Skip to main content

Advertisement

Log in

Comparison of 18F-GE-180 and dynamic 18F-FET PET in high grade glioma: a double-tracer pilot study

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

Abstract

Background

PET represents a valuable tool for glioma imaging. In addition to amino acid tracers such as 18F-FET, PET targeting the 18-kDa mitochondrial translocator-protein (TSPO) is of high interest for high-grade glioma (HGG) imaging due to its upregulation in HGG cells. 18F-GE-180, a novel TSPO ligand, has shown a high target-to-background contrast in HGG. Therefore, we intra-individually compared its uptake characteristics to dynamic 18F-FET PET and contrast-enhanced MRI in patients with HGG.

Methods

Twenty HGG patients (nine IDH-wildtype, 11 IDH-mutant) at initial diagnosis (n = 8) or recurrence (n = 12) were consecutively included and underwent 18F-GE-180 PET, dynamic 18F-FET PET, and MRI. The maximal tumour-to-background ratios (TBRmax) and biological tumour volumes (BTV) were evaluated in 18F-GE-180 and 18F-FET PET. Dynamic 18F-FET PET analysis included the evaluation of minimal time-to-peak (TTPmin). In MRI, the volume of contrast-enhancement was delineated (VOLCE). Volumes were spatially correlated using the Sørensen–Dice coefficient.

Results

The median TBRmax tended to be higher in 18F-GE-180 PET compared to 18F-FET PET [4.58 (2.33–8.95) vs 3.89 (1.56–7.15); p = 0.062] in the overall group. In subgroup analyses, IDH-wildtype gliomas showed a significantly higher median TBRmax in 18F-GE-180 PET compared to 18F-FET PET [5.45 (2.56–8.95) vs 4.06 (1.56–4.48); p = 0.008]; by contrast, no significant difference was observed in IDH-mutant gliomas [3.97 (2.33–6.81) vs 3.79 (2.01–7.15) p = 1.000]. Only 5/20 cases showed higher TBRmax in 18F-FET PET compared to 18F-GE-180 PET, all of them being IDH-mutant gliomas. No parameter in 18F-GE-180 PET correlated with TTPmin (p > 0.05 each). There was a tendency towards higher median BTVGE-180 [32.1 (0.4–236.0) ml] compared to BTVFET [19.3 (0.7–150.2) ml; p = 0.062] with a moderate spatial overlap [median Sørensen–Dice coefficient 0.55 (0.07–0.85)]. In MRI, median VOLCE [9.7 (0.1–72.5) ml] was significantly smaller than both BTVFET and BTVGE180 (p < 0.001 each), leading to a poor spatial correlation with BTVGE-180 [0.29 (0.01–0.48)] and BTVFET [0.38 (0.01–0.68)].

Conclusion

PET with 18F-GE-180 and 18F-FET provides differing imaging information in HGG dependent on the IDH-mutational status, with diverging spatial overlap and vast exceedance of contrast-enhancement in MRI. Combined PET imaging might reveal new insights regarding non-invasive characterization of tumour heterogeneity and might influence patients’ management.

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

Access this article

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. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol. 2010;28:1963–72.

    Article  PubMed  Google Scholar 

  2. Watanabe M, Tanaka R, Takeda N. Magnetic resonance imaging and histopathology of cerebral gliomas. Neuroradiology. 1992;34:463–9.

    Article  CAS  PubMed  Google Scholar 

  3. Suchorska B, Jansen NL, Linn J, Kretzschmar H, Janssen H, Eigenbrod S, et al. Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM. Neurology. 2015;84:710–9.

    Article  CAS  PubMed  Google Scholar 

  4. 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 Oncol. 2015;7(11):1434–44.

    Article  CAS  Google Scholar 

  5. 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 Oncol. 2016;18:1199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Habermeier A, Graf J, Sandhöfer BF, Boissel J-P, Roesch F, Closs EI. System l amino acid transporter LAT1 accumulates O-(2-fluoroethyl)-l-tyrosine (FET). Amino Acids. 2015;47:335–44. https://doi.org/10.1007/s00726-014-1863-3.

