Clinical and Translational Imaging

, Volume 3, Issue 6, pp 423–435 | Cite as

TSPO imaging in stroke: from animal models to human subjects

Review Article


Stroke is a major health problem in developed countries and neuroinflammation has emerged over the last 2 decades as major contributor to the pathophysiological processes of brain damage following stroke. PET imaging of the translocator 18 kDa protein (TSPO) provides a unique non-invasive point of access to neuroinflammatory processes and more specifically microglial and astrocytic reaction after stroke in both animal models and patients. Here, we are reviewing both the experimental and clinical literature about in vivo TSPO PET and SPECT imaging in stroke. The studies in animal models of stroke reviewed here highlight a slightly faster time-course for TSPO expression in permanent vs. temporary stroke and a stronger activation in the infarct core in temporary stroke vs. a stronger activation in peri-infarct areas in permanent stroke. Altogether these findings suggest that areas where neuroinflammatory events occur post-stroke are at higher risk of secondary damage. The time-course of TSPO expression is slower in humans versus animal models of stroke. In human studies, the TSPO expression in the peri-infarct areas peaks 3–4 weeks after stroke and increased TSPO expression is demonstrated for months after the stroke in remote areas both ipsilesional to pyramidal tracts damage and in the contralesional hemisphere. Further clinical studies are warranted to address the role of TSPO and neuroinflammation in functional recovery and reorganization after stroke and the possible therapeutic implications. TSPO imaging appears to be a valid biomarker for demonstrating the dynamic process of neuroinflammation in stroke. But it is also clear that as the processes of microglial activation are increasingly complex, the need for new biomarkers and tracers targeting other aspect of glial reaction are needed to further investigate neuroinflammatory processes in patients.


Translocator protein 18 kDa TSPO Neuroinflammation PET Stroke 



This work was financially supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2011-278850 (INMiND), the Danish Council for Independent Research, the Research Committee of Rigshospitalet.

Compliance with ethical standards

Hervé Boutin and Lars H. Pinborg declare no conflicts of interest. The article contains data from studies with human and animal subjects performed by the authors of this article. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.


