Skip to main content

Advertisement

SpringerLink
Log in

TSPO PET for glioma imaging using the novel ligand 18F-GE-180: first results in patients with glioblastoma

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Objective

The 18-kDa mitochondrial translocator protein (TSPO) was reported to be upregulated in gliomas. 18F-GE-180 is a novel 3rd generation TSPO receptor ligand with improved target-to-background contrast compared to previous tracers. In this pilot study, we compared PET imaging with 18F-GE-180 and MRI of patients with untreated and recurrent pretreated glioblastoma.

Methods

Eleven patients with histologically confirmed IDH wildtype gliomas (10 glioblastomas, 1 anaplastic astrocytoma) underwent 18F-GE-180 PET at initial diagnosis or recurrence. The PET parameters mean background uptake (SUVBG), maximal tumour-to-background ratio (TBRmax) and PET volume using different thresholds (SUVBG × 1.6, 1.8 and 2.0) were evaluated in the 60-80 min p.i. summation images. The different PET volumes were compared to the contrast-enhancing tumour volume on MRI.

Results

All gliomas were positive on 18F-GE-180 PET and were depicted with extraordinarily high tumour-to-background contrast (median SUVBG 0.47 (0.37-0.93), TBRmax 6.61 (3.88-9.07)). 18F-GE-180 uptake could be found even in areas without contrast enhancement on MRI, leading to significantly larger PET volumes than MRI-based volumes (median 90.5, 74.5, and 63.8 mL vs. 31.0 mL; p = 0.003, 0.004, 0.013). In percentage difference, the PET volumes were on average 179%, 135%, and 90% larger than the respective MRI volumes. The median spatial volumetric correlation (Sørensen-Dice coefficient) of PET volumes and MRI volumes prior to radiotherapy was 0.48, 0.54, and 0.58.

Conclusion

18F-GE-180 PET provides a remarkably high tumour-to-background contrast in untreated and pretreated glioblastoma and shows tracer uptake even beyond contrast enhancement on MRI. To what extent 18F-GE-180 uptake reflects the tumour extent of human gliomas and inflammatory cells remains to be evaluated in future prospective studies with guided stereotactic biopsies and correlation of histopathological results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66. doi:10.1016/S1470-2045(09)70025-7.

    Article  CAS  PubMed  Google Scholar 

  2. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15:1100–8. doi:10.1016/S1470-2045(14)70379-1.

    Article  CAS  PubMed  Google Scholar 

  3. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370:699–708. doi:10.1056/NEJMoa1308573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Weller M, van den Bent M, Hopkins K, Tonn JC, Stupp R, Falini A, et al. EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma. Lancet Oncol. 2014;15:e395–403. doi:10.1016/S1470-2045(14)70011-7.

    Article  PubMed  Google Scholar 

  5. Suchorska B, Albert NL, Tonn JC. Usefulness of PET imaging to guide treatment options in gliomas. Curr Treat Options Neurol. 2016;18:4. doi:10.1007/s11940-015-0384-z.

    Article  PubMed  Google Scholar 

  6. Hutterer M, Hattingen E, Palm C, Proescholdt MA, Hau P. Current standards and new concepts in MRI and PET response assessment of antiangiogenic therapies in high-grade glioma patients. Neuro-Oncology. 2015;17:784–800. doi:10.1093/neuonc/nou322.

    Article  CAS  PubMed  Google Scholar 

  7. Galldiks N, Langen KJ, Pope WB. From the clinician’s point of view - what is the status quo of positron emission tomography in patients with brain tumors? Neuro-Oncology. 2015; doi:10.1093/neuonc/nov118.

  8. Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, et al. Response assessment in neuro-oncology working group and European Association for neuro-oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-Oncology. 2016;18:1199–208. doi:10.1093/neuonc/now058.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Owen DR, Matthews PM. Imaging brain microglial activation using positron emission tomography and translocator protein-specific radioligands. Int Rev Neurobiol. 2011;101:19–39. doi:10.1016/B978-0-12-387718-5.00002-X.

