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18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Neuroinflammation plays a critical role in various neuropathological conditions, and hence there is renewed interest in the translocator protein (TSPO) as a biomarker of microglial activation and macrophage infiltration in the brain. This is reflected in the large amount of research conducted seeking to replace the prototypical PET radiotracer 11C-R-PK11195 with a TSPO ligand with higher performance. Here we report the in vivo preclinical investigation of the novel TSPO tracer 18F-GE-180 in a rat model of stroke.

Methods

Focal cerebral ischaemia was induced in Wistar rats by 60-min occlusion of the middle cerebral artery (MCAO). Brain damage was assessed 24 h after MCAO by T2 MRI. Rats were scanned with 11C-R-PK11195 and 18F-GE-180 5 or 6 days after MCAO. Specificity of binding was confirmed by injection of unlabelled R-PK11195 or GE-180 20 min after injection of 18F-GE-180. In vivo data were confirmed by ex vivo immunohistochemistry for microglial (CD11b) and astrocytic biomarkers (GFAP).

Results

18F-GE-180 uptake was 24 % higher in the core of the ischaemic lesion and 18 % lower in the contralateral healthy tissue than that of 11C-R-PK11195 uptake (1.5 ± 0.2-fold higher signal to noise ratio). We confirmed this finding using the simplified reference tissue model (BPND = 3.5 ± 0.4 and 2.4 ± 0.5 for 18F-GE-180 and 11C-R-PK11195, respectively, with R 1 = 1). Injection of unlabelled R-PK11195 or GE-180 20 min after injection of 18F-GE-180 significantly displaced 18F-GE-180 (69 ± 5 % and 63 ± 4 %, respectively). Specificity of the binding was also confirmed by in vitro autoradiography, and the location and presence of activated microglia and infiltrated macrophages were confirmed by immunohistochemistry.

Conclusion

The in vivo binding characteristics of 18F-GE-180 demonstrate a better signal to noise ratio than 11C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that 18F-GE-180 is a strong candidate to replace 11C-R-PK11195.

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References

  1. Denes A, Thornton P, Rothwell NJ, Allan SM. Inflammation and brain injury: acute cerebral ischaemia, peripheral and central inflammation. Brain Behav Immun. 2010;24:708–23.

    Article  CAS  PubMed  Google Scholar 

  2. McColl BW, Allan SM, Rothwell NJ. Systemic inflammation and stroke: aetiology, pathology and targets for therapy. Biochem Soc Trans. 2007;35:1163–5.

    Article  CAS  PubMed  Google Scholar 

  3. Heneka MT, O’Banion MK, Terwel D, Kummer MP. Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm. 2010;117:919–47.

    Article  CAS  PubMed  Google Scholar 

  4. Johnston H, Boutin H, Allan SM. Assessing the contribution of inflammation in models of Alzheimer’s disease. Biochem Soc Trans. 2011;39:886–90.

    Article  CAS  PubMed  Google Scholar 

  5. Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer’s disease. Arch Pharm Res. 2010;33:1539–56.

    Article  CAS  PubMed  Google Scholar 

  6. Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology. 2009;73:768–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Lee JK, Tran T, Tansey MG. Neuroinflammation in Parkinson’s disease. J Neuroimmune Pharmacol. 2009;4:419–29

    Article  PubMed Central  PubMed  Google Scholar 

  9. Gerhard A, Pavese N, Hotton G, Turkheimer F, Es M, Hammers A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006;21:404–12.

    Article  CAS  PubMed  Google Scholar 

  10. Long-Smith CM, Sullivan AM, Nolan YM. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog Neurobiol. 2009;89:277–87.

    Article  CAS  PubMed  Google Scholar 

  11. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol. 2007;208:1–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Ringheim GE, Conant K. Neurodegenerative disease and the neuroimmune axis (Alzheimer’s and Parkinson’s disease, and viral infections). J Neuroimmunol. 2004;147(1–2):43–9.

    Article  PubMed  Google Scholar 

  13. Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123(11):2321–37.

    Article  PubMed  Google Scholar 

  14. Oh U, Fujita M, Ikonomidou VN, Evangelou IE, Matsuura E, Harberts E, et al. Translocator protein PET imaging for glial activation in multiple sclerosis. J Neuroimmune Pharmacol. 2011;6:354–61.

    Article  PubMed Central  PubMed  Google Scholar 

  15. 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;35:2304–19.

    Article  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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;32:1608–10.

    CAS  PubMed  Google Scholar 

  18. Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med. 2007;48:158–67.

    PubMed  Google Scholar 

  19. Folkersma H, Boellaard R, Vandertop WP, Kloet RW, Lubberink M, Lammertsma AA, et al. Reference tissue models and blood–brain barrier disruption: lessons from (R)-[11C]PK11195 in traumatic brain injury. J Nucl Med. 2009;50:1975–9.

    Article  PubMed  Google Scholar 

  20. 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;27:1965–74.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Tang D, McKinley ET, Hight MR, Uddin MI, Harp JM, Fu A, et al. Synthesis and structure-activity relationships of 5,6,7-substituted pyrazolopyrimidines: discovery of a novel TSPO PET ligand for cancer imaging. J Med Chem. 2013;56:3429–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A, et al. [18F]DPA-714: direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats. PLoS ONE. 2013;8:e56441.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Doorduin J, Klein HC, Dierckx RA, James M, Kassiou M, de Vries EF. [11C]-DPA-713 and [18F]-DPA-714 as new PET tracers for TSPO: a comparison with [11C]-(R)-PK11195 in a rat model of herpes encephalitis. Mol Imaging Biol. 2009;11:386–98.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Takano A, Piehl F, Hillert J, Varrone A, Nag S, Gulyas B, et al. In vivo TSPO imaging in patients with multiple sclerosis: a brain PET study with [18F]FEDAA1106. EJNMMI Res. 2013;3:30–3.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Takano A, Arakawa R, Ito H, Tateno A, Takahashi H, Matsumoto R, et al. Peripheral benzodiazepine receptors in patients with chronic schizophrenia: a PET study with [11C]DAA1106. Int J Neuropsychopharmacol. 2010;13:943–50.