  1. 1.
    Braestrup C, Squires RF (1977) Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H)diazepam binding. Proc Natl Acad Sci 74(9):3805–3809CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Le Fur G, Vaucher N, Perrier ML, Flamier A, Benavides J, Renault C, Dubroeucq MC, Gueremy C, Uzan A (1983) Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195, by thermodynamic studies. Life Sci 33:449–457CrossRefPubMedGoogle Scholar
  3. 3.
    Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (2006) Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27(8):402–409. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  4. 4.
    Dubois A, Benavides J, Peny B, Duverger D, Fage D, Gotti B, MacKenzie ET, Scatton B (1988) Imaging of primary and remote ischaemic and excitotoxic brain lesions. An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat. Brain Res 445(1):77–90CrossRefPubMedGoogle Scholar
  5. 5.
    Benavides J, Capdeville C, Dauphin F, Dubois A, Duverger D, Fage D, Gotti B, MacKenzie ET, Scatton B (1990) The quantification of brain lesions with an w3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration. Brain Res 522:275–289CrossRefPubMedGoogle Scholar
  6. 6.
    Petit-Taboue MC, Baron JC, Barre L, Travere JM, Speckel D, Camsonne R, MacKenzie ET (1991) Brain kinetics and specific binding of [11C] PK 11195 to omega 3 sites in baboons: positron emission tomography study. Eur J Pharmacol 200:347–351CrossRefPubMedGoogle Scholar
  7. 7.
    Myers R, Manjil LG, Cullen BM, Price GW, Frackowiak RS, Cremer JE (1991) Macrophage and astrocyte populations in relation to [3H] PK 11195 binding in rat cerebral cortex following a local ischaemic lesion. J Cereb Blood Flow Metab 11:314–322CrossRefPubMedGoogle Scholar
  8. 8.
    Stephenson DT, Schober DA, Smalstig EB, Mincy RE, Gehlert DR, Clemens JA (1995) Peripheral benzodiazepine receptors are colocalized with activated microglia following transient global forebrain ischemia in the rat. J Neurosci 15:5263–5274PubMedGoogle Scholar
  9. 9.
    Cremer JE, Hume SP, Cullen BM, Myers R, Manjil LG, Turton DR, Luthra SK, Bateman DM, Pike VW (1992) 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 19:159–166CrossRefPubMedGoogle Scholar
  10. 10.
    Shah F, Hume SP, Pike VW, Ashworth S, McDermott J (1994) Synthesis of the enantiomers of [N-methyl-11C] PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats. Nucl Med Biol 21:573–581CrossRefPubMedGoogle Scholar
  11. 11.
    Stoll G, Jander S, Schroeter M (1998) Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol 56:149–171CrossRefPubMedGoogle Scholar
  12. 12.
    Touzani O, Boutin H, Chuquet J, Rothwell N (1999) Potential mechanisms of interleukin-1 involvement in cerebral ischaemia. J Neuroimmunol 100:203–215CrossRefPubMedGoogle Scholar
  13. 13.
    Sette G, Baron JC, Young AR, Miyazawa H, Tillet I, Barré L, Travère JM, Derlon JM, MacKenzie ET (1993) In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in the anesthetized baboon. Stroke J Cereb Circ 24:2046–2057CrossRefGoogle Scholar
  14. 14.
    Imaizumi M, Kim HJ, Zoghbi SS, Briard E, Hong J, Musachio JL, Ruetzler C, Chuang DM, Pike VW, Innis RB, Fujita M (2007) PET imaging with [(11)C] PBR28 can localize and quantify upregulated peripheral benzodiazepine receptors associated with cerebral ischemia in rat. Neurosci Lett 411:200–205CrossRefPubMedGoogle Scholar
  15. 15.
    Kenny BA, MacKinnon AC, Spedding M, Brown CM (1993) Changes in [3H]-PK 11195 and [3H]-8-OH-DPAT binding following forebrain ischaemia in the gerbil. Br J Pharmacol 109(2):437–442CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Earley B, Canney M, Clune B, Caldwell M, Leonard BE, Junien JL (1996) The effects of MK-801, ifenprodil, JO 1784, JO 1994 and JO 1997 on PK 11195 receptor binding, nitric oxide synthase (NO synthase) activity and infarct volume in a mouse model of focal cerebral ischaemia. Neurochem Int 28(5–6):509–521CrossRefPubMedGoogle Scholar
  17. 17.
