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Influence of blood-brain barrier permeability on O-(2-18F-fluoroethyl)-L-tyrosine uptake in rat gliomas

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Abstract

Purpose

O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on 18F-FET uptake in two rat glioma models and one human xenograft model.

Methods

F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent 18F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of 18F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs.

Results

In Dex treated animals EBD extravasation was significantly reduced in 9L (P < 0.001) and U87 (P = 0.008) models and showed a trend in F98 models (P = 0.053). In contrast, no significant differences of 18F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P < 0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P = 0.010).

Conclusion

Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of 18F-FET uptake were noted in this experimental study. Thus, 18F-FET uptake in gliomas appears to be widely independent of the permeability of the BBB.

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References

  1. Galldiks N, Langen KJ. Applications of PET imaging of neurological tumors with radiolabeled amino acids. Q J Nucl Med Mol Imaging. 2015;59:70–82.

    CAS  PubMed  Google Scholar 

  2. Herholz K, Langen KJ, Schiepers C, Mountz JM. Brain tumors. Semin Nucl Med. 2012;42:356–70. doi:10.1053/j.semnuclmed.2012.06.001.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Langen KJ, Hamacher K, Weckesser M, Floeth F, Stoffels G, Bauer D, et al. O-(2-[18F]fluoroethyl)-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol. 2006;33:287–94. doi:10.1016/j.nucmedbio.2006.01.002.

    Article  CAS  PubMed  Google Scholar 

  4. Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, et al. Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med: Off Publ, Soc Nucl Med. 1999;40:205–12.

    CAS  Google Scholar 

  5. Galldiks N, Stoffels G, Filss C, Rapp M, Blau T, Tscherpel C, et al. The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. Neuro-Oncology. 2015;17:1293–300. doi:10.1093/neuonc/nov088.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Galldiks N, Langen K, Holy R, Pinkawa M, Stoffels G, Nolte K, et al. Assessment of treatment response in patients with glioblastoma using [18F]Fluoroethyl-L-Tyrosine PET in comparison to MRI. J Nucl Med: Off Publ, Soc Nucl Med. 2012;53:1048–57.

    Article  CAS  Google Scholar 

  7. 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: J Neurol. 2005;128:678–87. doi:10.1093/brain/awh399.

    Article  Google Scholar 

  8. Pauleit D, Stoffels G, Bachofner A, Floeth FW, Sabel M, Herzog H, et al. Comparison of (18)F-FET and (18)F-FDG PET in brain tumors. Nucl Med Biol. 2009;36:779–87. doi:10.1016/j.nucmedbio.2009.05.005.

    Article  CAS  PubMed  Google Scholar 

  9. Pichler R, Dunzinger A, Wurm G, Pichler J, Weis S, Nussbaumer K, et al. Is there a place for FET PET in the initial evaluation of brain lesions with unknown significance? Eur J Nucl Med Mol Imaging. 2010;37:1521–8. doi:10.1007/s00259-010-1457-6.

    Article  PubMed  Google Scholar 

  10. 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 

  11. Floeth FW, Pauleit D, Sabel M, Stoffels G, Reifenberger G, Riemenschneider MJ, et al. Prognostic value of O-(2-18F-fluoroethyl)-L-tyrosine PET and MRI in low-grade glioma. J Nucl Med: Off Publ, Soc Nucl Med. 2007;48:519–27.

    Article  CAS  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. Popperl G, Kreth FW, Herms J, Koch W, Mehrkens JH, Gildehaus FJ, et al. Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods? J Nucl Med: Off Publ, Soc Nucl Med. 2006;47:393–403.

    Google Scholar 

  14. Weckesser M, Langen KJ, Rickert CH, Kloska S, Straeter R, Hamacher K, et al. O-(2-[18F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours. Eur J Nucl Med Mol Imaging. 2005;32:422–9. doi:10.1007/s00259-004-1705-8.

    Article  CAS  PubMed  Google Scholar 

  15. Popperl G, Kreth FW, Mehrkens JH, Herms J, Seelos K, Koch W, et al. FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging. 2007;34:1933–42. doi:10.1007/s00259-007-0534-y.