    Article  CAS  PubMed  Google Scholar 

  10. Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol. 2010;327:1–12. doi:10.1016/j.mce.2010.06.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Batarseh A, Li J, Papadopoulos V. Protein kinase C epsilon regulation of translocator protein (18 kDa) Tspo gene expression is mediated through a MAPK pathway targeting STAT3 and c-Jun transcription factors. Biochemistry. 2010;49:4766–78. doi:10.1021/bi100020e.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Katz Y, Ben-Baruch G, Kloog Y, Menczer J, Gavish M. Increased density of peripheral benzodiazepine-binding sites in ovarian carcinomas as compared with benign ovarian tumours and normal ovaries. Clin Sci (Lond). 1990;78:155–8.

    Article  CAS  Google Scholar 

  13. Katz Y, Eitan A, Gavish M. Increase in peripheral benzodiazepine binding sites in colonic adenocarcinoma. Oncology. 1990;47:139–42.

    Article  CAS  PubMed  Google Scholar 

  14. Vlodavsky E, Soustiel JF. Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. J Neuro-Oncol. 2007;81:1–7. doi:10.1007/s11060-006-9199-9.

    Article  Google Scholar 

  15. Roncaroli F, Su Z, Herholz K, Gerhard A, Turkheimer FE. TSPO expression in brain tumours: is TSPO a target for brain tumour imaging? Clin Transl imaging. 2016;4:145–56. doi:10.1007/s40336-016-0168-9.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Awde AR, Boisgard R, Theze B, Dubois A, Zheng J, Dolle F, et al. The translocator protein radioligand 18F-DPA-714 monitors antitumor effect of erufosine in a rat 9L intracranial glioma model. J Nucl Med Off Publ Soc Nucl Med. 2013;54:2125–31. doi:10.2967/jnumed.112.118794.

    CAS  Google Scholar 

  17. Buck JR, McKinley ET, Fu A, Abel TW, Thompson RC, Chambless L, et al. Preclinical TSPO ligand PET to visualize human glioma xenotransplants: a preliminary study. PLoS One. 2015;10:e0141659. doi:10.1371/journal.pone.0141659.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tang D, Hight MR, McKinley ET, Fu A, Buck JR, Smith RA, et al. Quantitative preclinical imaging of TSPO expression in glioma using N,N-diethyl-2-(2-(4-(2-18F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimi din-3-yl)acetamide. J Nucl Med Off Publ Soc Nucl Med. 2012;53:287–94. doi:10.2967/jnumed.111.095653.

    CAS  Google Scholar 

  19. Winkeler A, Boisgard R, Awde AR, Dubois A, Theze B, Zheng J, et al. The translocator protein ligand [(1)(8)F]DPA-714 images glioma and activated microglia in vivo. Eur J Nucl Med Mol Imaging. 2012;39:811–23. doi:10.1007/s00259-011-2041-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tang D, Nickels ML, Tantawy MN, Buck JR, Manning HC. Preclinical imaging evaluation of novel TSPO-PET ligand 2-(5,7-diethyl-2-(4-(2-[(18)F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)- N,N-diethylacetamide ([ (18)F]VUIIS1008) in glioma. Mol Imaging Biol MIB Off Publ Acad Mol Imaging. 2014;16:813–20. doi:10.1007/s11307-014-0743-2.

    Article  Google Scholar 

  21. Su Z, Roncaroli F, Durrenberger PF, Coope DJ, Karabatsou K, Hinz R, et al. The 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology study. J Nucl Med Off Publ Soc Nucl Med. 2015;56:512–7. doi:10.2967/jnumed.114.151621.

    CAS  Google Scholar 

  22. Takaya S, Hashikawa K, Turkheimer FE, Mottram N, Deprez M, Ishizu K, et al. The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas. J Neuro-Oncol. 2007;85:95–103. doi:10.1007/s11060-007-9396-1.

    Article  Google Scholar 

  23. Junck L, Olson JM, Ciliax BJ, Koeppe RA, Watkins GL, Jewett DM, et al. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding site. Ann Neurol. 1989;26:752–8. doi:10.1002/ana.410260611.

    Article  CAS  PubMed  Google Scholar 

  24. Pappata S, Cornu P, Samson Y, Prenant C, Benavides J, Scatton B, et al. PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: a case report. J Nucl Med Off Publ Soc Nucl Med. 1991;32:1608–10.

    CAS  Google Scholar 

  25. Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M, et al. Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2010;30:1608–18. doi:10.1038/jcbfm.2010.63.