    Craven JA, Conway EL (1997) Effects of alpha 2-adrenoceptor antagonists and imidazoline2-receptor ligands on neuronal damage in global ischaemia in the rat. Clin Exp Pharmacol Physiol 24(2):204–207CrossRefPubMedGoogle Scholar
  18. 18.
    Conway EL, Gundlach AL, Craven JA (1998) Temporal changes in glial fibrillary acidic protein messenger RNA and [3H] PK11195 binding in relation to imidazoline-I2-receptor and alpha 2-adrenoceptor binding in the hippocampus following transient global forebrain ischaemia in the rat. Neuroscience 82(3):805–817CrossRefPubMedGoogle Scholar
  19. 19.
    Miyazawa N, Saji H, Takaishi Y, Nukui H (2000) Protective effect of FK506 in the reperfusion model after short-term occlusion of middle cerebral artery in the rat: assessment by autoradiography using [125I] PK-11195. Neurol Res 22(6):630–633CrossRefPubMedGoogle Scholar
  20. 20.
    Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B (2008) Nuclear imaging of neuroinflammation: a comprehensive review of [11C] PK11195 challengers. Eur J Nucl Med Mol Imaging 35(12):2304–2319. doi: 10.1007/s00259-008-0908-9 CrossRefPubMedGoogle Scholar
  21. 21.
    Bacigaluppi M, Comi G, Hermann DM (2010) Animal models of ischemic stroke. Part two: modeling cerebral ischemia. Open Neurol J 4:34–38. doi: 10.2174/1874205X01004020034 PubMedPubMedCentralGoogle Scholar
  22. 22.
    Bacigaluppi M, Comi G, Hermann DM (2010) Animal models of ischemic stroke. Part one: modeling risk factors. Open Neurol J 4:26–33. doi: 10.2174/1874205X01004020026 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Durukan A, Tatlisumak T (2009) Animal models of ischemic stroke. Handb Clin Neurol 92:43–66. doi: 10.1016/S0072-9752(08)01903-9 (edited by PJ Vinken and GW Bruyn) CrossRefPubMedGoogle Scholar
  24. 24.
    Fluri F, Schuhmann MK, Kleinschnitz C (2015) Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther 9:3445–3454. doi: 10.2147/DDDT.S56071 PubMedPubMedCentralGoogle Scholar
  25. 25.
    Rojas S, Martin A, Arranz MJ, Pareto D, Purroy J, Verdaguer E, Llop J, Gomez V, Gispert JD, Millan O, Chamorro A, Planas AM (2007) Imaging brain inflammation with [(11)C] PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J Cereb Blood Flow Metab 27:1975–1986CrossRefPubMedGoogle Scholar
  26. 26.
    Martin A, Boisgard R, Kassiou M, Dolle F, Tavitian B (2010) Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a pet study using [(18)F] DPA-714. Mol Imag Biol 13:10–15CrossRefGoogle Scholar
  27. 27.
    Martin A, Boisgard R, Theze B, Van CN, Kuhnast B, Damont A, Kassiou M, Dolle F, Tavitian B (2010) Evaluation of the PBR/TSPO radioligand [(18)F] DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab 30:230–241CrossRefPubMedGoogle Scholar
  28. 28.
    Martin A, Boisgard R, Theze B, Van Camp N, Kuhnast B, Damont A, Kassiou M, Dolle F, Tavitian B (2010) Evaluation of the PBR/TSPO radioligand [(18)F] DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab 30(1):230–241. doi: 10.1038/jcbfm.2009.205 CrossRefPubMedGoogle Scholar
  29. 29.
    Hughes JL, Jones PS, Beech JS, Wang D, Menon DK, Aigbirhio FI, Fryer TD, Baron JC (2012) 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 59(3):2007–2016. doi: 10.1016/j.neuroimage.2011.10.060 CrossRefPubMedGoogle Scholar
  30. 30.
    Lavisse S, Guillermier M, Herard AS, Petit F, Delahaye M, Van CN, Ben HL, Lebon V, Remy P, Dolle F, Delzescaux T, Bonvento G, Hantraye P, Escartin C (2012) Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J Neurosci 32:10809–10818CrossRefPubMedGoogle Scholar
  31. 31.
    Arnberg F, Lundberg J, Soderman M, Damberg P, Holmin S (2012) Image-guided method in the rat for inducing cortical or striatal infarction and for controlling cerebral blood flow under MRI. Stroke J Cereb Circ 43(9):2437–2443. doi: 10.1161/STROKEAHA.112.655126 CrossRefGoogle Scholar
  32. 32.
    Toth M, Little P, Arnberg F, Haggkvist J, Mulder J, Halldin C, Gulyas B, Holmin S (2015) Acute neuroinflammation in a clinically relevant focal cortical ischemic stroke model in rat: longitudinal positron emission tomography and immunofluorescent tracking. Brain Struct Funct. doi: 10.1007/s00429-014-0970-y Google Scholar