    Article  CAS  PubMed  Google Scholar 

  7. Unterrainer M, Schweisthal F, Suchorska B, Wenter V, Schmid-Tannwald C, Fendler WP, et al. Serial 18F-FET PET imaging of primarily 18F-FET–negative glioma: does it make sense? J Nucl Med. 2016;57:1177–82.

    Article  CAS  PubMed  Google Scholar 

  8. 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 Neurooncol. 2007;81:1–7.

    Article  PubMed  Google Scholar 

  9. 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. 2015;56:512–7.

    Article  CAS  PubMed  Google Scholar 

  10. 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. 2013;54:2125–31.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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. Molec Imaging Biol. 2014;16:813–20.

    Article  Google Scholar 

  14. 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 Neurooncol. 2007;85:95–103.

    Article  PubMed  Google Scholar 

  15. 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. https://doi.org/10.1002/ana.410260611.

    Article  CAS  PubMed  Google Scholar 

  16. 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. 1991;32:1608–10.

    CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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. 2014;55:466–72.

    Article  CAS  PubMed  Google Scholar 

  20. Sridharan S, Lepelletier F-X, Trigg W, Banister S, Reekie T, Kassiou M, et al. Comparative evaluation of three TSPO PET radiotracers in a LPS-induced model of mild neuroinflammation in rats. Mol Imaging Biol. 2017;19:77–89.

    Article  CAS  PubMed  Google Scholar 

  21. 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. 2016;57(11):1753–1759.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vomacka L, Albert NL, Lindner S, Unterrainer M, Mahler C, Brendel M, et al. TSPO imaging using the novel PET ligand [18F]GE-180: quantification approaches in patients with multiple sclerosis. EJNMMI Res. 2017;7:89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Unterrainer M, Mahler C, Vomacka L, Lindner S, Havla J, Brendel M, et al. TSPO PET with [18F]GE-180 sensitively detects focal neuro-inflammation in patients with relapsing-remitting multiple sclerosis. Eur J Nucl Med Mol Imaging. 2018;45:1423–31.

    Article  PubMed  Google Scholar 

  25. Albert NL, Unterrainer M, Fleischmann D, Lindner S, Vettermann F, Brunegraf A, 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. 2017;44(13):2230–2238

    Article  CAS  PubMed  Google Scholar 

  26. 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. 2015;56:1386–90.

    Article  CAS  PubMed  Google Scholar 

  27. Louis DN, Perry A, Reifenberger G, Von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803–20.

    Article  PubMed  Google Scholar 

  28. Suchorska B, Giese A, Biczok A, Unterrainer M, Weller M, Drexler M, et al. Identification of time-to-peak on dynamic 18F-FET-PET as a prognostic marker specifically in IDH1/2 mutant diffuse astrocytoma. Neurooncol. 2017;20(2):279–288.

    Google Scholar 

  29. Eigenbrod S, Trabold R, Brucker D, Erös C, Egensperger R, La Fougere C, et al. Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients. Acta Neurochir. 2014;156:1427–40.

    Article  PubMed  Google Scholar 

  30. Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. Journal of nuclear medicine : official publication. Soc Nucl Med. 2011;52:24–32.

    Article  CAS  Google Scholar 

  31. Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32:1–5.

    Article  CAS  PubMed  Google Scholar 

  32. Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN. Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo. NeuroImage. 2012;60:902–10.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wickstrøm T, Clarke A, Gausemel I, Horn E, Jørgensen K, Khan I, et al. The development of an automated and GMP compliant FASTlab™ synthesis of [18F] GE-180; a radiotracer for imaging translocator protein (TSPO). J Label Compd Radiopharm. 2014;57:42–8.

    Article  CAS  Google Scholar 

  34. Unterrainer M, Vettermann F, Brendel M, Holzgreve A, Lifschitz M, Zähringer M, et al. Towards standardization of 18 F-FET PET imaging: do we need a consistent method of background activity assessment? EJNMMI Res. 2017;7:48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jansen NL, Graute V, Armbruster L, Suchorska B, Lutz J, Eigenbrod S, et al. MRI-suspected low-grade glioma: is there a need to perform dynamic FET PET? Eur J Nucl Med Mol Imaging. 2012;39:1021–9.