    Article  Google Scholar 

  26. Wadsworth H, Jones PA, Chau WF, Durrant C, Fouladi N, Passmore J, et al. [(1)(8)F]GE-180: a novel fluorine-18 labelled PET tracer for imaging translocator protein 18 kDa (TSPO). Bioorg Med Chem Lett. 2012;22:1308–13. doi:10.1016/j.bmcl.2011.12.084.

    Article  CAS  PubMed  Google Scholar 

  27. Boutin H, Murray K, Pradillo J, Maroy R, Smigova A, Gerhard A, et al. 18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke. Eur J Nucl Med Mol Imaging. 2015;42:503–11. doi:10.1007/s00259-014-2939-8.

    Article  CAS  PubMed  Google Scholar 

  28. Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, et al. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med Off Publ Soc Nucl Med. 2014;55:466–72. doi:10.2967/jnumed.113.125625.

    CAS  Google Scholar 

  29. Fan Z, Calsolaro V, Atkinson RA, Femminella GD, Waldman A, Buckley C, et al. Flutriciclamide (18F-GE180) PET: first in human PET study of novel 3rd generation in vivo marker of human translator protein. J Nucl Med Off Publ Soc Nucl Med. 2016; doi:10.2967/jnumed.115.169078.

  30. Feeney C, Scott G, Raffel J, Roberts S, Coello C, Jolly A, et al. Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain. Eur J Nucl Med Mol Imaging. 2016;43:2201–10. doi:10.1007/s00259-016-3444-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brendel M, Probst F, Jaworska A, Overhoff F, Korzhova V, Albert NL, et al. Glial activation and glucose metabolism in a transgenic Amyloid mouse model: a triple-tracer PET study. J Nucl Med Off Publ Soc Nucl Med. 2016;57:954–60. doi:10.2967/jnumed.115.167858.

    CAS  Google Scholar 

  32. Vomacka LA, Albert N, Lindner S, Unterrainer M, Mahler C, Brendel M, et al. Quantification of the new TSPO ligand [18F]GE-180 in patients with multiple sclerosis - initial results. J Nucl Med Off Publ Soc Nucl Med. 2017;58:208.

    Google Scholar 

  33. Jansen NL, Suchorska B, Wenter V, Schmid-Tannwald C, Todica A, Eigenbrod S, et al. Prognostic significance of dynamic 18F-FET PET in newly diagnosed astrocytic high-grade glioma. J Nucl Med Off Publ Soc Nucl Med. 2015;56:9–15. doi:10.2967/jnumed.114.144675.

    CAS  Google Scholar 

  34. Albert NL, Winkelmann I, Suchorska B, Wenter V, Schmid-Tannwald C, Mille E, et al. Early static (18)F-FET-PET scans have a higher accuracy for glioma grading than the standard 20-40 min scans. Eur J Nucl Med Mol Imaging. 2016;43:1105–14. doi:10.1007/s00259-015-3276-2.

    Article  PubMed  Google Scholar 

  35. Romagna A, Unterrainer M, Schmid-Tannwald C, Brendel M, Tonn JC, Nachbichler SB, et al. Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties? Radiat Oncol (Lond Engl). 2016;11:139. doi:10.1186/s13014-016-0713-8.

    Article  Google Scholar 

  36. Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Muller HW, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain. 2005;128:678–87. doi:10.1093/brain/awh399.

    Article  PubMed  Google Scholar 

  37. Mehrkens JH, Popperl G, Rachinger W, Herms J, Seelos K, Tatsch K, et al. The positive predictive value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment. J Neuro-Oncol. 2008;88:27–35. doi:10.1007/s11060-008-9526-4.

    Article  CAS  Google Scholar 

  38. Niyazi M, Brada M, Chalmers AJ, Combs SE, Erridge SC, Fiorentino A, et al. ESTRO-ACROP guideline “target delineation of glioblastomas”. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2016;118:35–42. doi:10.1016/j.radonc.2015.12.003.

    Article  Google Scholar 

  39. Buck JR, McKinley ET, Hight MR, Fu A, Tang D, Smith RA, et al. Quantitative, preclinical PET of translocator protein expression in glioma using 18F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline. J Nucl Med Off Publ Soc Nucl Med. 2011;52:107–14. doi:10.2967/jnumed.110.081703.

