Clinical and Translational Imaging

, Volume 3, Issue 6, pp 417–422 | Cite as

The impact of the rs6971 polymorphism in TSPO for quantification and study design

Review Article

Abstract

Second-generation translocator protein (TSPO) radioligands were developed to circumvent the technical short comings of 11C-PK11195, the first TSPO targeting tracer. However, in early clinical positron emission tomography (PET) studies they displayed greater inter- and intra-subject variability than was expected given the promising characteristics they showed in preclinical and in vitro studies. A great deal of this variability, although not all, can be explained by the rs6971 polymorphism in the gene encoding TSPO. This polymorphism causes a single amino acid substitution in the TSPO which, for all second-generation tracers tested in man hitherto, reduces binding affinity in mutants relative to wild type. This has obvious implications for interpretation of data, because inter-subject comparisons in PET studies are predicated on the assumption that binding affinity is consistent across all subjects. In this paper, we discuss the implications of the rs6971 polymorphism on study design, analysis and interpretation of data for clinical PET studies using second-generation TSPO radioligands.

Keywords

TSPO PET imaging rs6971 polymorphism 

Notes

Compliance with ethical standards

This review was not funded. This is a review paper, and as such no experiments were performed, and hence no animals or humans were involved and no approval was required.

Conflict of interest

D. R. Owen declares that he has no conflict of interest. Q. Guo declares that she has no conflict of interest. E. A. Rabiner declares that he has no conflict of interest. R. N. Gunn declares that he has no conflict of interest.

