Somatostatin Receptor Analogs (68Ga-DOTATOC, 68Ga-DOTANOC, 68Ga-DOTATATE)

  • Luca Filippi
  • Patrizia Pizzichini
  • Oreste Bagni
  • Francesco Scopinaro


Neuroendocrine tumors (NETs) are rare neoplasms originating from neuroendocrine cells and characterized by the property of producing hormones and biogenic amines. NETs can present an indolent clinical course, thus diagnosis may be delayed when disease is at an advanced stage. A number of different techniques can be applied for NET diagnosis and localization: magnetic resonance, contrast-enhanced computed tomography, gastrointestinal endoscopy, and ultrasonography. Since NETs are known to overexpress somatostatin receptors, somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide has been widely used for NET diagnosis, staging and monitoring response to treatment. Nevertheless, conventional scintigraphic approach presents some limitations due to poor spatial resolution. Positron emission tomography (PET) with 18F-fluorodeoxyglucose has a limited role for the imaging of NETs that are slow-growing neoplasms with reduced expression of glucose transporter receptors. To overcome these drawbacks, three different radiopharmaceuticals binding to somatostatin receptors have been introduced: 68Ga-DOTA-Phe1-Tyr3-Octreotide (TOC), 68Ga-DOTA-NaI3-Octreotide (NOC), and 68Ga-DOTA-Tyr3-Octreotate (TATE). This chapter is aimed to review these 68Ga-DOTA-compounds with particular emphasis on their synthesis, pharmacokinetic/pharmacodynamic properties and on the clinical application in NETs diagnosis and follow-up.


