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European Journal of Nuclear Medicine and Molecular Imaging

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Open Access 01-05-2012 | Original Article

The translocator protein ligand [¹⁸F]DPA-714 images glioma and activated microglia in vivo

Authors: Alexandra Winkeler, Raphael Boisgard, Ali R. Awde, Albertine Dubois, Benoit Thézé, Jinzi Zheng, Luisa Ciobanu, Frédéric Dollé, Thomas Viel, Andreas H. Jacobs, Bertrand Tavitian

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 5/2012

Abstract

Purpose

In recent years there has been an increase in the development of radioligands targeting the 18-kDa translocator protein (TSPO). TSPO expression is well documented in activated microglia and serves as a biomarker for imaging neuroinflammation. In addition, TSPO has also been reported to be overexpressed in a number of cancer cell lines and human tumours including glioma. Here we investigated the use of [¹⁸F]DPA-714, a new TSPO positron emission tomography (PET) radioligand to image glioma in vivo.

Methods

We studied the uptake of [¹⁸F]DPA-714 in three different rat strains implanted with 9L rat glioma cells: Fischer (F), Wistar (W) and Sprague Dawley (SD) rats. Dynamic [¹⁸F]DPA-714 PET imaging, kinetic modelling of PET data and in vivo displacement studies using unlabelled DPA-714 and PK11195 were performed. Validation of TSPO expression in 9L glioma cell lines and intracranial 9L gliomas were investigated using Western blotting and immunohistochemistry of brain tissue sections.

Results

All rats showed significant [¹⁸F]DPA-714 PET accumulation at the site of 9L tumour implantation compared to the contralateral brain hemisphere with a difference in uptake among the three strains (F > W > SD). The radiotracer showed high specificity for TSPO as demonstrated by the significant reduction of [¹⁸F]DPA-714 binding in the tumour after administration of unlabelled DPA-714 or PK11195. TSPO expression was confirmed by Western blotting in 9L cells in vitro and by immunohistochemistry ex vivo.

Conclusion

The TSPO radioligand [¹⁸F]DPA-714 can be used for PET imaging of intracranial 9L glioma in different rat strains. This preclinical study demonstrates the feasibility of employing [¹⁸F]DPA-714 as an alternative radiotracer to image human glioma.

Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, et al. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006;27(8):402–9.PubMedCrossRef

Chauveau F, Boutin H, Van Camp N, Dollé F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging 2008;35(12):2304–19.PubMedCrossRef

Doorduin J, de Vries EF, Dierckx RA, Klein HC. PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des 2008;14(31):3297–315.PubMedCrossRef

Venneti S, Lopresti BJ, Wiley CA. The peripheral benzodiazepine receptor (translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 2006;80(6):308–22.PubMedCrossRef

Dollé F, Luus C, Reynolds A, Kassiou M. Radiolabelled molecules for imaging the translocator protein (18 kDa) using positron emission tomography. Curr Med Chem 2009;16(22):2899–923.PubMedCrossRef

Scarf AM, Kassiou M. The translocator protein. J Nucl Med 2011;52(5):677–80.PubMedCrossRef

Batarseh A, Papadopoulos V. Regulation of translocator protein 18 kDa (TSPO) expression in health and disease states. Mol Cell Endocrinol 2010;327(1–2):1–12.PubMedCrossRef

Corsi L, Geminiani E, Baraldi M. Peripheral benzodiazepine receptor (PBR) new insight in cell proliferation and cell differentiation review. Curr Clin Pharmacol 2008;3(1):38–45.PubMedCrossRef

Black KL, Ikezaki K, Santori E, Becker DP, Vinters HV. Specific high-affinity binding of peripheral benzodiazepine receptor ligands to brain tumors in rat and man. Cancer 1990;65(1):93–7.PubMedCrossRef

10.

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(6):752–8.PubMedCrossRef

11.

Olson JM, Junck L, Young AB, Penney JB, Mancini WR. Isoquinoline and peripheral-type benzodiazepine binding in gliomas: implications for diagnostic imaging. Cancer Res 1988;48(20):5837–41.PubMed

12.

Starosta-Rubinstein S, Ciliax BJ, Penney JB, McKeever P, Young AB. Imaging of a glioma using peripheral benzodiazepine receptor ligands. Proc Natl Acad Sci U S A 1987;84(3):891–5.PubMedCrossRef

13.

