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Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

An Erratum to this article was published on 04 February 2010

Abstract

Purpose

Quantitative imaging of the type 1 cannabinoid receptor (CB1R) opens perspectives for many neurological and psychiatric disorders. We characterized the kinetics and reproducibility of the CB1R tracer [18F]MK-9470 in human brain.

Methods

[18F]MK-9470 data were analysed using reversible models and the distribution volume V T and V ND k 3 (V ND k 3 = K 1 k 2) were estimated. Tracer binding was also evaluated using irreversible kinetics and the irreversible uptake constant K i and fractional uptake rate (FUR) were estimated. The effect of blood flow on these parameters was evaluated. Additionally, the possibility of determining the tracer plasma kinetics using a reduced number of blood samples was also examined.

Results

A reversible two-tissue compartment model using a global k 4 value was necessary to describe brain kinetics. Both V T and V ND k 3 were estimated satisfactorily and their test–retest variability was between 10% and 30%. Irreversible methods adequately described brain kinetics and FUR values were equivalent to K i. The linear relationship between K i and V ND k 3 demonstrated that K i or FUR and thus the simple measure of tracer brain uptake provide CB1R availability information. The test–retest variability of K i and FUR was <10% and estimates were independent of blood flow. Brain uptake can be used as a receptor availability index, albeit at the expense of potential bias due to between-subject differences in tracer plasma kinetics.

Conclusion

[18F]MK-9470 specific binding can be accurately determined using FUR values requiring a short scan 90 to 120 min after tracer administration. Our results suggest that [18F]MK-9470 plasma kinetics can be assessed using a few venous samples.

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References

  1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561–4.

    Article  CAS  PubMed  Google Scholar 

  2. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61–5.

    Article  CAS  PubMed  Google Scholar 

  3. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54:161–202.

    Article  CAS  PubMed  Google Scholar 

  4. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 2008;14:923–30.

    Article  CAS  PubMed  Google Scholar 

  5. Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004;3:771–84.

    Article  PubMed  Google Scholar 

  6. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389–97.

    Article  PubMed  Google Scholar 

  7. Addy C, Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ, et al. The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 2008;7:68–78.

    Article  CAS  PubMed  Google Scholar 

  8. Eggan SM, Lewis DA. Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. Cereb Cortex 2007;17:175–91.

    Article  PubMed  Google Scholar 

  9. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990;87:1932–6.

    Article  CAS  PubMed  Google Scholar 

  10. Grimsey NL, Goodfellow CE, Scotter EL, Dowie MJ, Glass M, Graham ES. Specific detection of CB1 receptors; cannabinoid CB1 receptor antibodies are not all created equal! J Neurosci Methods 2008;171:78–86.

    Article  CAS  PubMed  Google Scholar 

  11. Horti AG, Van Laere K. Development of radioligands for in vivo imaging of type 1 cannabinoid receptors (CB1) in human brain. Curr Pharm Des 2008;14:3363–83.

    Article  CAS  PubMed  Google Scholar 

  12. Liu P, Lin LS, Hamill TG, Jewell JP, Lanza TJ Jr, Gibson RE, et al. Discovery of N-{(1S,2S)-2-(3-cyanophenyl)- 3-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylpropyl}- 2-methyl-2-[(5-methylpyridin-2-yl)oxy]propanamide, a cannabinoid-1 receptor positron emission tomography tracer suitable for clinical use. J Med Chem 2007;50:3427–30.

    Article  CAS  PubMed  Google Scholar 

  13. Burns HD, Van Laere K, Sanabria-Bohorquez S, Hamill TG, Bormans G, Eng WS, et al. [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci U S A 2007;104:9800–5.

    Article  CAS  PubMed  Google Scholar 

  14. Van Laere K, Koole M, Sanabria Bohórquez SM, Goffin K, Guenther I, Belanger MJ, et al. Whole-body biodistribution and radiation dosimetry of the human cannabinoid type-1 receptor ligand 18F-MK-9470 in healthy subjects. J Nucl Med 2008;49:439–45.

    Article  PubMed  Google Scholar 

  15. Van Laere K, Goffin K, Casteels C, Dupont P, Mortelmans L, de Hoon J, et al. Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [(18)F]MK-9470 PET. Neuroimage 2008;39:1533–41.