    Article  PubMed  Google Scholar 

  16. Calcagni ML, Galli G, Giordano A, Taralli S, Anile C, Niesen A, et al. Dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (F-18 FET) PET for glioma grading: assessment of individual probability of malignancy. Clin Nucl Med. 2011;36:841–7. doi:10.1097/RLU.0b013e3182291b40.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Nedergaard MK, Kristoffersen K, Michaelsen SR, Madsen J, Poulsen HS, Stockhausen MT, et al. The use of longitudinal 18F-FET MicroPET imaging to evaluate response to irinotecan in orthotopic human glioblastoma multiforme xenografts. PLoS One. 2014;9:e100009. doi:10.1371/journal.pone.0100009.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kunz M, Thon N, Eigenbrod S, Hartmann C, Egensperger R, Herms J, et al. Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas. Neuro-Oncology. 2011;13:307–16. doi:10.1093/neuonc/noq196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Langen KJ, Galldiks N. Reply to "[18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma" by Hutterer et al. Neuro-Oncology. 2013;15:816–7. doi:10.1093/neuonc/not059.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kotsarini C, Griffiths PD, Wilkinson ID, Hoggard N. A systematic review of the literature on the effects of dexamethasone on the brain from in vivo human-based studies: implications for physiological brain imaging of patients with intracranial tumors. Neurosurgery. 2010;67:1799–815. doi:10.1227/NEU.0b013e3181fa775b. discussion 815.

    Article  PubMed  Google Scholar 

  23. Sarin R, Murthy V. Medical decompressive therapy for primary and metastatic intracranial tumours. Lancet Neurol. 2003;2:357–65.

    Article  CAS  PubMed  Google Scholar 

  24. Stegmayr C, Schoneck M, Oliveira D, Willuweit A, Filss C, Galldiks N, et al. Reproducibility of O-(2-(18)F-fluoroethyl)-L-tyrosine uptake kinetics in brain tumors and influence of corticoid therapy: an experimental study in rat gliomas. Eur J Nucl Med Mol Imaging. 2016;43:1115–23. doi:10.1007/s00259-015-3274-4.

    Article  CAS  PubMed  Google Scholar 

  25. Piroth MD, Prasath J, Willuweit A, Stoffels G, Sellhaus B, van Osterhout A, et al. Uptake of O-(2-[18F]fluoroethyl)-L-tyrosine in reactive astrocytosis in the vicinity of cerebral gliomas. Nucl Med Biol. 2013;40:795–800. doi:10.1016/j.nucmedbio.2013.05.001.

    Article  CAS  PubMed  Google Scholar 

  26. Langen KJ, Jarosch M, Muhlensiepen H, Hamacher K, Broer S, Jansen P, et al. Comparison of fluorotyrosines and methionine uptake in F98 rat gliomas. Nucl Med Biol. 2003;30:501–8.

    Article  CAS  PubMed  Google Scholar 

  27. Bao Q, Newport D, Chen M, Stout DB, Chatziioannou AF. Performance evaluation of the inveon dedicated PET preclinical tomograph based on the NEMA NU-4 standards. J Nucl Med: Off Publ, Soc Nucl Med. 2009;50:401–8. doi:10.2967/jnumed.108.056374.

    Article  Google Scholar 

  28. Hamacher K, Coenen HH. Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L-tyrosine. Appl Radiat Isot : Incl Data, Instrum Methods for Use in Agric, Ind Med. 2002;57:853–6.

    Article  CAS  Google Scholar 

  29. 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. doi:10.1200/JCO.2009.26.3541.

    Article  PubMed  Google Scholar 

  30. Galldiks N, Dunkl V, Stoffels G, Hutterer M, Rapp M, Sabel M, et al. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-L-tyrosine PET. Eur J Nucl Med Mol Imaging. 2015;42:685–95. doi:10.1007/s00259-014-2959-4.

    Article  CAS  PubMed  Google Scholar 

  31. Spaeth N, Wyss MT, Weber B, Scheidegger S, Lutz A, Verwey J, et al. Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence. J Nucl Med: Off Publ, Soc Nucl Med. 2004;45:1931–8.