    Article  CAS  PubMed  Google Scholar 

  27. Wadsworth H, Jones PA, Chau WF, Durrant C, Fouladi N, Passmore J, et al. [18F]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 

  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. 2014;55:466–72.

    Article  CAS  PubMed  Google Scholar 

  29. Calamante F, Lythgoe MF, Pell GS, Thomas DL, King MD, Busza AL, et al. Early changes in water diffusion, perfusion, T1, and T2 during focal cerebral ischemia in the rat studied at 8.5 T. Magn Reson Med. 1999;41:479–85.

    Article  CAS  PubMed  Google Scholar 

  30. Wegener S, Weber R, Ramos-Cabrer P, Uhlenkueken U, Sprenger C, Wiedermann D, et al. Temporal profile of T2-weighted MRI distinguishes between pannecrosis and selective neuronal death after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab. 2006;26:38–47.

    Article  PubMed  Google Scholar 

  31. Camsonne R, Crouzel C, Comar D, Maziere M, Prenant C, Sastre J, et al. Synthesis of N-(11C) methyl, N-(methyl-1 propyl), (chloro-2 phenyl)-1 isoquinoleine carboxamide-3 (PK 11195): a new ligand for peripheral benzodiazepine receptors. J Labelled Comp Radiopharm. 1984;21:985–91.

    Article  CAS  Google Scholar 

  32. Cremer JE, Hume SP, Cullen BM, Myers R, Manjil LG, Turton DR, et al. The distribution of radioactivity in brains of rats given [N-methyl-11C]PK 11195 in vivo after induction of a cortical ischaemic lesion. Int J Rad Appl Instrum B. 1992;19:159–66.

    Article  CAS  PubMed  Google Scholar 

  33. Maroy R, Boisgard R, Comtat C, Frouin V, Cathier P, Duchesnay E, et al. Segmentation of rodent whole-body dynamic PET images: an unsupervised method based on voxel dynamics. IEEE Trans Med Imaging. 2008;27:342–54.

    Article  PubMed  Google Scholar 

  34. Maroy R, Boisgard R, Comtat C, Jego B, Fontyn Y, Jan S, et al. Quantitative organ time activity curve extraction from rodent PET images without anatomical prior. Med Phys. 2010;37:1507–17.

    Article  CAS  PubMed  Google Scholar 

  35. Cawthorne C, Prenant C, Smigova A, Julyan P, Maroy R, Herholz K, et al. Biodistribution, pharmacokinetics and metabolism of interleukin-1 receptor antagonist (IL-1RA) using [18F]-IL1RA and PET imaging in rats. Br J Pharmacol. 2011;162:659–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage. 2005;24:591–5.

    Article  PubMed  Google Scholar 

  37. Thiel A, Radlinska BA, Paquette C, Sidel M, Soucy JP, Schirrmacher R, et al. The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J Nucl Med. 2010;51:1404–12.

    Article  CAS  PubMed  Google Scholar 

  38. Boutin H, Chauveau F, Thominiaux C, Gregoire 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;48:573–81.

    Article  CAS  PubMed  Google Scholar 

  39. Chauveau F, Van Camp N, Dolle 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;50:468–76.

    Article  CAS  PubMed  Google Scholar 

  40. Hughes JL, Jones PS, Beech JS, Wang D, Menon DK, Aigbirhio FI, et al. A microPET study of the regional distribution of [11C]-PK11195 binding following temporary focal cerebral ischemia in the rat. Correlation with post mortem mapping of microglia activation. Neuroimage. 2012;59:2007–16.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by GE Healthcare Ltd, the Wolfson Molecular Imaging Centre, Manchester, and the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement HEALTH-F2-2011-278850 (INMiND). The authors thank the personnel of the Wolfson Molecular Imaging Centre, especially Miss Gemma Chapman and Messrs Marc Radigois and Michael Green for facilitating this study. The Bioimaging Facility microscopes used in this study were purchased with grants from BBSRC, Wellcome Trust, and the University of Manchester Strategic Fund. The authors also thank Peter March, Jane Kott and Robert Fernandez for running the Bioimaging Facility.

Disclosure

This study was supported by GE Healthcare Ltd. GE Healthcare Ltd was involved in the design of the study and performed the metabolite analyses. GE Healthcare Ltd was not involved in other experiments.

Author information

Author notes

  1. Jesus Pradillo

    Present address: Universidad Complutense/Politecnica de Madrid, Madrid, Spain

Authors and Affiliations

  1. Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK

    Hervé Boutin & Alexander Gerhard

  2. Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, Manchester, M20 3LJ, UK

    Hervé Boutin, Alison Smigova & Alexander Gerhard

  3. Faculty of Life Sciences, University of Manchester, Manchester, UK

    Katie Murray & Jesus Pradillo

  4. SHFJ - CEA Orsay, Orsay, France

    Renaud Maroy

  5. GE Healthcare Ltd., Amersham, UK

    Paul A. Jones & William Trigg

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  1. Hervé Boutin
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Correspondence to Hervé Boutin.

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Boutin, H., Murray, K., Pradillo, J. 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 42, 503–511 (2015). https://doi.org/10.1007/s00259-014-2939-8

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  • DOI: https://doi.org/10.1007/s00259-014-2939-8

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