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Head-to-head comparison of 11C-PBR28 and 11C-ER176 for quantification of the translocator protein in the human brain

  • Paolo Zanotti-FregonaraEmail author
  • Belen Pascual
  • Mattia Veronese
  • Meixiang Yu
  • David Beers
  • Stanley H. Appel
  • Joseph C. Masdeu
Original Article
Part of the following topical collections:
  1. Neurology

Abstract

Introduction

11C-ER176 is a new PET tracer to quantify the translocator protein (TSPO), a biomarker for inflammation. The aim of this study was to perform a head-to-head comparison between 11C-ER176 and the widely used 11C-PBR28.

Methods

Seven healthy volunteers had a 90-min PET scan and metabolite-corrected arterial input function with 11C-PBR28 in the morning and 11C-ER176 in the afternoon. Binding was quantified at the regional level in terms of VT with a two-tissue compartmental model. By using VND values from the literature obtained with pharmacological blockade, we derived the binding potential BPND for both tracers.

Results

11C-ER176 was more stable in arterial blood than 11C-PBR28 (the percentages of unmetabolized parent in plasma at 90 min were 29.0 ± 8.3% and 8.8 ± 2.9% respectively). The brain time–activity curves for both tracers were well fitted by the two-tissue model, but 11C-ER176 had higher VT values than 11C-PBR28 (5.74 ± 1.54 vs 4.43 ± 1.99 ml/cm3) and a lower coefficient of variation. The BPND of 11C-ER176 was more than 4 times larger than that of 11C-PBR28 for high-affinity binders, and more than 9 times larger for mixed-affinity binders.

Conclusion

11C-ER176 displays a higher binding potential and a smaller variability of VT values. Thanks to these characteristics, clinical studies performed with 11C-ER176 are expected to have higher statistical power and thus require fewer subjects.

Keywords

11C-PBR28 11C-ER176 TSPO PET 

Notes

Funding

This study was partially funded by the Harrison, Chao, Graham, and Nantz Funds of the Houston Methodist Foundation.

Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

Joseph Masdeu is on a General Electric Healthcare advisory board and receives research support from GE, Eli Lilly, Biogen, Abbvie, and Novartis. The other authors declare no conflict of interest.

Disclosure

No potential conflicts of interest relevant to this article exist.

