Skip to main content

Advertisement

SpringerLink
Log in

In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients

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

Abstract

Purpose

Imaging the 18-kDa translocator protein (TSPO) is considered a potential tool for in vivo evaluation of microglial activation and neuroinflammation in the early stages of Alzheimer’s disease (AD). ((R)-1-(2-chlorophenyl)-N-[11C]-methyl-N-(1-methylpropyl)-3-isoquinoline caboxamide ([11C]-(R)-PK11195) has been widely used for PET imaging of TSPO and, despite its low specific-to-nondisplaceable binding ratio, increased TSPO binding has been shown in AD patients. The high-affinity radioligand N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide ([18F]FEDAA1106) has been developed as a potential in vivo imaging tool for better quantification of TSPO binding. The aim of this study was to quantify in vivo binding of [18F]FEDAA1106 to TSPO in control subjects and AD patients.

Methods

Seven controls (five men, two women, age 68±3 years, MMSE score 29±1) and nine AD patients (six men, three women, age 69±4 years, MMSE score 25±3) were studied with [18F]FEDAA1106. PET measurements were performed on an ECAT EXACT HR system (Siemens Medical Solutions) in two 60-min dynamic PET sessions with a 30-min interval between sessions. Arterial blood radioactivity was measured using an automated blood sampling system for the first 5 min and using manually drawn samples thereafter. Quantification was performed using both kinetic analysis based on a two-tissue compartment model and Logan graphical analysis. Outcome measures were total distribution volume (V T) and binding potential (BP ND=k 3/k 4). An estimate of nondisplaceable distribution volume was obtained with the Logan graphical analysis using the first 15 min of PET measurements (V ND 1-15 min). Binding potential (BP ND) was also calculated as: V T/V ND 1-15 min − 1.

Results

No statistically significant differences in V T, k 3/k 4 or BP ND were observed between controls and AD patients.

Conclusion

This study suggests that TSPO imaging with [18F]FEDAA1106 does not enable the detection of microglial activation in AD.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010;9:971–88.

    Article  PubMed  CAS  Google Scholar 

  2. Scarf AM, Kassiou M. The translocator protein. J Nucl Med. 2011;52:677–80.

    Article  PubMed  CAS  Google Scholar 

  3. Bird JL, Izquierdo-Garcia D, Davies JR, Rudd JH, Probst KC, Figg N, et al. Evaluation of translocator protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis. Atherosclerosis. 2010;210:388–91.

    Article  PubMed  CAS  Google Scholar 

  4. Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, et al. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 2009;35:306–28.

    Article  PubMed  CAS  Google Scholar 

  5. Kuhlmann AC, Guilarte TR. Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem. 2000;74:1694–704.

    Article  PubMed  CAS  Google Scholar 

  6. Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia. 2013;61:10–23.

    Article  PubMed  Google Scholar 

  7. Pappata S, Levasseur M, Gunn RN, Myers R, Crouzel C, Syrota A, et al. Thalamic microglial activation in ischemic stroke detected in vivo by PET and [11C]PK1195. Neurology. 2000;55:1052–4.

    Article  PubMed  CAS  Google Scholar 

  8. Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70:374–83.

    Article  PubMed  Google Scholar 

  9. 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(Pt 11):2321–37.

    Article  PubMed  Google Scholar 

  10. Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, et al. In-vivo measurement of activated microglia in dementia. Lancet. 2001;358:461–7.

    Article  PubMed  CAS  Google Scholar 

  11. 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  PubMed  CAS  Google Scholar 

  12. Halliday G, Robinson SR, Shepherd C, Kril J. Alzheimer’s disease and inflammation: a review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol. 2000;27:1–8.

    Article  PubMed  CAS  Google Scholar 

  13. Akiyama H, Arai T, Kondo H, Tanno E, Haga C, Ikeda K. Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis Assoc Disord. 2000;14 Suppl 1:S47–53.

