Measurement of central µ-opioid receptor binding in vivo with PET and [11C]carfentanil: a test–retest study in healthy subjects

  • Jussi HirvonenEmail author
  • Sargo Aalto
  • Nora Hagelberg
  • Anu Maksimow
  • Kimmo Ingman
  • Vesa Oikonen
  • Jussi Virkkala
  • Kjell Någren
  • Harry Scheinin
Original Article



[11C]Carfentanil has been widely used in positron emission tomography (PET) studies for measuring µ-opioid receptor binding in humans, but the reproducibility of the binding parameter estimates is unknown.

Materials and methods

Eight healthy volunteers were scanned twice during the same day with [11C]carfentanil PET, and binding to receptors was assessed with both reference tissue and arterial plasma input-based models using region of interest (ROI) and voxel-based quantification.


The two-tissue compartmental model distribution volume (VT) was highly reproducible as indicated by low variability (VAR < 6%) and high intraclass correlation coefficients (ICC > 0.93). BPND (BP relative to the nondisplaceable tissue compartment) was also highly reproducible (VAR < 10%, ICC > 0.90) both at ROI- and voxel-level, and reference tissue-based models provided stable estimates after 40 min.


The reproducibility of [11C]carfentanil binding parameter estimates is excellent with outcome measures based on both arterial plasma and reference tissue input, and a scanning time of 40 min appears sufficient.


(11C)carfentanil Mu opioid receptor Positron emission tomography Imaging 



The staffs of the MRI and PET units at Turku PET Centre are gratefully appreciated.

Disclosures/Conflicts of Interest

The authors declare no conflicts of interest.


  1. 1.
    Frost JJ, Wagner HN Jr, Dannals RF, Ravert HT, Links JM, Wilson AA et al. Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomogr 1985;9:231–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Frost JJ, Douglass KH, Mayberg HS, Dannals RF, Links JM, Wilson AA et al. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab 1989;9:398–409.PubMedGoogle Scholar
  3. 3.
    Endres CJ, Bencherif B, Hilton J, Madar I, Frost JJ. Quantification of brain mu-opioid receptors with [11C]carfentanil: reference-tissue methods. Nucl Med Biol 2003;30:177–86.PubMedCrossRefGoogle Scholar
  4. 4.
    Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood-sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996;16:834–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Henriksen G, Willoch F. Imaging of opioid receptors in the central nervous system. Brain 2008;131:1171–96.PubMedCrossRefGoogle Scholar
  7. 7.
    Larsen P, Ulin J, Dahlström K, Jensen M. Synthesis of [11C]methyl iodide by iodination of [11C]methane. Appl Radiat Isot 1997;48:153–7.CrossRefGoogle Scholar
  8. 8.
    Någren K, Truong P, Helin S, Amir A, Halldin C. Experience from two systems for recirculating production of [11C]methyl iodide from target produced [11C]methane. J Labelled Compds Radiopharm 2003;46(Suppl. 1):S76.Google Scholar
  9. 9.
    Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S et al. Prolonged central µ-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology 2005;30:2245–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Friston KJ, Holmes AP, Worsley KJ, Poline JP, Frith C, Frackowiak RSJ. Statistical parametric maps in functional imaging: a general linear approach. Hum Brain Mapp 1995;2:189–210.CrossRefGoogle Scholar
  11. 11.
    Zhou Y, Brasic J, Endres CJ, Kuwabara H, Kimes A, Contoreggi C et al. Binding potential image based statistical mapping for detection of dopamine release by 11C-raclopride dynamic PET. NeuroImage 2002;16:S91.Google Scholar
  12. 12.
    Zhou Y, Brasic JR, Ye W, Dogan AS, Hilton J, Singer HS et al. Quantification of cerebral serotonin binding in normal controls and subjects with Tourette’s syndrome using [11C]MDL 100,907 and (+)[11C]McN 5652 dynamic PET with parametric imaging approach. NeuroImage 2004;22(Suppl 2):T98.Google Scholar
  13. 13.
    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;279:1533–9.CrossRefGoogle Scholar
  14. 14.
    Heinz A, Reimold M, Wrase J, Hermann D, Croissant B, Mundle G et al. Correlation of stable elevations in striatal mu-opioid receptor availability in detoxified alcoholic patients with alcohol craving: a positron emission tomography study using carbon 11-labeled carfentanil. Arch Gen Psychiatry 2005;62:57–64.PubMedCrossRefGoogle Scholar
  15. 15.
    Meyer JH, Gunn RN, Myers R, Grasby PM. Assessment of spatial normalization of PET ligand images using ligand-specific templates. NeuroImage 1999;9:545–53.PubMedCrossRefGoogle Scholar
  16. 16.
    Salmi E, Laitio RM, Aalto S, Maksimow AT, Långsjö JW, Kaisti KK et al. Xenon does not affect gamma-aminobutyric acid type A receptor binding in humans. Anesth Analg 2008;106:129–34.PubMedCrossRefGoogle Scholar
  17. 17.
    Kemppainen NM, Aalto S, Wilson IA, Någren K, Helin S, Brück A et al. Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology 2006;67:1575–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Hirvonen J, Johansson J, Teräs M, Oikonen V, Lumme V, Virsu P et al. Measurement of striatal and extrastriatal dopamine transporter binding with high-resolution PET and [(11)C]PE2I: quantitative modeling and test–retest reproducibility. J Cereb Blood Flow Metab 2008;28(5):1059–69.PubMedCrossRefGoogle Scholar
  19. 19.
    Sprenger T, Berthele A, Platzer S, Boecker H, Tolle TR. What to learn from in vivo opioidergic brain imaging? Eur J Pain 2005;9:117–21.PubMedCrossRefGoogle Scholar
  20. 20.
    Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, Portoghese PS et al. International Union of Pharmacology. XII. Classification of opioid receptors. Pharmacol Rev 1996;48:567–92.PubMedGoogle Scholar
  21. 21.
    Contet C, Kieffer BL, Befort K. Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 2004;14:370–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Herz A. Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl) 1997;129:99–111.CrossRefGoogle Scholar
  23. 23.
    Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 2001;293:311–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA et al. Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Arch Gen Psychiatry 2003;60:1145–53.PubMedCrossRefGoogle Scholar
  25. 25.
    Slifstein M, Laruelle M. Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radiotracers. Nucl Med Biol 2001;28:595–608.PubMedCrossRefGoogle Scholar
  26. 26.
    Slifstein M, Parsey RV, Laruelle M. Derivation of [(11)C]WAY-100635 binding parameters with reference tissue models: effect of violations of model assumptions. Nucl Med Biol 2000;27(5):487–92.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Jussi Hirvonen
    • 1
    • 5
    Email author
  • Sargo Aalto
    • 1
  • Nora Hagelberg
    • 1
    • 2
  • Anu Maksimow
    • 1
  • Kimmo Ingman
    • 3
  • Vesa Oikonen
    • 1
  • Jussi Virkkala
    • 4
  • Kjell Någren
    • 1
  • Harry Scheinin
    • 1
    • 2
  1. 1.Turku PET Centre, University of Turku and Turku University Central HospitalTurkuFinland
  2. 2.Department of Anaesthesiology, Intensive Care, Emergency Care and Pain MedicineTurku University Central HospitalTurkuFinland
  3. 3.Department of Pharmacology, Drug Development and TherapeuticsUniversity of TurkuTurkuFinland
  4. 4.Department of Clinical Neurophysiology, Medical Imaging CentrePirkanmaa Hospital DistrictTampereFinland
  5. 5.Turku PET CentreTurkuFinland

Personalised recommendations