  33. 33.
    Rueger MA, Muesken S, Walberer M, Jantzen SU, Schnakenburg K, Backes H, Graf R, Neumaier B, Hoehn M, Fink GR, Schroeter M (2012) Effects of minocycline on endogenous neural stem cells after experimental stroke. Neuroscience 215:174–183. doi: 10.1016/j.neuroscience.2012.04.036 CrossRefPubMedGoogle Scholar
  34. 34.
    Banwell V, Sena ES, Macleod MR (2009) Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke. J Stroke Cerebrovasc Dis 18:269–276CrossRefPubMedGoogle Scholar
  35. 35.
    Parry-Jones A, Boutin H, Denes A, McColl B, Hopkins S, Allan S, Tyrrell P (2010) Interleukin-1 receptor antagonist in animal models of stroke: a fair summing up? J Stroke Cerebrovasc Dis 19:512–513CrossRefPubMedGoogle Scholar
  36. 36.
    Pinteaux E, Rothwell NJ, Boutin H (2006) Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia 53:551–556CrossRefPubMedGoogle Scholar
  37. 37.
    Pradillo JM, Denes A, Greenhalgh AD, Boutin H, Drake C, McColl BW, Barton E, Proctor SD, Russell JC, Rothwell NJ, Allan SM (2012) Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inflammation in comorbid rats. J Cereb Blood Flow Metab 32:1810–1819CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ali C, Nicole O, Docagne F, Lesne S, MacKenzie ET, Nouvelot A, Buisson A, Vivien D (2000) Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain. J Cereb Blood Flow Metab 20:956–966CrossRefPubMedGoogle Scholar
  39. 39.
    Ali C, Nicole O, Docagne F, Lesne S, Nouvelot A, MacKenzie ET, Buisson A, Vivien D (1999) Evidence that IL-6 is selectively neuroprotective against excitotoxic-type of ischemic neuronal death. Paper presented at the J Cereb Blood Flow Metab, 1999Google Scholar
  40. 40.
    Hill JK, Gunion-Rinker L, Kulhanek D, Lessov N, Kim S, Clark WM, Dixon MP, Nishi R, Stenzel-Poore MP, Eckenstein FP (1999) Temporal modulation of cytokine expression following focal cerebral ischemia in mice. Brain Res 820:45–54CrossRefPubMedGoogle Scholar
  41. 41.
    Dodel R, Spottke A, Gerhard A, Reuss A, Reinecker S, Schimke N, Trenkwalder C, Sixel-Doring F, Herting B, Kamm C, Gasser T, Sawires M, Geser F, Kollensperger M, Seppi K, Kloss M, Krause M, Daniels C, Deuschl G, Bottger S, Naumann M, Lipp A, Gruber D, Kupsch A, Du Y, Turkheimer F, Brooks DJ, Klockgether T, Poewe W, Wenning G, Schade-Brittinger C, Oertel WH, Eggert K (2010) Minocycline 1-year therapy in multiple-system-atrophy: effect on clinical symptoms and [(11)C] (R)-PK11195 PET (MEMSA-trial). Mov Disord: Off J Mov Disord Soc 25:97–107CrossRefGoogle Scholar
  42. 42.
    Wang Y, Yue X, Kiesewetter DO, Wang Z, Lu J, Niu G, Teng G, Chen X (2014) [(18)F]DPA-714 PET imaging of AMD3100 treatment in a mouse model of stroke. Mol Pharm 11:3463–3470CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Boutin H, Prenant C, Galea J, Greenhalgh A, Julyan P, Brown G, Herholz K, Kassiou M, Rothwell NJ (2008) [18F]DPA-714: evaluation and direct comparison with [11C]PK11195 in a model of cerebral ischemia in rats. Paper presented at the 1st world molecular imaging congress, 11/10/2008Google Scholar
  44. 44.
    Schroeter M, Dennin MA, Walberer M, Backes H, Neumaier B, Fink GR, Graf R (2009) Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study. J Cereb Blood Flow Metab 29:1216–1225CrossRefPubMedGoogle Scholar
  45. 45.
    Fukumoto D, Hosoya T, Nishiyama S, Harada N, Iwata H, Yamamoto S, Tsukada H (2011) Multiparametric assessment of acute and subacute ischemic neuronal damage: a small animal positron emission tomography study with rat photochemically induced thrombosis model. Synapse 65:207–214CrossRefPubMedGoogle Scholar
  46. 46.
    Fukumoto D, Nishiyama S, Harada N, Yamamoto S, Tsukada H (2012) Detection of ischemic neuronal damage with [(1)(8)F] BMS-747158-02, a mitochondrial complex-1 positron emission tomography ligand: small animal PET study in rat brain. Synapse 66:909–917CrossRefPubMedGoogle Scholar
