/2 = 6.65 d) and copper-64 (T1/2 = 12.7 h) to form radiopharmaceuticals for positron emission tomography (PET) imaging or radionuclide therapy. 177Lu DOTA-TATE therapy is a form of peptide receptor radionuclide therapy (PRRT) which targets somatostatin receptors (SSR). [3] [4] In that form of application it is a form of targeted drug delivery.

Chemistry and mechanism of action

DOTA-TATE is a compound containing tyrosine3-octreotate, [2] an SSR agonist, and the bifunctional chelator DOTA (tetraxetan). [5] [6] SSRs are found with high density in numerous malignancies, including CNS, breast, lung, and lymphatics. [7] The role of SSR agonists (i.e. somatostatin and its analogs such as octreotide, somatuline and vapreotide) in neuroendocrine tumours (NETs) is well established, [8] and massive SSR overexpression is present in several NETs. (Tyr 3)-octreotate binds the transmembrane receptors of NETs with highest activity for SSR2 and is actively transported into the cell via endocytosis, 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 emitted by 177Lu, which have a maximum range in tissue of <2 mm. [9] [8] [10] Bystander effects include cellular damage by free radical formation.

Clinical applications

Gallium-68 DOTA-TATE

68Ga DOTA-TATE (gallium-68 dotatate, GaTate) is used to measure tumor SSR density and whole-body bio-distribution via PET imaging. [11] [12] 68Ga DOTA-TATE imagery has a much higher sensitivity and resolution compared to 111In octreotide gamma camera or SPECT scans, due to intrinsic modality differences. [11] It is commonly used to confirm the presence of paragangliomas and pheochromocytomas. [13]

Copper-64 DOTA-TATE

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 neuroendocrine tumors (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. [14] [15]

Lutetium-177 DOTA-TATE

The combination of the beta emitter 177Lu with DOTA-TATE can be used in the treatment of cancers expressing the relevant somatostatin receptors. [16] The U.S. Food and Drug Administration (FDA) considers 177Lu-dotatate to be a first-in-class medication. [17]

Alternatives to 177Lu-DOTA-TATE include 90Y (T1/2 = 64.6 h) DOTA-TATE. The longer penetration range in the target tissues of the more energetic beta particles 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. [18] [19]

See also

Related Research Articles

Natural gallium (31Ga) consists of a mixture of two stable isotopes: gallium-69 and gallium-71. Twenty-nine radioisotopes are known, all synthetic, with atomic masses ranging from 56 to 86; along with three nuclear isomers, 64mGa, 72mGa and 74mGa. Most of the isotopes with atomic mass numbers below 69 decay to isotopes of zinc, while most of the isotopes with masses above 71 decay to isotopes of germanium. Among them, the most commercially important radioisotopes are gallium-67 and gallium-68.

A gallium scan is a type of nuclear medicine test that uses either a gallium-67 (67Ga) or gallium-68 (68Ga) radiopharmaceutical to obtain images of a specific type of tissue, or disease state of tissue. Gallium salts like gallium citrate and gallium nitrate may be used. The form of salt is not important, since it is the freely dissolved gallium ion Ga3+ which is active. Both 67Ga and 68Ga salts have similar uptake mechanisms. Gallium can also be used in other forms, for example 68Ga-PSMA is used for cancer imaging. The gamma emission of gallium-67 is imaged by a gamma camera, while the positron emission of gallium-68 is imaged by positron emission tomography (PET).

<span class="mw-page-title-main">Neuroendocrine tumor</span> Medical condition

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, and the rest of the body.

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 useful when attached to various ligands, for PET and PET-CT scanning.

<span class="mw-page-title-main">Octreotide scan</span> Type of medical imaging

An octreotide scan is a type of SPECT scintigraphy used to find carcinoid, pancreatic neuroendocrine tumors, and to localize sarcoidosis. It is also called somatostatin receptor scintigraphy (SRS). Octreotide, a drug similar to somatostatin, is radiolabeled with indium-111, and is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A gamma camera detects the radioactive octreotide, and makes pictures showing where the tumor cells are in the body, typically by a SPECT technique. A technetium-99m based radiopharmaceutical kit is also available.

<span class="mw-page-title-main">DOTA (chelator)</span> Chemical compound

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.

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

Minigastrin is a form of gastrin. Its sequence is H-Leu-Glu-Glu-Glu-Glu-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2.

A germanium-68/gallium-68 generator is a device used to extract the positron-emitting isotope 68Ga of gallium from a source of decaying germanium-68. The parent isotope 68Ge has a half-life of 271 days and can be easily utilized for in-hospital production of generator produced 68Ga. Its decay product gallium-68 is extracted and used for certain positron emission tomography nuclear medicine diagnostic procedures, where the radioisotope's relatively short half-life and emission of positrons for creation of 3-dimensional PET scans, are useful.