Benavides J, Cornu P, Dennis T, Dubois A, Hauw JJ, MacKenzie ET, et al. Imaging of human brain lesions with an omega 3 site radioligand. Ann Neurol 1988;24(6):708–12.PubMedCrossRef

14.

Syapin PJ, Skolnick P. Characterization of benzodiazepine binding sites in cultured cells of neural origin. J Neurochem 1979;32(3):1047–51.PubMedCrossRef

15.

Miettinen H, Kononen J, Haapasalo H, Helén P, Sallinen P, Harjuntausta T, et al. Expression of peripheral-type benzodiazepine receptor and diazepam binding inhibitor in human astrocytomas: relationship to cell proliferation. Cancer Res 1995;55(12):2691–5.PubMed

16.

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):1–7.PubMedCrossRef

17.

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(8):1608–10.PubMed

18.

Chauveau F, Van Camp N, Dollé F, Kuhnast B, Hinnen F, Damont A, et al. Comparative evaluation of the translocator protein radioligands 11C-DPA-713, 18F-DPA-714, and 11C-PK11195 in a rat model of acute neuroinflammation. J Nucl Med 2009;50(3):468–76.PubMedCrossRef

19.

Lodi F, Trespidi S, Di Pierro D, Marengo M, Farsad M, Fanti S, et al. A simple Tracerlab module modification for automated on-column [11C]methylation and [11C]carboxylation. Appl Radiat Isot 2007;65(6):691–5.PubMedCrossRef

20.

James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, et al. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med 2008;49(5):814–22.PubMedCrossRef

21.

Kuhnast B, Damont A, Hinnen F, Catarina T, Demphel S, Le Helleix S, et al. [(18)F]DPA-714, [(18)F]PBR111 and [(18)F]FEDAA1106–selective radioligands for imaging TSPO 18 kDa with PET: automated radiosynthesis on a TRACERLAb FX-FN synthesizer and quality controls. Appl Radiat Isot 2011 [Epub ahead of print].

22.

Damont A, Hinnen F, Kuhnast B, Schöllhorn-Peyronneau MA, James M, Luus C, et al. Radiosynthesis of [18F]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET. J Labelled Comp Radiopharm 2008;51(7–8):286–92.CrossRef

23.

Van Camp N, Boisgard R, Kuhnast B, Thézé B, Viel T, Grégoire MC, et al. In vivo imaging of neuroinflammation: a comparative study between [(18)F]PBR111, [(11)C]CLINME and [(11)C]PK11195 in an acute rodent model. Eur J Nucl Med Mol Imaging 2010;37(5):962–72.PubMedCrossRef

24.

Čížek J, Herholz K, Vollmar S, Schrader R, Klein J, Heiss WD. Fast and robust registration of PET and MR images of human brain. Neuroimage 2004;22(1):434–42.PubMedCrossRef

25.

Groom GN, Junck L, Foster NL, Frey KA, Kuhl DE. PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer’s disease. J Nucl Med 1995;36(12):2207–10.PubMed

26.

Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ, et al. Evaluation of reference regions for (R)-[(11)C]PK11195 studies in Alzheimer’s disease and mild cognitive impairment. J Cereb Blood Flow Metab 2007;27(12):1965–74.PubMedCrossRef

27.

Versijpt JJ, Dumont F, Van Laere KJ, Decoo D, Santens P, Audenaert K, et al. Assessment of neuroinflammation and microglial activation in Alzheimer’s disease with radiolabelled PK11195 and single photon emission computed tomography. A pilot study. Eur Neurol 2003;50(1):39–47.PubMedCrossRef

28.

Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4(3 Pt 1):153–8.PubMedCrossRef

29.

Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007;27(9):1533–9.PubMedCrossRef

30.

Boutin H, Chauveau F, Thominiaux C, Grégoire MC, James ML, Trebossen R, et al. 11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J Nucl Med 2007;48(4):573–81.PubMedCrossRef

31.

Ji B, Maeda J, Sawada M, Ono M, Okauchi T, Inaji M, et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer’s and other CNS pathologies. J Neurosci 2008;28(47):12255–67.PubMedCrossRef

32.