  47. 47.
    Walberer M, Jantzen SU, Backes H, Rueger MA, Keuters MH, Neumaier B, Hoehn M, Fink GR, Graf R, Schroeter M (2014) In-vivo detection of inflammation and neurodegeneration in the chronic phase after permanent embolic stroke in rats. Brain Res 1581:80–88. doi: 10.1016/j.brainres.2014.05.030 CrossRefPubMedGoogle Scholar
  48. 48.
    Fujie W, Kirino T, Tomukai N, Iwasawa T, Tamura A (1990) Progressive shrinkage of the thalamus following middle cerebral artery occlusion in rats. Stroke J Cereb Circ 21:1485–1488CrossRefGoogle Scholar
  49. 49.
    Iizuka H, Sakatani K, Young W (1990) Neural damage in the rat thalamus after cortical infarcts. Stroke J Cereb Circ 21:790–794CrossRefGoogle Scholar
  50. 50.
    Yui J, Maeda J, Kumata K, Kawamura K, Yanamoto K, Hatori A, Yamasaki T, Nengaki N, Higuchi M, Zhang MR (2010) 18F-FEAC and 18F-FEDAC: PET of the monkey brain and imaging of translocator protein (18 kDa) in the infarcted rat brain. J Nucl Med 51:1301–1309CrossRefPubMedGoogle Scholar
  51. 51.
    Yui J, Hatori A, Kawamura K, Yanamoto K, Yamasaki T, Ogawa M, Yoshida Y, Kumata K, Fujinaga M, Nengaki N, Fukumura T, Suzuki K, Zhang MR (2011) Visualization of early infarction in rat brain after ischemia using a translocator protein (18 kDa) PET ligand [11C] DAC with ultra-high specific activity. Neuroimage 54:123–130CrossRefPubMedGoogle Scholar
  52. 52.
    Yui J, Hatori A, Yanamoto K, Takei M, Nengaki N, Kumata K, Kawamura K, Yamasaki T, Suzuki K, Zhang MR (2010) Imaging of the translocator protein (18 kDa) in rat brain after ischemia using [11C] DAC with ultra-high specific activity. Synapse 64(6):488–493. doi: 10.1002/syn.20761 CrossRefPubMedGoogle Scholar
  53. 53.
    Boutin H, Prenant C, Maroy R, Galea J, Greenhalgh AD, Smigova A, Cawthorne C, Julyan P, Wilkinson SM, Banister SD, Brown G, Herholz K, Kassiou M, Rothwell NJ (2013) [18F]DPA-714: direct comparison with [11C] PK11195 in a model of cerebral ischemia in rats. PLoS One 8(2):e56441. doi: 10.1371/journal.pone.0056441 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Boutin H, Murray K, Pradillo J, Maroy R, Smigova A, Gerhard A, Jones PA, Trigg W (2015) 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(3):503–511. doi: 10.1007/s00259-014-2939-8 CrossRefPubMedGoogle Scholar
  55. 55.
    Higuchi M (2009) Visualization of brain amyloid and microglial activation in mouse models of Alzheimer’s disease. Curr Alzheimer Res 6:137–143CrossRefPubMedGoogle Scholar
  56. 56.
    Hume SP, Gunn RN, Jones T (1998) Pharmacological constraints associated with positron emission tomographic scanning of small laboratory animals. Eur J Nucl Med 25(2):173–176CrossRefPubMedGoogle Scholar
  57. 57.
    Lartey FM, Ahn GO, Shen B, Cord KT, Smith T, Chua JY, Rosenblum S, Liu H, James ML, Chernikova S, Lee SW, Pisani LJ, Tirouvanziam R, Chen JW, Palmer TD, Chin FT, Guzman R, Graves EE, Loo BW Jr (2014) PET imaging of stroke-induced neuroinflammation in mice using [18F] PBR06. Mol Imag Biol 16(1):109–117. doi: 10.1007/s11307-013-0664-5 CrossRefGoogle Scholar
  58. 58.
    Dolle F, Luus C, Reynolds A, Kassiou M (2009) Radiolabelled molecules for imaging the translocator protein (18 kDa) using positron emission tomography. Curr Med Chem 16(22):2899–2923CrossRefPubMedGoogle Scholar
  59. 59.
    Chauveau F, Van Camp N, Dolle F, Kuhnast B, Hinnen F, Damont A, Boutin H, James M, Kassiou M, Tavitian B (2009) 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 50(3):468–476. doi: 10.2967/jnumed.108.058669 CrossRefPubMedGoogle Scholar
  60. 60.
    Tiwari AK, Ji B, Yui J, Fujinaga M, Yamasaki T, Xie L, Luo R, Shimoda Y, Kumata K, Zhang Y, Hatori A, Maeda J, Higuchi M, Wang F, Zhang MR (2015) [(18)F]FEBMP: positron emission tomography imaging of TSPO in a model of neuroinflammation in rats, and in vitro autoradiograms of the human brain. Theranostics 5(9):961–969. doi: 10.7150/thno.12027 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Tiwari AK, Yui J, Fujinaga M, Kumata K, Shimoda Y, Yamasaki T, Xie L, Hatori A, Maeda J, Nengaki N, Zhang MR (2014) Characterization of a novel acetamidobenzoxazolone-based PET ligand for translocator protein (18 kDa) imaging of neuroinflammation in the brain. J Neurochem 129:712–720CrossRefPubMedGoogle Scholar