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

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 example of peptide receptor radionuclide therapy.

Advanced Accelerator Applications is a France-based pharmaceutical group, specialized in the field of nuclear medicine. The group operates in all three segments of nuclear medicine to diagnose and treat serious conditions in the fields of oncology, neurology, cardiology, infectious and inflammatory diseases.

Sandip Basu is an Indian physician of Nuclear Medicine and the Head, Nuclear Medicine Academic Program at the Radiation Medicine Centre. He is also the Dean-Academic (Health-Sciences), BARC at Homi Bhabha National Institute and is known for his services and research in Nuclear Medicine, particularly on Positron emission tomography diagnostics and Targeted Radionuclide Therapy in Cancer. The Council of Scientific and Industrial Research, the apex agency of the Government of India for scientific research, awarded him the Shanti Swarup Bhatnagar Prize for Science and Technology, one of the highest Indian science awards for his contributions to Nuclear Medicine in 2012.

<span class="mw-page-title-main">Andreas Kjær (scientist)</span> Danish physician-scientist

Andreas Kjær is a Danish physician-scientist and European Research Council (ERC) advanced grantee. He is professor at the University of Copenhagen and chief physician at Rigshospitalet, the National University Hospital of Denmark. He is board certified in Nuclear Medicine and his research is focused on molecular imaging with PET and PET/MRI and targeted radionuclide therapies (theranostics) in cancer. His achievements include development of several new PET tracers that have reached first-in-human clinical use. He has published more than 400 peer-review articles, filed 10 patents, supervised more than 40 PhD students and received numerous prestigious scientific awards over the years. He is a member of the Danish Academy of Technical Sciences

A PSMA scan is a nuclear medicine imaging technique used in the diagnosis and staging of prostate cancer. It is carried out by injection of a radiopharmaceutical with a positron or gamma emitting radionuclide and a prostate-specific membrane antigen (PSMA) targeting ligand. After injection, imaging of positron emitters such as gallium-68 (68Ga), copper-64 (64Cu), and fluorine-18 (18F) is carried out with a positron emission tomography (PET) scanner. For gamma emitters such as technetium-99m (99mTc) and indium-111 (111In) single-photon emission computed tomography (SPECT) imaging is performed with a gamma camera.

<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).

Lutetium (<sup>177</sup>Lu) oxodotreotide Chelate of Lu-177 with DOTA-TATE, a peptide derivative bound to a DOTA molecule

Lutetium (177Lu) oxodotreotide (INN) or 177Lu DOTA-TATE, trade name Lutathera, is a chelated complex of a radioisotope of the element lutetium with DOTA-TATE, used in peptide receptor radionuclide therapy (PRRT). Specifically, it is used in the treatment of cancers which express somatostatin receptors.

Jamshed Bomanji is a full professor, clinical lead, and head of the Institute of Nuclear medicine department at the University College Hospital (UCLH) NHS foundation trust based in London, UK.

Copper (<sup>64</sup>Cu) oxodotreotide Radioactive diagnostic agent used in PET scan to localize tumors

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 neuroendocrine tumors (NETs) in adults.

Gallium (<sup>68</sup>Ga) gozetotide Radiopharmaceutical medication

Gallium (68Ga) gozetotide or Gallium (68Ga) PSMA-11 sold under the brand name Illuccix among others, is a radiopharmaceutical made of 68Ga conjugated to prostate-specific membrane antigen (PSMA) targeting ligand, Glu-Urea-Lys(Ahx)-HBED-CC, used for imaging prostate cancer by positron emission tomography (PET). The PSMA targeting ligand specifically directs the radiolabeled imaging agent towards the prostate cancerous lesions in men.

<span class="mw-page-title-main">Somatostatin receptor antagonist</span> Class of chemical compounds

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans are sstr1, 2A, 2 B, 3, 4 and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas and hepatocellular carcinomas.

<span class="mw-page-title-main">Somatostatin inhibitor</span> Class of pharmaceuticals

Somatostatin receptor antagonists are a class of chemical compounds that work by imitating the structure of the neuropeptide somatostatin, which is an endogenous hormone found in the human body. The somatostatin receptors are G protein-coupled receptors. Somatostatin receptor subtypes in humans include sstr1, 2A, 2 B, 3, 4, and 5. While normally expressed in the gastrointestinal (GI) tract, pancreas, hypothalamus, and central nervous system (CNS), they are expressed in different types of tumours. The predominant subtype in cancer cells is the ssrt2 subtype, which is expressed in neuroblastomas, meningiomas, medulloblastomas, breast carcinomas, lymphomas, renal cell carcinomas, paragangliomas, small cell lung carcinomas, and hepatocellular carcinomas.

