Development and evaluation of [64Cu]Cu-DOTATATE for clinical applications

Document Type : Original Article

Authors

1 Radiation Application Research School, Nuclear Science and Technology Research Institute, Tehran, Iran

2 Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Introduction: Peptide-based radiopharmaceuticals have great advantages that make them one of the most interesting radiotracers for theranostic applications. This study aims to develop [64Cu]Cu-DOTATATE as a beneficial agent for PET imaging of neuroendocrine tumors (NETs).
Methods: 64Cu was produced via 68Zn(p,αn)64Cu reaction using 30 MeV Cyclotron. [64Cu]Cu-DOTATATE was prepared at optimized labeling conditions by varying parameters. The radiochemical purity of [64Cu]Cu-DOTATATE was checked by various methods. The stability of the final radiolabeled compound was assessed in PBS buffer and human serum. Binding affinity and internalization rate of [64Cu]Cu-DOTATATE were studied on the Rat C6 glioma cell line.  The biodistribution of [64Cu]Cu-DOTATATE was studied in normal and tumor-bearing rats at different intervals. Finally, the images were taken after the administration of the radiopharmaceutical by a dual-head SPECT system.
Results: [64Cu]Cu-DOTATATE was produced with radiochemical purity >99% (RTLC & HPLC) and specific activity of 22.4 GBq/mg in optimized conditions. [64Cu]Cu-DOTATATE demonstrated high stability in vitro and in vivo. The binding studies showed a high binding affinity of the radiopharmaceutical to somatostatin-receptor-expressing cells. The internalization studies showed >58% of the radiopharmaceutical is internalized into the C6 cells within 6 h after incubation. The biodistribution of [64Cu]Cu-DOTATATE in normal and tumor-bearing rats showed high uptake of somatostatin-receptor-expressing organs and tumors, respectively. The images of tumor-bearing rats were consistent with the results of the biodistribution study.
Conclusion: Preclinical studies of [64Cu]Cu-DOTATATE showed that the radiopharmaceutical has a high potential for domestic use in  PET imaging of patients with NETs.