  62. 62.
    Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M, Gunn RN, Rabiner EA, Wilkins MR, Reynolds R, Matthews PM, Parker CA (2010) Two binding sites for [3H] PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30(9):1608–1618. doi: 10.1038/jcbfm.2010.63 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, Innis RB, Pike VW, Reynolds R, Matthews PM, Parker CA (2011) Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 52(1):24–32. doi: 10.2967/jnumed.110.079459 CrossRefPubMedGoogle Scholar
  64. 64.
    Guo Q, Owen DR, Rabiner EA, Turkheimer FE, Gunn RN (2012) Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo. Neuroimage 60(2):902–910. doi: 10.1016/j.neuroimage.2011.12.078 CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ramsay SC, Weiller C, Myers R, Cremer JE, Luthra SK, Lammertsma AA, Frackowiak RS (1992) Monitoring by PET of macrophage accumulation in brain after ischaemic stroke. Lancet 339(8800):1054–1055CrossRefPubMedGoogle Scholar
  66. 66.
    Gerhard A, Neumaier B, Elitok E, Glatting G, Ries V, Tomczak R, Ludolph AC, Reske SN (2000) In vivo imaging of activated microglia using [11C] PK11195 and positron emission tomography in patients after ischemic stroke. NeuroReport 11(13):2957–2960CrossRefPubMedGoogle Scholar
  67. 67.
    Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, Jones T, Kreutzberg GW, Banati RB (2000) Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C] PK1195. Neurology 55(7):1052–1054CrossRefPubMedGoogle Scholar
  68. 68.
    Gerhard A, Schwarz J, Myers R, Wise R, Banati RB (2005) Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage 24(2):591–595. doi: 10.1016/j.neuroimage.2004.09.034 CrossRefPubMedGoogle Scholar
  69. 69.
    Price CJ, Wang D, Menon DK, Guadagno JV, Cleij M, Fryer T, Aigbirhio F, Baron JC, Warburton EA (2006) Intrinsic activated microglia map to the peri-infarct zone in the subacute phase of ischemic stroke. Stroke J Cereb Circ 37(7):1749–1753. doi: 10.1161/01.STR.0000226980.95389.0b CrossRefGoogle Scholar
  70. 70.
    Radlinska BA, Ghinani SA, Lyon P, Jolly D, Soucy JP, Minuk J, Schirrmacher R, Thiel A (2009) Multimodal microglia imaging of fiber tracts in acute subcortical stroke. Ann Neurol 66(6):825–832. doi: 10.1002/ana.21796 CrossRefPubMedGoogle Scholar
  71. 71.
    Thiel A, Radlinska BA, Paquette C, Sidel M, Soucy JP, Schirrmacher R, Minuk J (2010) The temporal dynamics of poststroke neuroinflammation: a longitudinal diffusion tensor imaging-guided PET study with 11C-PK11195 in acute subcortical stroke. J Nucl Med 51(9):1404–1412. doi: 10.2967/jnumed.110.076612 CrossRefPubMedGoogle Scholar
  72. 72.
    Gulyas B, Toth M, Schain M, Airaksinen A, Vas A, Kostulas K, Lindstrom P, Hillert J, Halldin C (2012) Evolution of microglial activation in ischaemic core and peri-infarct regions after stroke: a PET study with the TSPO molecular imaging biomarker [((11))C] vinpocetine. J Neurol Sci 320(1–2):110–117. doi: 10.1016/j.jns.2012.06.026 CrossRefPubMedGoogle Scholar
  73. 73.
    Gulyas B, Toth M, Vas A, Shchukin E, Kostulas K, Hillert J, Halldin C (2012) Visualising neuroinflammation in post-stroke patients: a comparative PET study with the TSPO molecular imaging biomarkers [11C] PK11195 and [11C] vinpocetine. Curr Radiopharm 5(1):19–28CrossRefPubMedGoogle Scholar
  74. 74.
    Ribeiro MJ, Vercouillie J, Debiais S, Cottier JP, Bonnaud I, Camus V, Banister S, Kassiou M, Arlicot N, Guilloteau D (2014) Could (18) F-DPA-714 PET imaging be interesting to use in the early post-stroke period? EJNMMI Res 4:28. doi: 10.1186/s13550-014-0028-4 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Feng L, Svarer C, Thomsen G, de Nijs R, Larsen VA, Jensen P, Adamsen D, Dyssegaard A, Fischer W, Meden P, Krieger D, Moller K, Knudsen GM, Pinborg LH (2014) In vivo quantification of cerebral translocator protein binding in humans using 6-chloro-2-(4’-123I-iodophenyl)-3-(N, N-diethyl)-imidazo[1,2-a]pyridine-3-acetamid e SPECT. J Nucl Med 55(12):1966–1972. doi: 10.2967/jnumed.114.143727 CrossRefPubMedGoogle Scholar
