Advertisement

Fundamental study of radiogallium-labeled aspartic acid peptides introducing octreotate derivatives

  • Atsushi Ishizaki
  • Kenji Mishiro
  • Kazuhiro Shiba
  • Hirofumi Hanaoka
  • Seigo Kinuya
  • Akira Odani
  • Kazuma OgawaEmail author
Original Article
  • 47 Downloads

Abstract

Objective

Somatostatin receptors are highly expressed in neuroendocrine tumors, and many radiolabeled somatostatin analogs for diagnosis and treatment have been developed. To simultaneously detect not only primary cancer but also bone metastases, this study aimed to develop a positron emission tomography probe using generator-produced nuclide Gallium-68 (T1/2 = 68 min), in which a carrier for primary cancer, a carrier for bone metastases lesions, and a stable gallium complex are introduced into the one molecule. Based on this strategy, the somatostatin receptor-targeted peptide, [Tyr3]-octreotate (TATE), aspartic acid peptide (Dn) with high binding affinity for hydroxyapatite, and Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a stable gallium complex were selected. The novel complexes, Ga-DOTA-Dn-TATE (n = 0, 2, 5, 8, or 11), were designed, synthesized, and evaluated. The radiogallium complexes were prepared using the easy-to-handle radioisotope 67Ga due to relatively long half-life.

Methods

The radiogallium complex precursor DOTA-Dn-TATE was synthesized by the Fmoc-based solid-phase method and by the air oxidation method to form the disulfide bond. [67Ga]Ga-DOTA-Dn-TATE was synthesized by reacting DOTA-Dn-TATE and 67Ga. Hydroxyapatite binding assays, in vitro cellular uptake experiments in AR42J tumor cells, in biodistribution experiments in AR42J tumor-bearing mice, were performed using [67Ga]Ga-DOTA-Dn-TATE.

Results

The radiochemical purities of [67Ga]Ga-DOTA-Dn-TATE were > 96.0%. In in vitro and in vivo experiments, [67Ga]Ga-DOTA-D11-TATE had a high affinity for hydroxyapatite and highly accumulated in bone. However, the uptake of [67Ga]Ga-DOTA-D11-TATE into somatostatin receptor-positive AR42J cells was lower than that of [67Ga]Ga-DOTA-TATE, and the accumulation of [67Ga]Ga-DOTA-D11-TATE in tumor was significantly low.

Conclusion

Ga-DOTA-D11-TATE may not be recognized by somatostatin receptor by the introduction of D11, and the charge adjustment may be important for somatostatin receptor-positive cell uptake.

Keywords

PET Imaging Somatostatin receptor Bone metastases Aspartic acid 

Notes

Acknowledgements

This work was supported in part by Sagawa Foundation for Promotion of Cancer Research, Grant-in-Aid for Scientific Research (C) (JSPS KAKENHI Grant Number 15K09948) from Japan Society for the Promotion of Science, Terumo Life Science Foundation, and Mochida Memorial Foundation for Medical and Pharmaceutical Research.

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.