Keywords

Main Subjects

References

  1. Historical Timeline, Society of nuclear medicine and molecular imaging [cited 2023 March 16]. Available from "http://www.snm.org/index.cfm?PageID=1107"
  2. Sakulpisuti C, Charoenphun P, Chamroonrat W. Positron emission tomography radiopharmaceuticals in differentiated thyroid cancer. Molecules. 2022 Aug 3;27(15):4936.
  3. Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJ, van Eijck CH, Valkema R, de Jong M, de Herder WW, Krenning EP. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010 Jan 29;17(1):R53-73.
  4. Krenning EP, Bakker WH, Breeman WA, Koper JW, Kooij PP, Ausema L, Lameris JS, Reubi JC, Lamberts SW. Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin. Lancet. 1989 Feb 4;1(8632):242-4.
  5. Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993 Aug;20(8):716-31.
  6. Virgolini I, Ambrosini V, Bomanji JB, Baum RP, Fanti S, Gabriel M, Papathanasiou ND, Pepe G, Oyen W, De Cristoforo C, Chiti A. Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging. 2010 Oct;37(10):2004-10.
  7. Hofmann M, Maecke H, Börner R, Weckesser E, Schöffski P, Oei L, Schumacher J, Henze M, Heppeler A, Meyer J, Knapp H. Biokinetics and imaging with the somatostatin receptor PET radioligand (68)Ga-DOTATOC: preliminary data. Eur J Nucl Med. 2001 Dec;28(12):1751-7.
  8. Thakur ML, Kolan H, Li J, Wiaderkiewicz R, Pallela VR, Duggaraju R, Schally AV. Radiolabeled somatostatin analogs in prostate cancer. Nucl Med Biol. 1997 Jan;24(1):105-13.
  9. Yang H, Gao F, McNeil B, Zhang C, Yuan Z, Zeisler S, Kumlin J, Zeisler J, Bénard F, Ramogida C, Schaffer P. Synthesis of DOTA-pyridine chelates for 64Cu coordination and radiolabeling of αMSH peptide. EJNMMI Radiopharm Chem. 2021 Jan 13;6(1):3.
  10. Grassi I, Nanni C, Cicoria G, Blasi C, Bunkheila F, Lopci E, Colletti PM, Rubello D, Fanti S. Usefulness of 64Cu-ATSM in head and neck cancer: a preliminary prospective study. Clin Nucl Med. 2014 Jan;39(1):e59-63.
  11. Lopci E, Grassi I, Rubello D, Colletti PM, Cambioli S, Gamboni A, Salvi F, Cicoria G, Lodi F, Dazzi C, Mattioli S, Fanti S. Prognostic evaluation of disease outcome in solid tumors investigated with 64Cu-ATSM PET/CT. Clin Nucl Med. 2016 Feb;41(2):e87-92.
  12. Sasada S, Kurihara H, Kinoshita T, Yoshida M, Honda N, Shimoi T, Shimomura A, Yunokawa M, Yonemori K, Shimizu C, Hamada A, Kanayama Y, Watanabe Y, Fujiwara Y, Tamura K. 64Cu-DOTA-trastuzumab PET imaging for HER2-specific primary lesions of breast cancer. Ann Oncol. 2017 Aug 1;28(8):2028-9.
  13. Mortimer JE, Bading JR, Colcher DM, Conti PS, Frankel PH, Carroll MI, Tong S, Poku E, Miles JK, Shively JE, Raubitschek AA. Functional imaging of human epidermal growth factor receptor 2-positive metastatic breast cancer using (64)Cu-DOTA-trastuzumab PET. J Nucl Med. 2014 Jan;55(1):23-9.
  14. Song IH, Lee TS, Park YS, Lee JS, Lee BC, Moon BS, An GI, Lee HW, Kim KI, Lee YJ, Kang JH, Lim SM. Immuno-PET Imaging and Radioimmunotherapy of 64Cu-/177Lu-Labeled Anti-EGFR Antibody in Esophageal Squamous Cell Carcinoma Model. J Nucl Med. 2016 Jul;57(7):1105-11.
  15. Riisbro R, Christensen IJ, Piironen T, Greenall M, Larsen B, Stephens RW, Han C, Høyer-Hansen G, Smith K, Brünner N, Harris AL. Prognostic significance of soluble urokinase plasminogen activator receptor in serum and cytosol of tumor tissue from patients with primary breast cancer. Clin Cancer Res. 2002 May;8(5):1132-41.
  16. Dohn LH, Illemann M, Høyer-Hansen G, Christensen IJ, Hostmark J, Litlekalsoy J, von der Maase H, Pappot H, Laerum OD. Urokinase-type plasminogen activator receptor (uPAR) expression is associated with T-stage and survival in urothelial carcinoma of the bladder. Urol Oncol. 2015 Apr;33(4):165.e15-24.