  76. 76.
    Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ (1997) Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage 6(4):279–287. doi: 10.1006/nimg.1997.0303 CrossRefPubMedGoogle Scholar
  77. 77.
    Folkersma H, Boellaard R, Vandertop WP, Kloet RW, Lubberink M, Lammertsma AA, van Berckel BN (2009) Reference tissue models and blood-brain barrier disruption: lessons from (R)-[11C] PK11195 in traumatic brain injury. J Nucl Med 50(12):1975–1979. doi: 10.2967/jnumed.109.067512 CrossRefPubMedGoogle Scholar
  78. 78.
    Jensen P, Feng L, Law I, Svarer C, Knudsen GM, Mikkelsen JD, de Nijs R, Larsen VA, Dyssegaard A, Thomsen G, Fischer W, Guilloteau D, Pinborg LH (2015) TSPO imaging in glioblastoma multiforme: a direct comparison between 123I-CLINDE SPECT, 18F-FET PET, and gadolinium-enhanced MR imaging. J Nucl Med 56(9):1386–1390. doi: 10.2967/jnumed.115.158998 CrossRefPubMedGoogle Scholar
  79. 79.
    Saleh A, Schroeter M, Jonkmanns C, Hartung HP, Modder U, Jander S (2004) In vivo MRI of brain inflammation in human ischaemic stroke. Brain J Neurol 127(Pt 7):1670–1677. doi: 10.1093/brain/awh191 CrossRefGoogle Scholar
  80. 80.
    Nighoghossian N, Wiart M, Cakmak S, Berthezene Y, Derex L, Cho TH, Nemoz C, Chapuis F, Tisserand GL, Pialat JB, Trouillas P, Froment JC, Hermier M (2007) Inflammatory response after ischemic stroke: a USPIO-enhanced MRI study in patients. Stroke J Cereb Circ 38(2):303–307. doi: 10.1161/01.STR.0000254548.30258.f2 CrossRefGoogle Scholar
  81. 81.
    Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (2012) An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 32(1):1–5. doi: 10.1038/jcbfm.2011.147 CrossRefPubMedGoogle Scholar
  82. 82.
    Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, Zoghbi SS, Hyde T, Kleinman JE, Pike VW, McMahon FJ, Innis RB (2013) A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J Cereb Blood Flow Metab 33(1):53–58. doi: 10.1038/jcbfm.2012.131 CrossRefPubMedGoogle Scholar
  83. 83.
    Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA, Allan SM (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 27(12):1941–1953. doi: 10.1038/sj.jcbfm.9600495 CrossRefPubMedGoogle Scholar
  84. 84.
    Rodriguez-Vieitez E, Ni R, Gulyas B, Toth M, Haggkvist J, Halldin C, Voytenko L, Marutle A, Nordberg A (2015) Astrocytosis precedes amyloid plaque deposition in alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study. Eur J Nucl Med Mol ImagGoogle Scholar
  85. 85.
    Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, Nordberg A (2012) Evidence for astrocytosis in prodromal alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53:37–46CrossRefPubMedGoogle Scholar
  86. 86.
    Evens N, Vandeputte C, Coolen C, Janssen P, Sciot R, Baekelandt V, Verbruggen AM, Debyser Z, Van Laere K, Bormans GM (2012) Preclinical evaluation of [11C]NE40, a type 2 cannabinoid receptor PET tracer. Nucl Med Biol 39(3):389–399. doi: 10.1016/j.nucmedbio.2011.09.005 CrossRefPubMedGoogle Scholar
  87. 87.
    Vandeputte C, Casteels C, Struys T, Koole M, van Veghel D, Evens N, Gerits A, Dresselaers T, Lambrichts I, Himmelreich U, Bormans G, Van Laere K (2012) Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model. Eur J Nucl Med Mol Imag 39:1796–1806CrossRefGoogle Scholar

Copyright information

© Italian Association of Nuclear Medicine and Molecular Imaging 2015

Authors and Affiliations

  1. 1.Wolfson Molecular Imaging Centre, Faculty of Medical and Human Sciences, University of ManchesterManchesterUK
  2. 2.Neurobiology Research Unit, Department of NeurologyRigshospitaletCopenhagenDenmark

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