    Article  PubMed  Google Scholar 

  16. Hudson HM, Larkin RS. Accelerated image reconstruction using ordered subsets of projection data. IEEE Trans Med Imaging 1994;13:601–9.

    Article  CAS  PubMed  Google Scholar 

  17. Zubieta JK, Heitzeg MM, Xu Y, Koeppe RA, Ni L, Guthrie S, et al. Regional cerebral blood flow responses to smoking in tobacco smokers after overnight abstinence. Am J Psychiatry 2005;162:567–77.

    Article  PubMed  Google Scholar 

  18. Vandenberghe J, Dupont P, Van Oudenhove L, Bormans G, Demyttenaere K, Fischler B, et al. Regional cerebral blood flow during gastric balloon distention in functional dyspepsia. Gastroenterology 2007;132:1684–93.

    Article  PubMed  Google Scholar 

  19. Innis RB, Carson R. Consensus nomenclature: its time has come. Eur J Nucl Med Mol Imaging 2007;34:1239.

    Article  PubMed  Google Scholar 

  20. Sanabria-Bohórquez SM, Maes A, Dupont P, Bormans G, de Groot T, Coimbra A, et al. Image-derived input function for [11C]flumazenil kinetic analysis in human brain. Mol Imaging Biol 2003;5:72–8.

    Article  PubMed  Google Scholar 

  21. Delforge J, Syrota A, Mazoyer BM. Identifiability analysis and parameter identification of an in vivo ligand-receptor model from PET data. IEEE Trans Biomed Eng 1990;37:653–61.

    Article  CAS  PubMed  Google Scholar 

  22. Gunn RN, Gunn SR, Cunningham VJ. Positron emission tomography compartmental models. J Cereb Blood Flow Metab 2001;21:635–52.

    Article  CAS  PubMed  Google Scholar 

  23. Cunningham VJ, Jones T. Spectral analysis of dynamic PET studies. J Cereb Blood Flow Metab 1993;13:15–23.

    CAS  PubMed  Google Scholar 

  24. Ishizu K, Nishizawa S, Yonekura Y, Sadato N, Magata Y, Tamaki N, et al. Effects of hyperglycemia on FDG uptake in human brain and glioma. J Nucl Med 1994;35:1104–9.

    CAS  PubMed  Google Scholar 

  25. Thie JA. Clarification of a fractional uptake concept. J Nucl Med 1995;36:711–2.

    CAS  PubMed  Google Scholar 

  26. Logan J. Graphical analysis of PET data applied to reversible and irreversible tracers. Nucl Med Biol 2000;27:661–70.

    Article  CAS  PubMed  Google Scholar 

  27. Terry GE, Liow J, Zoghbi SS, Hirvonen J, Farris AG, Lerner A, et al. Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand. Neuroimage 2009;48:362–70.

    Article  PubMed  Google Scholar 

  28. Fowler JS, Wang GJ, Logan J, Xie S, Volkow ND, MacGregor RR, et al. Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping. J Nucl Med 1995;36:1255–62.

    CAS  PubMed  Google Scholar 

  29. Terry GE, Hiervonen J, Liow JS, Zoghbi SS, Gladding R, Tauscher JT, et al. Imaging and quantification of cannabinoid CB1 receptors in human and monkey brain using 18F-labeled inverse agonist radioligands. J Nucl Med 2009;in press.

  30. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 1997;77:299–318.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Tom Muylle and Dr. Patrick Dupont for their helpful suggestions.

Conflicts of interest

S.M.S.B., T.G.H. and I.D.L. are employees of Merck Inc., Co.

H.D.B. is a consultant to Merck Inc., Co.

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Correspondence to Sandra Marina Sanabria-Bohórquez.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00259-010-1395-3

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Sanabria-Bohórquez, S.M., Hamill, T.G., Goffin, K. et al. Kinetic analysis of the cannabinoid-1 receptor PET tracer [18F]MK-9470 in human brain. Eur J Nucl Med Mol Imaging 37, 920–933 (2010). https://doi.org/10.1007/s00259-009-1340-5

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  • DOI: https://doi.org/10.1007/s00259-009-1340-5

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