Neuroendocrine tumors PET 18F-FDG 68Ga-DOTA-compounds 



Computed tomography


1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid




Magnetic resonance imaging


Neuroendocrine tumors


Positron emission tomography


Peptide receptor radionuclide therapy


Somatostatin receptor scintigraphy




  1. 1.
    Wadas TJ, Wong EH, Weisman GR, et al. Coordinating radiometals of copper, gallium, indium, yttrium, and zirconium for PET and SPECT imaging of disease. Chem Rev. 2010;110(5):2858–902.CrossRefGoogle Scholar
  2. 2.
    Antunes P, Ginj M, Zhang H, et al. The renaissance of the Ge/Ga radionuclide generator initiates new developments in Ga radiopharmaceutical chemistry. Curr Top Med Chem. 2010;10(16):1633–68.CrossRefGoogle Scholar
  3. 3.
    Breeman WA, De Jong M, Visser TJ, et al. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur J Nucl Med Mol Imaging. 2003;30(6):917–20.CrossRefGoogle Scholar
  4. 4.
    Antunes P, Ginj M, Zhang H, et al. Are radiogallium-labelled DOTA conjugated somatostatin analogues superior to those labelled with other radiometals? Eur J Nucl Med Mol Imaging. 2007;34(7):982–93.CrossRefGoogle Scholar
  5. 5.
    Breeman WA, de Blois E, Sze Chan H, et al. (68)Ga-labeled DOTA-peptides and (68)Ga-labeled radiopharmaceuticals for positron emission tomography: current status of research, clinical applications, and future perspectives. Semin Nucl Med. 2011;41(4):314–21.CrossRefGoogle Scholar
  6. 6.
    Reubi JC, Waser B, Schaer JC, et al. Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur J Nucl Med. 2001;28(7):836–46.CrossRefGoogle Scholar
  7. 7.
    Poeppel TD, Binse I, Petersenn S, et al. 68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors. J Nucl Med. 2011;52(12):1864–70.CrossRefGoogle Scholar
  8. 8.
    Hofmann M1, Maecke H, Börner R, et al. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001;28(12):1751–7.CrossRefGoogle Scholar
  9. 9.
    Prasad V, Baum RP. Biodistribution of the Ga-68 labeled somatostatin analogue DOTA-NOC in patients with neuroendocrine tumors: characterization of uptake in normal organs and tumor lesions. Q J Nucl Med Mol Imaging. 2010;54(1):61–7.PubMedGoogle Scholar
  10. 10.
    Reubi JC, Schaer JC, Markwalder R, et al. Distribution of somatostatin receptors in normal and neoplastic human tissues: recent advances and potential relevance. Yale J Biol Med. 1997;70(5–6):471–9.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Rindi G, Petrone G, Inzani F. The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction. Endocr Pathol. 2014;25(2):186–92.CrossRefGoogle Scholar
  12. 12.
    Sommer WH, Zech CJ, Bamberg F, et al. Fluid-fluid level in hepatic metastases: a characteristic sign of metastases of neuroendocrine origin. Eur J Radiol. 2012;81(9):2127–32.CrossRefGoogle Scholar
  13. 13.
    Sankowski AJ, Ćwikla JB, Nowicki M, et al. The clinical value of MRI using single-shot echoplanar DWI to identify liver involvement in patients with advanced gastroenteropancreatic-neuroendocrine tumors (GEP-NETs), compared to FSE T2 and FFE T1 weighted image after i.v. Gd-EOB-DTPA contrast enhancement. Med Sci Monit. 2012;18(5):MT33–40.CrossRefGoogle Scholar
  14. 14.
    Song YS, Lee WW, Chung JH, et al. Correlation between FDG uptake and glucose transporter type 1 expression in neuroendocrine tumors of the lung. Lung Cancer. 2008;61(1):54–60.CrossRefGoogle Scholar
  15. 15.
    Kowalski J, Henze M, Schuhmacher J, et al. Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe(1)-Tyr(3)-octreotide in comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol. 2003;5(1):42–8.CrossRefGoogle Scholar
  16. 16.
    Gabriel M, Decristoforo C, Kendler D, et al. 68Ga-DOTA-Tyr3-octreotide PET in neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and CT. J Nucl Med. 2007;48(4):508–18.CrossRefGoogle Scholar
  17. 17.
    Putzer D, Gabriel M, Henninger B, et al. Bone metastases in patients with neuroendocrine tumor: 68Ga-DOTA-Tyr3-octreotide PET in comparison to CT and bone scintigraphy. J Nucl Med. 2009;50(8):1214–21.CrossRefGoogle Scholar
  18. 18.
    Haug AR, Cindea-Drimus R, Auernhammer CJ, et al. The role of 68Ga-DOTATATE PET/CT in suspected neuroendocrine tumors. J Nucl Med. 2012;53(11):1686–92.CrossRefGoogle Scholar
  19. 19.
    Treglia G, Castaldi P, Rindi G, et al. Diagnostic performance of Gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis. Endocrine. 2012;42(1):80–7.CrossRefGoogle Scholar
  20. 20.
    Kabasakal L, Demirci E, Ocak M, et al. Comparison of 68Ga-DOTATATE and 68Ga-DOTANOC PET/CT imaging in the same patient group with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2012;39(8):1271–7.CrossRefGoogle Scholar
  21. 21.
    Wild D, Bomanji JB, Benkert P, et al. Comparison of 68Ga-DOTANOC and 68Ga-DOTATATE PET/CT within patients with gastroenteropancreatic neuroendocrine tumors. J Nucl Med. 2013;54(3):364–72.CrossRefGoogle Scholar
  22. 22.
    Boy C, Heusner TA, Poeppel TD, et al. 68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax. Eur J Nucl Med Mol Imaging. 2011;38(7):1224–36.CrossRefGoogle Scholar
  23. 23.
    Campana D, Ambrosini V, Pezzilli R, et al. Standardized uptake values of (68)Ga-DOTANOC PET: a promising prognostic tool in neuroendocrine tumors. J Nucl Med. 2010;51(3):353–9.CrossRefGoogle Scholar
  24. 24.
    Bodei L, Ferone D, Grana CM, et al. Peptide receptor therapies in neuroendocrine tumors. J Endocrinol Invest. 2009;32(4):360–9.. ReviewCrossRefGoogle Scholar
  25. 25.
    Bodei L, Pepe G, Paganelli G. Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors with somatostatin analogues. Eur Rev Med Pharmacol Sci. 2010;14(4):347–51.. ReviewPubMedGoogle Scholar
  26. 26.
    Falletta S, Partelli S, Rubini C, et al. mTOR inhibitors response and mTOR pathway in pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016. pii: ERC-16-0329Google Scholar
  27. 27.
    Kratochwil C, Stefanova M, Mavriopoulou E, et al. SUV of [68Ga]DOTATOC-PET/CT predicts response probability of PRRT in neuroendocrine tumors. Mol Imaging Biol. 2015;17(3):313–8.CrossRefGoogle Scholar
  28. 28.
    Haug AR, Auernhammer CJ, Wängler B, et al. 68Ga-DOTATATE PET/CT for the early prediction of response to somatostatin receptor-mediated radionuclide therapy in patients with well-differentiated neuroendocrine tumors. J Nucl Med. 2010;51(9):1349–56.CrossRefGoogle Scholar
  29. 29.
    Filippi L, Scopinaro F, Pelle G, et al. Molecular response assessed by (68)Ga-DOTANOC and survival after (90)Y microsphere therapy in patients with liver metastases from neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2016;43(3):432–40.CrossRefGoogle Scholar
  30. 30.
    Naji M, Zhao C, Welsh SJ, et al. 68Ga-DOTA-TATE PET vs. 123I-MIBG in identifying malignant neural crest tumours. Naji Mol Imaging Biol. 2011;13(4):769–75.CrossRefGoogle Scholar
  31. 31.
    Kroiss A, Shulkin BL, Uprimny C, et al. (68)Ga-DOTATOC PET/CT provides accurate tumour extent in patients with extraadrenal paraganglioma compared to (123)I-MIBG SPECT/CT. Eur J Nucl Med Mol Imaging. 2015;42(1):33–41.CrossRefGoogle Scholar
  32. 32.
    Rinzivillo M, Partelli S, Prosperi D, et al. Clinical usefulness of 18F-fluorodeoxyglucose positron emission tomography in the diagnostic algorithm of advanced Entero-pancreatic neuroendocrine neoplasms. Oncologist. 2018;23(2):186–92.CrossRefGoogle Scholar
  33. 33.
    Filippi L, Schillaci O, Cianni R, et al. Imaging neuroendocrine hepatic metastases following 90Y-Radioembolization: is it time to implement routine use of PET molecular/metabolic probes? Cardiovasc Intervent Radiol. 2019;42(6):933–4. Scholar
  34. 34.
    Kayani I, Bomanji JB, Groves A, et al. Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (Dota-DPhe1Tyr-octreotate) and 18F-FDG. Cancer. 2008;112(11):2447–55.CrossRefGoogle Scholar
  35. 35.
    Panagiotidis E, Alshammari A, Michopoulou S, et al. Comparison of the impact of 68Ga-DOTATATE and 18F-FDG PET/CT on clinical management in patients with neuroendocrine tumors. J Nucl Med. 2016. pii: jnumed.116.178095Google Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Luca Filippi
    • 1
  • Patrizia Pizzichini
    • 2
  • Oreste Bagni
    • 1
  • Francesco Scopinaro
    • 2
  1. 1.Department of Nuclear MedicineSanta Maria Goretti HospitalLatinaItaly
  2. 2.Department of Nuclear MedicineSant’Andrea HospitalRomeItaly

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