Martín A, Boisgard R, Thézé B, Van Camp N, Kuhnast B, Damont A, et al. Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab 2010;30(1)230–41.PubMedCrossRef

33.

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 2011;52(1):107–14.PubMedCrossRef

34.

Levin E, Premkumar A, Veenman L, Kugler W, Leschiner S, Spanier I, et al. The peripheral-type benzodiazepine receptor and tumorigenicity: isoquinoline binding protein (IBP) antisense knockdown in the C6 glioma cell line. Biochemistry 2005;44(29):9924–35.PubMedCrossRef

35.

Stojiljkovic M, Piperski V, Dacevic M, Rakic L, Ruzdijic S, Kanazir S. Characterization of 9L glioma model of the Wistar rat. J Neurooncol 2003;63(1):1–7.PubMedCrossRef

36.

Lorusso G, Rüegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem Cell Biol 2008;130(6):1091–103.PubMedCrossRef

37.

Badie B, Schartner JM. Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery 2000;46(4):957–61. discussion 961–2.PubMed

38.

Parney IF, Waldron JS, Parsa AT. Flow cytometry and in vitro analysis of human glioma-associated macrophages. Laboratory investigation. J Neurosurg 2009;110(3):572–82.PubMedCrossRef

39.

Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia 2011;59(8):1169–80.PubMedCrossRef

40.

Jacobs AH, Kracht LW, Gossmann A, Rüger MA, Thomas AV, Thiel A, et al. Imaging in neurooncology. NeuroRx 2005;2(2):333–47.PubMedCrossRef

41.

Dhermain FG, Hau P, Lanfermann H, Jacobs AH, van den Bent MJ. Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas. Lancet Neurol 2010;9(9):906–20.PubMedCrossRef

42.

Kläsner BD, Krause BJ, Beer AJ, Drzezga A. PET imaging of gliomas using novel tracers: a sleeping beauty waiting to be kissed. Expert Rev Anticancer Ther 2010;10(5):609–13.PubMedCrossRef

43.

Venneti S, Lopresti BJ, Wang G, Slagel SL, Mason NS, Mathis CA, et al. A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation. J Neurochem 2007;102(6):2118–31.PubMedCrossRef

44.

Fujimura Y, Zoghbi SS, Simèon FG, Taku A, Pike VW, Innis RB, et al. Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, (18)F-PBR06. J Nucl Med 2009;50(7):1047–53.PubMedCrossRef

45.

Imaizumi M, Briard E, Zoghbi SS, Gourley JP, Hong J, Fujimura Y, et al. Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors. Neuroimage 2008;39(3):1289–98.PubMedCrossRef

46.

Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol 2009;94(3):299–312.PubMedCrossRef

47.

Orringer DA, Chen T, Huang DL, Armstead WM, Hoff BA, Koo YE, et al. The brain tumor window model: a combined cranial window and implanted glioma model for evaluating intraoperative contrast agents. Neurosurgery 2010;66(4):736–43.PubMedCrossRef

48.

Herz RCG, Jonker M, Verheul HB, Hillen B, Versteeg DHG, de Wildt DJ. Middle cerebral artery occlusion in Wistar and Fischer-344 rats: functional and morphological assessment of the model. J Cereb Blood Flow Metab 1996;16(2):296–302.PubMedCrossRef

49.

Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage 2008;40(1):43–52.PubMedCrossRef

50.

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. J Nucl Med 2011;52(1):24–32.PubMedCrossRef

51.

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 2010;30(9):1608–18.PubMedCrossRef

52.

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 2011 [Epub ahead of print].

53.

Le DM, Besson A, Fogg DK, Choi KS, Waisman DM, Goodyer CG, et al. Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade. J Neurosci 2003;23(10):4034–43.PubMed

Title: The translocator protein ligand [18F]DPA-714 images glioma and activated microglia in vivo
Authors: Alexandra Winkeler
Raphael Boisgard
Ali R. Awde
Albertine Dubois
Benoit Thézé
Jinzi Zheng
Luisa Ciobanu
Frédéric Dollé
Thomas Viel
Andreas H. Jacobs
Bertrand Tavitian
Publication date: 01-05-2012
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 5/2012
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-011-2041-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The translocator protein ligand [¹⁸F]DPA-714 images glioma and activated microglia in vivo

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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