References

  1. ↑ Nockel P, Millo C, Keutgen X, Klubo-Gwiezdzinska J, Shell J, Patel D, Nilubol N, Herscovitch P, Sadowski SM, Kebebew E (June 2016). "The Rate and Clinical Significance of Incidental Thyroid Uptake as Detected by Gallium-68 DOTATATE Positron Emission Tomography/Computed Tomography". Thyroid. 26 (6): 831–5. doi:10.1089/thy.2016.0174. PMC   4913484 . PMID   27094616.
  2. 1 2 Pubchem. "[Tyr3]octreotate". pubchem.ncbi.nlm.nih.gov. Retrieved 2 April 2018.
  3. ↑ Papotti, M.; Herder, W. W. de (2015). Neuroendocrine Tumors: A Multidisciplinary Approach. Karger Medical and Scientific Publishers. p. 77. ISBN   9783318027730.
  4. ↑ Aktolun, Cumali; Goldsmith, Stanley J. (2012). Nuclear Medicine Therapy: Principles and Clinical Applications. Springer. p. 364. ISBN   9781461440215.
  5. ↑ Pubchem. "Tetraxetan". pubchem.ncbi.nlm.nih.gov. Retrieved 2 April 2018.
  6. ↑ Fani M, Nicolas GP, Wild D (September 2017). "Somatostatin Receptor Antagonists for Imaging and Therapy". Journal of Nuclear Medicine. 58 (Suppl 2): 61S–66S. doi: 10.2967/jnumed.116.186783 . PMID   28864614.
  7. ↑ Reubi JC, Laissue JA (March 1995). "Multiple actions of somatostatin in neoplastic disease". Trends in Pharmacological Sciences. 16 (3): 110–5. doi:10.1016/S0165-6147(00)88992-0. PMID   7792931.
  8. 1 2 Mazziotti G, Mosca A, Frara S, Vitale G, Giustina A (November 2017). "Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects". Expert Opinion on Pharmacotherapy. 18 (16): 1679–1689. doi:10.1080/14656566.2017.1391217. PMID   29067877. S2CID   46747267.
  9. ↑ Emmett L, Willowson K, Violet J, Shin J, Blanksby A, Lee J (March 2017). "177 PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy". Journal of Medical Radiation Sciences. 64 (1): 52–60. doi:10.1002/jmrs.227. PMC   5355374 . PMID   28303694.
  10. ↑ Reubi JC, Schonbrunn A (December 2013). "Illuminating somatostatin analog action at neuroendocrine tumor receptors". Trends in Pharmacological Sciences. 34 (12): 676–88. doi:10.1016/j.tips.2013.10.001. PMC   3883302 . PMID   24183675.
  11. 1 2 Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ (February 2012). "High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours". Journal of Medical Imaging and Radiation Oncology. 56 (1): 40–7. doi: 10.1111/j.1754-9485.2011.02327.x . PMID   22339744. S2CID   21843609.
  12. ↑ Breeman WA, de Blois E, Sze Chan H, Konijnenberg M, Kwekkeboom DJ, Krenning EP (July 2011). "(68)Ga-labeled DOTA-peptides and (68)Ga-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.
  13. ↑ Chang, Chian A.; Pattison, David A.; Tothill, Richard W.; Kong, Grace; Akhurst, Tim J.; Hicks, Rodney J.; Hofman, Michael S. (17 August 2016). "68Ga-DOTATATE and 18F-FDG PET/CT in Paraganglioma and Pheochromocytoma: utility, patterns and heterogeneity". Cancer Imaging. 16 (1): 22. doi: 10.1186/s40644-016-0084-2 . ISSN   1740-5025. PMC   4989291 . PMID   27535829.
  14. ↑ "FDA approval letter" (PDF). 3 September 2020. Retrieved 5 September 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  15. ↑ "RadioMedix and Curium Announce FDA Approval of Detectnet (copper Cu 64 dotatate injection) in the U.S." (Press release). Curium. 8 September 2020. Retrieved 9 September 2020– via GlobeNewswire.
  16. ↑ Wang L, Tang K, Zhang Q, Li H, Wen Z, Zhang H, Zhang H (2013). "Somatostatin receptor-based molecular imaging and therapy for neuroendocrine tumors". BioMed Research International. 2013: 102819. doi: 10.1155/2013/102819 . PMC   3784148 . PMID   24106690.
  17. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  18. ↑ Ramage JK, Ahmed A, Ardill J, Bax N, Breen DJ, Caplin ME, et al. (January 2012). "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)". Gut. 61 (1): 6–32. doi:10.1136/gutjnl-2011-300831. PMC   3280861 . PMID   22052063.
  19. ↑ Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O'Dorisio MS, O'Dorisio TM, O'Dorisiol TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ (May 2013). "The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours". European Journal of Nuclear Medicine and Molecular Imaging. 40 (5): 800–16. doi:10.1007/s00259-012-2330-6. PMC   3622744 . PMID   23389427.
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