References

  1. 1.
    Cumming P, Burgher B, Patkar O, Breakspear M, Vasdev N, Thomas P, et al. Sifting through the surfeit of neuroinflammation tracers. J Cereb Blood Flow Metab. 2018;38:204–24.CrossRefPubMedGoogle Scholar
  2. 2.
    Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain. 2013;136:2228–38.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Richards EM, Zanotti-Fregonara P, Fujita M, Newman L, Farmer C, Ballard ED, et al. PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects. EJNMMI Res. 2018;8:57.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Plaven-Sigray P, Matheson GJ, Collste K, Ashok AH, Coughlin JM, Howes OD, et al. Positron emission tomography studies of the glial cell marker translocator protein in patients with psychosis: a meta-analysis using individual participant data. Biol Psychiatry. 2018;84:433–42.CrossRefPubMedGoogle Scholar
  5. 5.
    Gershen LD, Zanotti-Fregonara P, Dustin IH, Liow JS, Hirvonen J, Kreisl WC, et al. Neuroinflammation in temporal lobe epilepsy measured using positron emission tomographic imaging of translocator protein. JAMA Neurol. 2015;72:882–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Narayan N, Owen DR, Mandhair H, Smyth E, Carlucci F, Saleem A, et al. Translocator protein as an imaging marker of macrophage and stromal activation in rheumatoid arthritis pannus. J Nucl Med. 2018;59:1125–32.CrossRefPubMedGoogle Scholar
  7. 7.
    Roncaroli F, Su Z, Herholz K, Gerhard A, Turkheimer FE. TSPO expression in brain tumours: is TSPO a target for brain tumour imaging? Clin Translat Imaging. 2016;4:145–56.CrossRefGoogle Scholar
  8. 8.
    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.CrossRefPubMedGoogle Scholar
  9. 9.
    Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL, et al. 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. 2013;33:53–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Zanotti-Fregonara P, Pascual B, Rizzo G, Yu M, Pal N, Beers D, et al. Head-to-head comparison of (11)C-PBR28 and (18)F-GE180 for quantification of the translocator protein in the human brain. J Nucl Med. 2018;59:1260–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Zanotti-Fregonara P, Veronese M, Pascual B, Rostomily RC, Turkheimer F, Masdeu JC. The validity of (18)F-GE180 as a TSPO imaging agent. Eur J Nucl Med Mol Imaging. 2019;46(6):1205–7.CrossRefPubMedGoogle Scholar
  12. 12.
    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;40:43–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Zanotti-Fregonara P, Zhang Y, Jenko KJ, Gladding RL, Zoghbi SS, Fujita M, et al. Synthesis and evaluation of translocator 18 kDa protein (TSPO) positron emission tomography (PET) radioligands with low binding sensitivity to human single nucleotide polymorphism rs6971. ACS Chem Neurosci. 2014;5:963–71.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ikawa M, Lohith TG, Shrestha S, Telu S, Zoghbi SS, Castellano S, et al. 11C-ER176, a radioligand for 18-kDa translocator protein, has adequate sensitivity to robustly image all three affinity genotypes in human brain. J Nucl Med. 2017;58:320–5.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Collste K, Forsberg A, Varrone A, Amini N, Aeinehband S, Yakushev I, et al. Test-retest reproducibility of [(11)C]PBR28 binding to TSPO in healthy control subjects. Eur J Nucl Med Mol Imaging. 2016;43:173–83.CrossRefPubMedGoogle Scholar
  16. 16.
    Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19:224–47.CrossRefPubMedGoogle Scholar
  17. 17.
    Tonietto M, Rizzo G, Veronese M, Fujita M, Zoghbi SS, Zanotti-Fregonara P, et al. Plasma radiometabolite correction in dynamic PET studies: insights on the available modeling approaches. J Cereb Blood Flow Metab. 2016;36:326–39.CrossRefPubMedGoogle Scholar
  18. 18.
    Gandelman MS, Baldwin RM, Zoghbi SS, Zea-Ponce Y, Innis RB. Evaluation of ultrafiltration for the free fraction determination of single photon emission computed tomography (SPECT) tracers: ß-CIT, IBF, and iomazenil. J Pharm Sci. 1994;83:1014–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Abi-Dargham A, Gandelman M, Zoghbi SS, Laruelle M, Baldwin RM, Randall P, et al. Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with [123I]iomazenil. J Nucl Med. 1995;36:167–75.PubMedGoogle Scholar
  20. 20.
    Pajevic S, Daube-Witherspoon ME, Bacharach SL, Carson RE. Noise characteristics of 3-D and 2-D PET images. IEEE Trans Med Imaging. 1998;17:9–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Krzanowski WJ. Permutational tests for correlation matrices. Stat Comput. 1993;3:37–44.CrossRefGoogle Scholar
  22. 22.
    Veronese M, Moro L, Arcolin M, Dipasquale O, Rizzo G, Expert P, et al. Covariance statistics and network analysis of brain PET imaging studies. Sci Rep. 2019;9(1):2496.Google Scholar
  23. 23.
    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;27:1533–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Lassen NA, Bartenstein PA, Lammertsma AA, Prevett MC, Turton DR, Luthra SK, et al. Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle. J Cereb Blood Flow Metab. 1995;15:152–65.CrossRefPubMedGoogle Scholar
  25. 25.
    Zanotti-Fregonara P, Xu R, Zoghbi SS, Liow JS, Fujita M, Veronese M, et al. The PET radioligand 18F-FIMX images and quantifies metabotropic glutamate receptor 1 in proportion to the regional density of its gene transcript in human brain. J Nucl Med. 2016;57:242–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Veronese M, Zanotti-Fregonara P, Rizzo G, Bertoldo A, Innis RB, Turkheimer FE. Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: the genomic plot. Neuroimage. 2016;130:1–12.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Guo Q, Colasanti A, Owen DR, Onega M, Kamalakaran A, Bennacef I, et al. Quantification of the specific translocator protein signal of 18F-PBR111 in healthy humans: a genetic polymorphism effect on in vivo binding. J Nucl Med. 2013;54:1915–23.CrossRefPubMedGoogle Scholar
  28. 28.
    Rizzo G, Veronese M, Heckemann RA, Selvaraj S, Howes OD, Hammers A, et al. The predictive power of brain mRNA mappings for in vivo protein density: a positron emission tomography correlation study. J Cereb Blood Flow Metab. 2014;34(5):827–35.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hawrylycz MJ, Lein ES, Guillozet-Bongaarts AL, Shen EH, Ng L, Miller JA, et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012;489:391–9.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Rizzo G, Veronese M, Expert P, Turkheimer FE, Bertoldo A. MENGA: a new comprehensive tool for the integration of neuroimaging data and the Allen human brain transcriptome atlas. PLoS One. 2016;11:e0148744.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Owen DR, Guo Q, Kalk NJ, Colasanti A, Kalogiannopoulou D, Dimber R, et al. Determination of [(11)C]PBR28 binding potential in vivo: a first human TSPO blocking study. J Cereb Blood Flow Metab. 2014;34:989–94.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fujita M, Kobayashi M, Ikawa M, Gunn RN, Rabiner EA, Owen DR, et al. Comparison of four (11)C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios. EJNMMI Res. 2017;7:84.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Owen DR, Guo Q, Rabiner EA, Gunn RN. The impact of the rs6971 polymorphism in TSPO for quantification and study design. Clin Translat Imaging. 2015;3:417–22.CrossRefGoogle Scholar
  34. 34.
    Paul S, Gallagher E, Liow JS, Mabins S, Henry K, Zoghbi SS, et al. Building a database for brain 18 kDa translocator protein imaged using [(11)C]PBR28 in healthy subjects. J Cereb Blood Flow Metab. 2018:271678x18771250 [Epub ahead of print].Google Scholar
  35. 35.
    Tuisku J, Plaven-Sigray P, Gaiser EC, Airas L, Al-Abdulrasul H, Bruck A, et al. Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre [11C]PBR28 HRRT PET study. bioRxiv. 2019:564831.Google Scholar
  36. 36.
    Rizzo G, Veronese M, Tonietto M, Zanotti-Fregonara P, Turkheimer FE, Bertoldo A. Kinetic modeling without accounting for the vascular component impairs the quantification of [(11)C]PBR28 brain PET data. J Cereb Blood Flow Metab. 2014;34:1060–9.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Nantz National Alzheimer Center and Houston Methodist Research Neurological Institute, and Weill Cornell MedicineHoustonUSA
  2. 2.Department of Neuroimaging, Institute of Psychiatry, Psychology and NeuroscienceKing’s College LondonLondonUK

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