References

  1. 1.
    Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. 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;26(18):3063–72.CrossRefGoogle Scholar
  2. 2.
    Johnbeck CB, Knigge U, Kjaer A. PET tracers for somatostatin receptor imaging of neuroendocrine tumors: current status and review of the literature. Future Oncol. 2014;10(14):2259–77.CrossRefGoogle Scholar
  3. 3.
    Heidari P, Wehrenberg-Klee E, Habibollahi P, Yokell D, Kulke M, Mahmood U. Free somatostatin receptor fraction predicts the antiproliferative effect of octreotide in a neuroendocrine tumor model: implications for dose optimization. Cancer Res. 2013;73(23):6865–73.CrossRefGoogle Scholar
  4. 4.
    Krenning EP, Bakker WH, Kooij PP, Breeman WA, Oei HY, de Jong M, et al. Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. J Nucl Med. 1992;33(5):652–8.Google Scholar
  5. 5.
    Buchmann I, Henze M, Engelbrecht S, Eisenhut M, Runz A, Schafer M, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2007;34(10):1617–26.CrossRefGoogle Scholar
  6. 6.
    Wild D, Schmitt JS, Ginj M, Macke HR, Bernard BF, Krenning E, et al. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals. Eur J Nucl Med Mol Imaging. 2003;30(10):1338–47.CrossRefGoogle Scholar
  7. 7.
    Virgolini I, Szilvasi I, Kurtaran A, Angelberger P, Raderer M, Havlik E, et al. Indium-111-DOTA-lanreotide: biodistribution, safety and radiation absorbed dose in tumor patients. J Nucl Med. 1998;39(11):1928–36.Google Scholar
  8. 8.
    Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J. The role of 68Ga-DOTATATE PET in patients with neuroendocrine tumors and negative or equivocal findings on 111In-DTPA-octreotide scintigraphy. J Nucl Med. 2010;51(6):875–82.CrossRefGoogle Scholar
  9. 9.
    Kjaer A, Knigge U. Use of radioactive substances in diagnosis and treatment of neuroendocrine tumors. Scand J Gastroenterol. 2015;50(6):740–7.Google Scholar
  10. 10.
    Kwekkeboom DJ, Kam BL, van Essen M, Teunissen JJ, van Eijck CH, Valkema R, et al. Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. Endocr Relat Cancer. 2010;17(1):R53–73.CrossRefGoogle Scholar
  11. 11.
    Poeppel TD, Binse I, Petersenn S, Lahner H, Schott M, Antoch G, 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
  12. 12.
    Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.CrossRefGoogle Scholar
  13. 13.
    Kim SJ, Kim JW, Han SW, Oh DY, Lee SH, Kim DW, et al. Biological characteristics and treatment outcomes of metastatic or recurrent neuroendocrine tumors: tumor grade and metastatic site are important for treatment strategy. BMC Cancer. 2010;10:448.CrossRefGoogle Scholar
  14. 14.
    Clohisy DR, Mantyh PW. Bone cancer pain. Cancer. 2003;97(3 Suppl):866–73.CrossRefGoogle Scholar
  15. 15.
    Ogawa K, Washiyama K. Bone target radiotracers for palliative therapy of bone metastases. Curr Med Chem. 2012;19(20):3290–300.CrossRefGoogle Scholar
  16. 16.
    Ogawa K, Ishizaki A, Takai K, Kitamura Y, Kiwada T, Shiba K, et al. Development of novel radiogallium-labeled bone imaging agents using oligo-aspartic acid peptides as carriers. PLoS One. 2013;8(12):e84335.CrossRefGoogle Scholar
  17. 17.
    Ogawa K, Ishizaki A. Well-designed bone-seeking radiolabeled compounds for diagnosis and therapy of bone metastases. Biomed Res Int. 2015;2015:676053.CrossRefGoogle Scholar
  18. 18.
    Ogawa K, Yu J, Ishizaki A, Yokokawa M, Kitamura M, Kitamura Y, et al. Radiogallium complex-conjugated bifunctional peptides for detecting primary cancer and bone metastases simultaneously. Bioconjug Chem. 2015;26(8):1561–70.CrossRefGoogle Scholar
  19. 19.
    Kaiser E, Colescott RL, Bossinger CD, Cook PI. Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem. 1970;34(2):595–8.CrossRefGoogle Scholar
  20. 20.
    Ogawa K, Mukai T, Arano Y, Otaka A, Ueda M, Uehara T, et al. Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation. Nucl Med Biol. 2006;33(4):513–20.CrossRefGoogle Scholar