    Article  CAS  PubMed  Google Scholar 

  36. 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. 2015;56:9–15.

    Article  CAS  PubMed  Google Scholar 

  37. Dice LR. Measures of the amount of ecologic association between species. Ecology. 1945;26:297–302.

    Article  Google Scholar 

  38. Sørensen T. A method of establishing groups of equal amplitude in plant sociology based on similarity of species and its application to analyses of the vegetation on Danish commons. Biol Skr. 1948;5:1–34.

    Google Scholar 

  39. Law I, Albert NL, Arbizu J, Boellaard R, Drzezga A, Galldiks N, et al. A joint RANO/EANO/EANM Practice Guideline/SNMMI Procedure Standard for Imaging of Gliomas using PET with Radiolabeled Amino Acids and [18F]FDG: Version 1.0. SNMMI Publications. 2018.

  40. Jansen NL, Schwartz C, Graute V, Eigenbrod S, Lutz J, Egensperger R, et al. Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [18F] FET-PET imaging in intracranial WHO grade II and III gliomas. Neurooncol. 2012;14:1473–80.

    CAS  Google Scholar 

  41. Jansen NL, Suchorska B, Wenter V, Eigenbrod S, Schmid-Tannwald C, Zwergal A, et al. Dynamic 18F-FET PET in newly diagnosed astrocytic low-grade glioma identifies high-risk patients. J Nucl Med. 2014;55:198–203.

    Article  CAS  PubMed  Google Scholar 

  42. Verger A, Stoffels G, Bauer EK, Lohmann P, Blau T, Fink GR, et al. Static and dynamic 18F–FET PET for the characterization of gliomas defined by IDH and 1p/19q status. Eur J Nucl Med Mol Imaging. 2018;45(3):443–451.

    Article  CAS  PubMed  Google Scholar 

  43. Unterrainer M, Winkelmann I, Suchorska B, Giese A, Wenter V, Kreth FW, et al. Biological tumour volumes of gliomas in early and standard 20–40 min 18F-FET PET images differ according to IDH mutation status. Eur J Nucl Med Mol Imaging. 2018;45:1242–9. https://doi.org/10.1007/s00259-018-3969-4.

    Article  CAS  PubMed  Google Scholar 

  44. Brendel M, Focke C, Blume T, Peters F, Deussing M, Probst F, et al. Time courses of cortical glucose metabolism and microglial activity across the life span of wild-type mice: a PET study. J Nucl Med. 2017;58:1984–90.

    Article  CAS  PubMed  Google Scholar 

  45. Deussing M, Blume T, Vomacka L, Mahler C, Focke C, Todica A, et al. Coupling between physiological TSPO expression in brain and myocardium allows stabilization of late-phase cerebral [18F] GE180 PET quantification. NeuroImage. 2018;165:83–91.

    Article  PubMed  Google Scholar 

  46. Deussing M, Blume T, Vomacka L, Mahler C, Focke C, Todica A, et al. Data on specificity of [18F] GE180 uptake for TSPO expression in rodent brain and myocardium. Data Brief. 2018;19:331–6.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. V. Milenkovic for the support regarding polymorphism genotyping. Additionally, we thank Joanne Stevens and GE-Healthcare for the support regarding tracer production.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nathalie L. Albert.

Ethics declarations

Conflict of interest

All authors declare that they have no relationships or interests that could have direct or potential influence or impart bias on the work.

Ethical approval

The study was authorized by the local ethics committee (IRB 17–769) in accordance with the ICH Guideline for Good Clinical Practice (GCP) and the Declaration of Helsinki.

Informed consent

All patients gave written consent to participate in the study.

Electronic supplementary material

ESM 1

(DOCX 2217 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Unterrainer, M., Fleischmann, D.F., Diekmann, C. et al. Comparison of 18F-GE-180 and dynamic 18F-FET PET in high grade glioma: a double-tracer pilot study. Eur J Nucl Med Mol Imaging 46, 580–590 (2019). https://doi.org/10.1007/s00259-018-4166-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-018-4166-1

Keywords

Navigation