DOTA-TATE

DOTA-TATE
Names
Other names
DOTA-(Tyr3)-octreotate
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
PubChem CID
UNII
InChI
  • 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
SMILES
  • 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
Chemical formula
 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).
Infobox references

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. (Tyr3)-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 wholebody 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]

Lutetium-177 DOTA-TATE

The combination of the beta emitter 177Lu with DOTA-TATE (also known as edotreotide or DOTA-TOC) can be used in the treatment of cancers expressing the relevant somatostatin receptors.[13] The U.S. Food and Drug Administration (FDA) considers 177Lu-dotatate to be a first-in-class medication.[14]

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.[15][16]

See also

References

  1. ↑ Nockel P, Millo C, Keutgen X, Klubo-Gwiezdzinska J, Shell J, Patel D, et al. (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.
  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): 314–21. doi:10.1053/j.semnuclmed.2011.02.001. PMID 21624565.
  13. ↑ 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.
  14. ↑ New Drug Therapy Approvals 2018 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2019. Retrieved 16 September 2020.
  15. ↑ 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.
  16. ↑ Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O'Dorisio MS, et al. (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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