    CAS  Google Scholar 

  32. Uyama O, Okamura N, Yanase M, Narita M, Kawabata K, Sugita M. Quantitative evaluation of vascular permeability in the gerbil brain after transient ischemia using Evans blue fluorescence. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab. 1988;8:282–4. doi:10.1038/jcbfm.1988.59.

    Article  CAS  Google Scholar 

  33. Yen LF, Wei VC, Kuo EY, Lai TW. Distinct patterns of cerebral extravasation by Evans blue and sodium fluorescein in rats. PLoS One. 2013;8:e68595. doi:10.1371/journal.pone.0068595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Darpolor MM, Molthen RC, Schmainda KM. Multimodality imaging of abnormal vascular perfusion and morphology in preclinical 9L gliosarcoma model. PLoS One. 2011;6:e16621. doi:10.1371/journal.pone.0016621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Badruddoja MA, Krouwer HG, Rand SD, Rebro KJ, Pathak AP, Schmainda KM. Antiangiogenic effects of dexamethasone in 9L gliosarcoma assessed by MRI cerebral blood volume maps. Neuro-Oncology. 2003;5:235–43. doi:10.1215/S1152851703000073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Saunders NR, Dziegielewska KM, Mollgard K, Habgood MD. Markers for blood-brain barrier integrity: how appropriate is Evans blue in the twenty-first century and what are the alternatives? Front Neurosci. 2015;9:385. doi:10.3389/fnins.2015.00385.

  37. Yu B, Ruan M, Dong X, Yu Y, Cheng H. The mechanism of the opening of the blood-brain barrier by borneol: A pharmacodynamics and pharmacokinetics combination study. J Ethnopharmacol. 2013. doi:10.1016/j.jep.2013.10.028.

    Google Scholar 

  38. Li Z, Liang G, Ma T, Li J, Wang P, Liu L, et al. Blood-brain barrier permeability change and regulation mechanism after subarachnoid hemorrhage. Metab Brain Dis. 2015;30:597–603. doi:10.1007/s11011-014-9609-1.

    Article  CAS  PubMed  Google Scholar 

  39. Fan Y, Yang X, Tao Y, Lan L, Zheng L, Sun J. Tight junction disruption of blood-brain barrier in white matter lesions in chronic hypertensive rats. Neuroreport. 2015;26:1039–43. doi:10.1097/WNR.0000000000000464.

    Article  CAS  PubMed  Google Scholar 

  40. Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol. 1969;40:648–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol. 1967;34:207–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, et al. Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol. 2000;100:323–31.

    Article  CAS  PubMed  Google Scholar 

  43. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol. 2003;161:653–60. doi:10.1083/jcb.200302070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors wish to thank the staff of the animal husbandry, Mrs. Erika Wabbals, Mrs. Silke Grafmüller and Mr. Sascha Rehbein for technical assistance in radiosynthesis of 18F-FET, and Dr. Astrid Rollenhagen for EM image editing.

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Authors and Affiliations

  1. Forschungszentrum Jülich, Institute of Neuroscience and Medicine, D-52425, Jülich, Germany

    Carina Stegmayr, Ulrike Bandelow, Dennis Oliveira, Philipp Lohmann, Antje Willuweit, Christian Filss, Norbert Galldiks, Joachim H. R. Lübke, N. Jon Shah, Johannes Ermert & Karl-Josef Langen

  2. Department of Nuclear Medicine and Neurology, RWTH/University Hospital Aachen, Aachen, Germany

    Christian Filss, N. Jon Shah, Johannes Ermert & Karl-Josef Langen

  3. Jülich-Aachen Research Alliance (JARA) – Section JARA-Brain, Aachen, Germany

    N. Jon Shah

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  1. Carina Stegmayr
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  2. Ulrike Bandelow
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Correspondence to Carina Stegmayr or Karl-Josef Langen.

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Stegmayr, C., Bandelow, U., Oliveira, D. et al. Influence of blood-brain barrier permeability on O-(2-18F-fluoroethyl)-L-tyrosine uptake in rat gliomas. Eur J Nucl Med Mol Imaging 44, 408–416 (2017). https://doi.org/10.1007/s00259-016-3508-0

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