    Article  PubMed  CAS  Google Scholar 

  14. Chaki S, Funakoshi T, Yoshikawa R, Okuyama S, Okubo T, Nakazato A, et al. Binding characteristics of [3H]DAA1106, a novel and selective ligand for peripheral benzodiazepine receptors. Eur J Pharmacol. 1999;371:197–204.

    Article  PubMed  CAS  Google Scholar 

  15. 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  PubMed  CAS  Google Scholar 

  16. Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y, et al. Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. Synapse. 2004;52:283–91.

    Article  PubMed  CAS  Google Scholar 

  17. Zhang MR, Maeda J, Furutsuka K, Yoshida Y, Ogawa M, Suhara T, et al. [18F]FMDAA1106 and [18F]FEDAA1106: two positron-emitter labeled ligands for peripheral benzodiazepine receptor (PBR). Bioorg Med Chem Lett. 2003;13:201–4.

    Article  PubMed  CAS  Google Scholar 

  18. Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H, et al. Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [(11)C]DAA1106. J Cereb Blood Flow Metab. 2007;27:173–84.

    Article  PubMed  CAS  Google Scholar 

  19. Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK, et al. Increased binding of peripheral benzodiazepine receptor in Alzheimer’s disease measured by positron emission tomography with [11C]DAA1106. Biol Psychiatry. 2008;64:835–41.

    Article  PubMed  CAS  Google Scholar 

  20. Zhang MR, Maeda J, Ogawa M, Noguchi J, Ito T, Yoshida Y, et al. Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for pet imaging of peripheral benzodiazepine receptor in primate brain. J Med Chem. 2004;47:2228–35.

    Article  PubMed  CAS  Google Scholar 

  21. Fujimura Y, Ikoma Y, Yasuno F, Suhara T, Ota M, Matsumoto R, et al. Quantitative analyses of 18F-FEDAA1106 binding to peripheral benzodiazepine receptors in living human brain. J Nucl Med. 2006;47:43–50.

    PubMed  CAS  Google Scholar 

  22. Takano A, Gulyas B, Varrone A, Karlsson P, Sjoholm N, Larsson S, et al. Biodistribution and radiation dosimetry of the 18 kDa translocator protein (TSPO) radioligand [18F]FEDAA1106: a human whole-body PET study. Eur J Nucl Med Mol Imaging. 2011;38:2058–65.

    Article  PubMed  CAS  Google Scholar 

  23. Bergstrom M, Boethius J, Eriksson L, Greitz T, Ribbe T, Widen L. Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr. 1981;5:136–41.

    Article  PubMed  CAS  Google Scholar 

  24. Wienhard K, Dahlbom M, Eriksson L, Michel C, Bruckbauer T, Pietrzyk U, et al. The ECAT EXACT HR: performance of a new high resolution positron scanner. J Comput Assist Tomogr. 1994;18:110–8.

    Article  PubMed  CAS  Google Scholar 

  25. Wahlund LO, Barkhof F, Fazekas F, Bronge L, Augustin M, Sjogren M, et al. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke. 2001;32:1318–22.

    Article  PubMed  CAS  Google Scholar 

  26. Roland PE, Geyer S, Amunts K, Schormann T, Schleicher A, Malikovic A, et al. Cytoarchitectural maps of the human brain in standard anatomical space. Hum Brain Mapp. 1997;5:222–7.

    Article  PubMed  CAS  Google Scholar 

  27. Varrone A, Toth M, Steiger C, Takano A, Guilloteau D, Ichise M, et al. Kinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2I. J Nucl Med. 2011;52:132–9.

    Article  PubMed  CAS  Google Scholar 

  28. Ito H, Yokoi T, Ikoma Y, Shidahara M, Seki C, Naganawa M, et al. A new graphic plot analysis for determination of neuroreceptor binding in positron emission tomography studies. Neuroimage. 2010;49:578–86.