  21. 21.
    Ogawa K, Mukai T, Inoue Y, Ono M, Saji H. Development of a novel 99mTc-chelate-conjugated bisphosphonate with high affinity for bone as a bone scintigraphic agent. J Nucl Med. 2006;47(12):2042–7.Google Scholar
  22. 22.
    Oshima N, Akizawa H, Zhao S, Zhao Y, Nishijima K, Kitamura Y, et al. Design, synthesis and biological evaluation of negatively charged 111In-DTPA-octreotide derivatives. Bioorg Med Chem. 2014;22(4):1377–82.CrossRefGoogle Scholar
  23. 23.
    Makris G, Radford LL, Kuchuk M, Gallazzi F, Jurisson SS, Smith CJ, et al. NOTA and NODAGA [99mTc]Tc- and [186Re]Re-tricarbonyl complexes: radiochemistry and first example of a [99mTc]Tc-NODAGA somatostatin receptor-targeting bioconjugate. Bioconjug Chem. 2018.Google Scholar
  24. 24.
    Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27(3):273–82.CrossRefGoogle Scholar
  25. 25.
    Schottelius M, Reubi JC, Eltschinger V, Schwaiger M, Wester HJ. N-terminal sugar conjugation and C-terminal Thr-for-Thr(ol) exchange in radioiodinated Tyr3-octreotide: effect on cellular ligand trafficking in vitro and tumor accumulation in vivo. J Med Chem. 2005;48(8):2778–89.CrossRefGoogle Scholar
  26. 26.
    Antunes P, Ginj M, Walter MA, Chen J, Reubi JC, Maecke HR. Influence of different spacers on the biological profile of a DOTA-somatostatin analogue. Bioconjug Chem. 2007;18(1):84–92.CrossRefGoogle Scholar
  27. 27.
    Whetstone PA, Akizawa H, Meares CF. Evaluation of cleavable (Tyr3)-octreotate derivatives for longer intracellular probe residence. Bioconjug Chem. 2004;15(3):647–57.CrossRefGoogle Scholar
  28. 28.
    Ogawa K, Ishizaki A, Takai K, Kitamura Y, Makino A, Kozaka T, et al. Evaluation of Ga-DOTA-(D-Asp)n as bone imaging agents: d-aspartic acid peptides as carriers to bone. Sci Rep. 2017;7(1):13971.CrossRefGoogle Scholar
  29. 29.
    Schottelius M, Simecek J, Hoffmann F, Willibald M, Schwaiger M, Wester HJ. Twins in spirit - episode I: comparative preclinical evaluation of [68Ga]DOTATATE and [68Ga]HA-DOTATATE. EJNMMI Res. 2015;5:22.CrossRefGoogle Scholar
  30. 30.
    de Jong M, Breeman WA, Bernard BF, Bakker WH, Schaar M, van Gameren A, et al. [177Lu-DOTA0,Tyr3] octreotate for somatostatin receptor-targeted radionuclide therapy. Int J Cancer. 2001;92(5):628–33.CrossRefGoogle Scholar
  31. 31.
    Froidevaux S, Eberle AN, Christe M, Sumanovski L, Heppeler A, Schmitt JS, et al. Neuroendocrine tumor targeting: study of novel gallium-labeled somatostatin radiopeptides in a rat pancreatic tumor model. Int J Cancer. 2002;98(6):930–7.CrossRefGoogle Scholar
  32. 32.
    Garcia Garayoa E, Schweinsberg C, Maes V, Brans L, Blauenstein P, Tourwe DA, et al. Influence of the molecular charge on the biodistribution of bombesin analogues labeled with the [99mTc(CO)3]-core. Bioconjug Chem. 2008;19(12):2409–16.CrossRefGoogle Scholar
  33. 33.
    Parry JJ, Kelly TS, Andrews R, Rogers BE. In vitro and in vivo evaluation of 64Cu-labeled DOTA-linker-bombesin(7–14) analogues containing different amino acid linker moieties. Bioconjug Chem. 2007;18(4):1110–7.CrossRefGoogle Scholar
  34. 34.
    Yim CB, van der Wildt B, Dijkgraaf I, Joosten L, Eek A, Versluis C, et al. Spacer effects on in vivo properties of DOTA-conjugated dimeric [Tyr3]octreotate peptides synthesized by a “CuI-click” and “sulfo-click” ligation method. Chembiochem. 2011;12(5):750–60.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Nuclear Medicine 2019

Authors and Affiliations

  1. 1.Graduate School of Medical SciencesKanazawa UniversityKanazawaJapan
  2. 2.Institute for Frontier Science InitiativeKanazawa UniversityKanazawaJapan
  3. 3.Advanced Science Research CenterKanazawa UniversityKanazawaJapan
  4. 4.Department of Bioimaging Information Analysis, Graduate School of MedicineGunma UniversityMaebashiJapan

Personalised recommendations