References

  1. 1.
    Hinz R, Boellaard R (2015) Challenges of quantification of TSPO in the human brain. Clin Transl Imaging. doi: 10.1007/s40336-015-0138-7 Google Scholar
  2. 2.
    Imaizumi M, Briard E, Zoghbi SS, Gourley JP, Hong J, Fujimura Y et al (2008) Brain and whole-body imaging in nonhuman primates of [11C] PBR28, a promising PET radioligand for peripheral benzodiazepine receptors. Neuroimage 39(3):1289–1298CrossRefPubMedGoogle Scholar
  3. 3.
    Chauveau F, Boutin H, Van CN, Dolle F, Tavitian B (2008) Nuclear imaging of neuroinflammation: a comprehensive review of [11C] PK11195 challengers. Eur J Nucl Med Mol Imagin 35(12):2304–2319CrossRefGoogle Scholar
  4. 4.
    Brown AK, Fujita M, Fujimura Y, Liow JS, Stabin M, Ryu YH et al (2007) Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: a PET radioligand to image inflammation. J Nucl Med 48(12):2072–2079CrossRefPubMedGoogle Scholar
  5. 5.
    Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T et al (2008) Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage 40(1):43–52CrossRefPubMedGoogle Scholar
  6. 6.
    Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H et al (2007) Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [(11)C] DAA1106. J Cereb Blood Flow Metab 27(1):173–184CrossRefPubMedGoogle Scholar
  7. 7.
    Fujimura Y, Zoghbi SS, Simeon FG, Taku A, Pike VW, Innis RB et al (2009) Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, (18)F-PBR06. J Nucl Med 50(7):1047–1053CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M et al (2010) Two binding sites for [3H] PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30(9):1608–1618CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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):902–910CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC et al (2011) Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 52(1):24–32CrossRefPubMedGoogle Scholar
  11. 11.
    Owen DR, Lewis AJ, Reynolds R, Rupprecht R, Eser D, Wilkins MR et al (2011) Variation in binding affinity of the novel anxiolytic XBD173 for the 18 kDa translocator protein in human brain. Synapse (NY) 65(3):257–259CrossRefGoogle Scholar
  12. 12.
    Guo Q, Colasanti A, Owen DR, Onega M, Kamalakaran A, Bennacef I et al (2013) Quantification of the specific translocator protein signal of 18F-PBR111 in healthy humans: a genetic polymorphism effect on in vivo binding. J Nucl Med 54(11):1915–1923CrossRefPubMedGoogle Scholar
  13. 13.
    Mizrahi R, Rusjan PM, Kennedy J, Pollock B, Mulsant B, Suridjan I et al (2012) Translocator protein (18 kDa) polymorphism (rs6971) explains in vivo brain binding affinity of the PET radioligand [(18)F]-FEPPA. J Cereb Blood Flow Metab 32(6):968–972CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lavisse S, Garcia-Lorenzo D, Peyronneau MA, Bodini B, Thiriez C, Kuhnast B et al (2015) Optimized quantification of translocator protein radioligand 18F-DPA-714 uptake in the brain of genotyped healthy volunteers. J Nucl Med 56(7):1048–1054CrossRefPubMedGoogle Scholar
  15. 15.
    Yoder KK, Nho K, Risacher SL, Kim S, Shen L, Saykin AJ (2013) Influence of TSPO genotype on 11C-PBR28 standardized uptake values. J Nucl Med 54:1320–1322CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kreisl WC, Jenko KJ, Hines CS, Lyoo CH, Corona W, Morse CL et al (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):53–58CrossRefPubMedGoogle Scholar
  17. 17.
    Kobayashi M, Jenko K, Zoghbi S, Lohith T, Rallis-Frutos D, Page E, Ikawa M, Pike V, Innis R, Fujita M (2015) Blockade of translocator protein (TSPO) to measure specific binding of 11C-(R)-PK 11195 in human brain. J Nucl Med 56:467Google Scholar
  18. 18.
    Owen DR, Guo Q, Kalk NJ, Colasanti A, Kalogiannopoulou D, Dimber R et al (2014) Determination of [(11)C] PBR28 binding potential in vivo: a first human TSPO blocking study. J Cereb Blood flow Metab 34(6):989–994CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Jucaite A, Cselenyi Z, Arvidsson A, Ahlberg G, Julin P, Varnas K et al (2012) Kinetic analysis and test-retest variability of the radioligand [11C] (R)-PK11195 binding to TSPO in the human brain—a PET study in control subjects. EJNMMI Res 2:15CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Park E, Gallezot JD, Delgadillo A, Liu S, Planeta B, Lin SF et al (2015) (11)C-PBR28 imaging in multiple sclerosis patients and healthy controls: test-retest reproducibility and focal visualization of active white matter areas. Eur J Nucl Med Mol Imagin 42(7):1081–1092CrossRefGoogle Scholar
  21. 21.
    Salinas CA, Searle GE, Gunn RN (2015) The simplified reference tissue model: model assumption violations and their impact on binding potential. J Cereb Blood Flow Metab 35(2):304–311CrossRefPubMedGoogle Scholar
  22. 22.
    Canat X, Carayon P, Bouaboula M, Cahard D, Shire D, Roque C et al (1993) Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells. Life Sci 52(1):107–118CrossRefPubMedGoogle Scholar
  23. 23.
    Rizzo G, Veronese M, Tonietto M, Zanotti-Fregonara P, Turkheimer FE, Bertoldo A (2014) Kinetic modeling without accounting for the vascular component impairs the quantification of [(11)C] PBR28 brain PET data. J Cereb Blood Flow Metab 34(6):1060–1069CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fan Z, Harold D, Pasqualetti G, Williams J, Brooks DJ, Edison P (2015) Can studies of neuroinflammation in a TSPO genetic subgroup (HAB or MAB) be applied to the entire AD cohort? J Nucl Med 56(5):707–713CrossRefPubMedGoogle Scholar
  25. 25.
    Lyoo CH, Ikawa M, Liow JS, Zoghbi SS, Morse CL, Pike VW et al (2015) Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. J Nucl Med 56(5):701–706CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hannestad J, Gallezot JD, Schafbauer T, Lim K, Kloczynski T, Morris ED et al (2012) Endotoxin-induced systemic inflammation activates microglia: [11C] PBR28 positron emission tomography in nonhuman primates. NeuroImage 63(1):232–239CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Yoder KK, Territo PR, Hutchins GD, Hannestad J, Morris ED, Gallezot JD et al (2015) Comparison of standardized uptake values with volume of distribution for quantitation of [(11)C] PBR28 brain uptake. Nucl Med Biol 42(3):305–308CrossRefPubMedGoogle Scholar

Copyright information

© Italian Association of Nuclear Medicine and Molecular Imaging 2015

Authors and Affiliations

  • D. R. Owen
    • 1
  • Q. Guo
    • 2
  • E. A. Rabiner
    • 3
    • 4
  • R. N. Gunn
    • 1
    • 3
  1. 1.Division of Brain Sciences, Department of MedicineImperial CollegeLondonUK
  2. 2.Abbvie, Integrated Sciences and TechnologyNorth ChicagoUSA
  3. 3.Imanova, Centre for Imaging SciencesLondonUK
  4. 4.Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College LondonLondonUK

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