  17. Grubmüller B, Baum RP, Capasso E, Singh A, Ahmadi Y, Knoll P, Floth A, Righi S, Zandieh S, Meleddu C, Shariat SF, Klingler HC, Mirzaei S. 64Cu-PSMA-617 PET/CT imaging of prostate adenocarcinoma: first in-human studies. Cancer Biother Radiopharm. 2016 Oct;31(8):277-86.
  18. Pfeifer A, Knigge U, Binderup T, Mortensen J, Oturai P, Loft A, Berthelsen AK, Langer SW, Rasmussen P, Elema D, von Benzon E, Højgaard L, Kjaer A. 64Cu-DOTATATE PET for neuroendocrine tumors: a prospective head-to-head comparison with 111In-DTPA-Octreotide in 112 patients. J Nucl Med. 2015 Jun;56(6):847-54
  19. Johnbeck CB, Knigge U, Loft A, Berthelsen AK, Mortensen J, Oturai P, Langer SW, Elema DR, Kjaer A. Head-to-head comparison of 64Cu-DOTATATE and 68Ga-DOTATOC PET/CT: a prospective study of 59 patients with neuroendocrine tumors. J Nucl Med. 2017 Mar;58(3):451-57.
  20. Lebedev AY, Holland JP, Lewis JS. Clickable bifunctional radiometal chelates for peptide labeling. Chem Commun (Camb). 2010 Mar 14;46(10):1706-8.
  21. Behnammanesh H, Jokar S, Erfani M, Geramifar P, Sabzevari O, Amini M, Mazidi SM, Hajiramezanali M, Beiki D. Design, preparation and biological evaluation of a 177Lu-labeled somatostatin receptor antagonist for targeted therapy of neuroendocrine tumors. Bioorg Chem. 2020 Jan;94:103381.
  22. Currie L. Quantifying Uncertainty in Nuclear Analytical Measurements. International Atomic Energy Agency IAEA-TECDOC-1401.  Austria, 2004.
  23. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008 Jun 20;26(18):3063-72.
  24. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O'Dorisio TM, Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T, Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Öberg K, Lopera Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P, Kwekkeboom D, Krenning E; NETTER-1 Trial Investigators. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017 Jan 12;376(2):125-135.
  25. Vahidfar N, Farzanehfar S, Abbasi M, Mirzaei S, Delpassand E, Abbaspour F, Salehi Y, Biersack HJ, Ahmadzadehfar H. Diagnostic value of radiolabelled somatostatin analogues for neuroendocrine tumour diagnosis: the benefits and drawbacks of [64Cu]Cu-DOTA-TOC. Cancers (Basel). 2022 Apr; 14(8): 1914.
  26. Rylova SN,  Stoykow C,  Pozzo LD,  Abiraj K,  Tamma M ,  Kiefer Y,  Fani M, Maecke HR, The somatostatin receptor 2 antagonist 64Cu-NODAGA-JR11 outperforms 64Cu-DOTA-TATE in a mouse xenograft model. PLoS One. 2018 April; 13(4): e0195802.
  27. Tapiero H, Townsend DM, Tew KD. Trace elements in human physiology and pathology. Copper. Biomed Pharmacother. 2003 Nov;57(9):386–98.
  28. Gupta A, Lutsenko S. Human copper transporters: mechanism, role in human diseases and therapeutic potential. Future Med Chem. 2009 Sep;1(6):1125-42.
  29. Kjærgaard K, Sandahl TD, Frisch K, Vase KH, Keiding S, Vilstrup H, Ott P, Gormsen LC, Munk OL. Intravenous and oral copper kinetics, biodistribution and dosimetry in healthy humans studied by [64Cu]copper PET/CT. EJNMMI Radiopharm Chem. 2020 June;15(5):1-12
  30. Aghanejad A, Jalilian A,  Maus ,  Yousefnia H,  Geramifar P,  Beiki  D. Optimized production and quality control of 68Ga-DOTATATE. Iran J Nucl Med. 2016 Jan;24(1):29-36.
  31. Yousefnia H, Mousavi-Daramoroudi MS, Zolghadri S, Abbasi-Davani F.  Preparation and biodistribution assessment of low specific activity 177Lu-DOTATOC for optimization studies. Iran J Nucl Med. 2016 July;24(2):85-91.
  32. Pfeifer A, Knigge U, Binderup T, Mortensen J, Oturai P, Loft A, Berthelsen AK, Langer SW, Rasmussen P, Elema D, von Benzon E, Højgaard L, Kjaer A. 64Cu-DOTATATE PET for neuroendocrine tumors: a prospective head-to-head comparison with 111In-DTPA-Octreotide in 112 patients. J Nucl Med. 2015 Jun;56(6):847-54.

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