    Article  PubMed  Google Scholar 

  29. Ikoma Y, Takano A, Varrone A, Halldin C. Graphic plot analysis for estimating binding potential of translocator protein (TSPO) in positron emission tomography studies with [(18)F]FEDAA1106. Neuroimage. 2012;69C:78–86.

    Google Scholar 

  30. 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  PubMed  CAS  Google Scholar 

  31. 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 

  32. Yaqub M, van Berckel BN, Schuitemaker A, Hinz R, Turkheimer FE, Tomasi G, et al. Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[(11)C]PK11195 brain PET studies. J Cereb Blood Flow Metab. 2012;32:1600–8.

    Article  PubMed  CAS  Google Scholar 

  33. Slifstein M, Laruelle M. Effects of statistical noise on graphic analysis of PET neuroreceptor studies. J Nucl Med. 2000;41:2083–8.

    PubMed  CAS  Google Scholar 

  34. 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  PubMed  CAS  Google Scholar 

  35. 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;52:24–32.

    Article  PubMed  CAS  Google Scholar 

  36. Gulyas B, Makkai B, Kasa P, Gulya K, Bakota L, Varszegi S, et al. A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system. Neurochem Int. 2009;54:28–36.

    Article  PubMed  CAS  Google Scholar 

  37. Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, et al. 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. 2012;53:37–46.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Bayer HealthCare AG. The authors thank the personnel of the Karolinska Institutet PET Centre and of the Karolinska Trial Alliance for excellent assistance in the performance of the PET studies.

Author information

Authors and Affiliations

  1. Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Hospital, R5:02, SE-17176, Stockholm, Sweden

    Andrea Varrone, Patrik Mattsson, Anton Forsberg, Akihiro Takano, Sangram Nag, Balázs Gulyás, Jacqueline Borg & Christer Halldin

  2. Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands

    Ronald Boellaard & Adriaan A. Lammertsma

  3. Karolinska Trial Alliance Phase-I Unit, Karolinska University Hospital, Stockholm, Sweden

    Nabil Al-Tawil

  4. Karolinska Institutet, Department of Neurobiology, Care Sciences and Society, Division of Clinical Geriatrics, Novum, Stockholm, Sweden

    Maria Eriksdotter

  5. Bayer HealthCare AG, Berlin, Germany

    Torsten Zimmermann, Marcus Schultze-Mosgau, Andrea Thiele & Anja Hoffmann

Authors
  1. Andrea Varrone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patrik Mattsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anton Forsberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akihiro Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sangram Nag
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Balázs Gulyás
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jacqueline Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald Boellaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nabil Al-Tawil
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maria Eriksdotter
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Torsten Zimmermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Marcus Schultze-Mosgau
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Andrea Thiele
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Anja Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Adriaan A. Lammertsma
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christer Halldin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea Varrone.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig. 1Supplementary Fig. 2Supplementary Fig. 3Supplementary Fig. 4Supplementary Fig. 5

Representative time–activity curves and nonlinear square fitting with two-tissue compartment model (2TCM) from the control subject (a) and AD patient (b) shown in Fig. 1

Representative graphical analysis plots using only the first 15 min of PET data from the control subject (a) and AD patient (b) shown in Fig. 1

Mean values of BP ND calculated as V T/V ND 0–15 min − 1 with Logan graphical analysis in control subjects (open bars) and AD patients (closed bars). V ND 0-15 min was estimated from the whole grey matter (error bars 1 SD)

V T in relation to K 1 estimated with the 2TCM in control subjects (a) and AD patients (b)

Plasma-to-blood ratio in relation to time in four different subjects (PPTX 658 kb)

ESM 2

(DOCX 12 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Varrone, A., Mattsson, P., Forsberg, A. et al. In vivo imaging of the 18-kDa translocator protein (TSPO) with [18F]FEDAA1106 and PET does not show increased binding in Alzheimer’s disease patients. Eur J Nucl Med Mol Imaging 40, 921–931 (2013). https://doi.org/10.1007/s00259-013-2359-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-013-2359-1

Keywords

Search

Navigation