    CAS  Google Scholar 

  40. Su Z, Herholz K, Gerhard A, Roncaroli F, Du Plessis D, Jackson A, et al. [(1)(1)C]-(R)PK11195 tracer kinetics in the brain of glioma patients and a comparison of two referencing approaches. Eur J Nucl Med Mol Imaging. 2013;40:1406–19. doi:10.1007/s00259-013-2447-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tarkkonen A, Rissanen E, Tuokkola T, Airas L. Utilization of PET imaging in differential diagnostics between a tumefactive multiple sclerosis lesion and low-grade glioma. Mult Scler Relat Disord. 2016;9:147–9. doi:10.1016/j.msard.2016.07.016.

    Article  PubMed  Google Scholar 

  42. Rapp M, Heinzel A, Galldiks N, Stoffels G, Felsberg J, Ewelt C, et al. Diagnostic performance of 18F-FET PET in newly diagnosed cerebral lesions suggestive of glioma. J Nucl Med Off Publ Soc Nucl Med. 2013;54:229–35. doi:10.2967/jnumed.112.109603.

    CAS  Google Scholar 

  43. Hutterer M, Nowosielski M, Putzer D, Jansen NL, Seiz M, Schocke M, et al. [18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Neuro-Oncology. 2013;15:341–51. doi:10.1093/neuonc/nos300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Popperl G, Gotz C, Rachinger W, Gildehaus FJ, Tonn JC, Tatsch K. Value of O-(2-[18F]fluoroethyl)- L-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging. 2004;31:1464–70. doi:10.1007/s00259-004-1590-1.

    Article  PubMed  Google Scholar 

  45. Nikaki A, Angelidis G, Efthimiadou R, Tsougos I, Valotassiou V, Fountas K, et al. 18F-fluorothymidine PET imaging in gliomas: an update. Ann Nucl Med. 2017; doi:10.1007/s12149-017-1183-2.

  46. Jensen P, Feng L, Law I, Svarer C, Knudsen GM, Mikkelsen JD, et al. TSPO imaging in glioblastoma multiforme: a direct comparison between 123I-CLINDE SPECT, 18F-FET PET, and gadolinium-enhanced MR imaging. J Nucl Med Off Publ Soc Nucl Med. 2015;56:1386–90. doi:10.2967/jnumed.115.158998.

    CAS  Google Scholar 

  47. Badie B, Schartner JM. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery. 2000;46:957–62.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank A. Elsner from Hermes Medical Solutions for his support in the usage of hybrid 3D and V. Milenkovic for the support regarding polymorphism genotyping. We thank GE Healthcare for the supply with GE-180 cassettes. This work was supported by the Friedrich-Baur-Stiftung.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany

    Nathalie L. Albert, M. Unterrainer, S. Lindner, F. Vettermann, A. Brunegraf, L. Vomacka, M. Brendel, V. Wenter & P. Bartenstein

  2. German Cancer Consortium (DKTK), partner site Munich; and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Nathalie L. Albert, D. F. Fleischmann, J.-C. Tonn, C. Belka, P. Bartenstein & M. Niyazi

  3. “Munich Cluster of Systems Neurology (SyNergy)”, Munich, Germany

    Nathalie L. Albert & P. Bartenstein

  4. Department of Radiation Oncology, LMU Munich, Munich, Germany

    D. F. Fleischmann, C. Belka & M. Niyazi

  5. Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany

    C. Wetzel & R. Rupprecht

  6. Department of Neurosurgery, LMU Munich, Munich, Germany

    J.-C. Tonn

Authors
  1. Nathalie L. Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Unterrainer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. F. Fleischmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Vettermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Brunegraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L. Vomacka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M. Brendel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. V. Wenter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C. Wetzel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R. Rupprecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J.-C. Tonn
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C. Belka
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P. Bartenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M. Niyazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nathalie L. Albert.

Ethics declarations

Conflict of interest

JCT received honoraria as a speaker and a research grant from BrainLab. MN received honoraria as a speaker and a research grant from Roche Pharma AG. The other authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Albert, N.L., Unterrainer, M., Fleischmann, D.F. et al. TSPO PET for glioma imaging using the novel ligand 18F-GE-180: first results in patients with glioblastoma. Eur J Nucl Med Mol Imaging 44, 2230–2238 (2017). https://doi.org/10.1007/s00259-017-3799-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-017-3799-9

Keywords

Search

Navigation