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Evaluation of cannabinoid type 1 receptor expression in the rat brain using [18F]MK-9470 microPET

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Abstract

Purpose

The ligand [18F]MK-9470 is an inverse agonist binding with high affinity and specificity to the cannabinoid type 1 (CB1) receptor. In this study, a semiquantitative acquisition and analysis protocol for investigation of the CB1 receptor distribution in the rat brain was established.

Methods

Two C57BL/6N mice (one CB1 −/− and one wild-type) and 19 Sprague Dawley rats were investigated using a Focus 120 microPET scanner. Seven rats were scanned twice for test–retest evaluation, six rats were scanned for blocking experiments using the inverse CB1 receptor agonist rimonabant, and 19 rats were scanned for baseline studies. Percentage injected dose per millilitre (%ID/ml) or uptake ratios (VOItarget/VOIwhole brain) were calculated. A Bland-Altman-plot was computed and mean values were compared using a two-sided paired t test.

Results

Comparing the data from the CB1 −/− mouse and the wild-type mouse, [18F]MK-9470 showed good specificity. Regarding the rat data, there was no relationship between the difference between the test and retest measurements or their mean value. The test and retest data showed a strong correlation (ρ c = 0.846, p ≤ 0.01; r Pearson = 0.857). Equivalence was not found for all regions and not even in the pons at baseline or under blocking condition. Only the baseline studies showed the highest levels of uptake in the caudate-putamen and thalamus, whereas moderate uptake was found in the hippocampus, hypothalamus and cerebellum, and the lowest uptake was observed in the cortex, amygdala and pons.

Conclusion

A reference region is not available; however, the proposed analysis method using the parameter uptake ratio is simple and delivers stable results allowing the discrimination of distinct brain regions.

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References

  1. Katona I, Freund TF. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci. 2012;35:529–58.

    Article  CAS  PubMed  Google Scholar 

  2. Lutz B. Endocannabinoid signals in the control of emotion. Curr Opin Pharmacol. 2009;9(1):46–52.

    Article  CAS  PubMed  Google Scholar 

  3. Parolaro D, Realini N, Vigano D, Guidali C, Rubino T. The endocannabinoid system and psychiatric disorders. Exp Neurol. 2010;224(1):3–14.

    Article  CAS  PubMed  Google Scholar 

  4. Gatley SJ, Lan R, Volkow ND, Pappas N, King P, Wong CT, et al. Imaging the brain marijuana receptor: development of a radioligand that binds to cannabinoid CB1 receptors in vivo. J Neurochem. 1998;70(1):417–23.

    Article  CAS  PubMed  Google Scholar 

  5. Lan R, Gatley J, Lu Q, Fan P, Fernando SR, Volkow ND, et al. Design and synthesis of the CB1 selective cannabinoid antagonist AM281: a potential human SPECT ligand. AAPS PharmSci. 1999;1(2):E4.

    Article  CAS  PubMed  Google Scholar 

  6. Gifford AN, Makriyannis A, Volkow ND, Gatley SJ. In vivo imaging of the brain cannabinoid receptor. Chem Phys Lipids. 2002;121(1–2):65–72.

    Article  CAS  PubMed  Google Scholar 

  7. Horti AG, Fan H, Kuwabara H, Hilton J, Ravert HT, Holt DP, et al. 11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. J Nucl Med. 2006;47(10):1689–96.

    CAS  PubMed  Google Scholar 

  8. Herance R, Rojas S, Abad S, Jiménez X, Gispert JD, Millán O, et al. Positron emission tomographic imaging of the cannabinoid type 1 receptor system with [(1)(1)C]OMAR ([(1)(1)C]JHU75528): improvements in image quantification using wild-type and knockout mice. Mol Imaging. 2011;10(6):481–7.

    CAS  PubMed  Google Scholar 

  9. Fan H, Kotsikorou E, Hoffman AF, Ravert HT, Holt D, Hurst DP, et al. Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): development of ligands with optimized lipophilicity and binding affinity. Eur J Med Chem. 2009;44(2):593–608.

    Article  CAS  PubMed  Google Scholar 

  10. Terry G, Liow JS, Chernet E, Zoghbi SS, Phebus L, Felder CC, et al. Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents. Neuroimage. 2008;41(3):690–8.

    Article  PubMed  Google Scholar 

  11. Casteels C, Bormans G, Van Laere K. The effect of anaesthesia on [(18)F]MK-9470 binding to the type 1 cannabinoid receptor in the rat brain. Eur J Nucl Med Mol Imaging. 2010;37(6):1164–73.

    Article  CAS  PubMed  Google Scholar 

  12. Casteels C, Lauwers E, Baitar A, Bormans G, Baekelandt V, Van Laere K. In vivo type 1 cannabinoid receptor mapping in the 6-hydroxydopamine lesion rat model of Parkinson’s disease. Brain Res. 2010;1316:153–62.

    Article  CAS  PubMed  Google Scholar 

  13. Casteels C, Martinez E, Bormans G, Camon L, de Vera N, Baekelandt V, et al. Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism. Eur J Nucl Med Mol Imaging. 2010;37(12):2354–63.

    Article  CAS  PubMed  Google Scholar 

  14. Casteels C, Vanbilloen B, Vercammen D, Bosier B, Lambert DM, Bormans G, et al. Influence of chronic bromocriptine and levodopa administration on cerebral type 1 cannabinoid receptor binding. Synapse. 2010;64(8):617–23.

    Article  CAS  PubMed  Google Scholar 

  15. Casteels C, Vandeputte C, Rangarajan JR, Dresselaers T, Riess O, Bormans G, et al. Metabolic and type 1 cannabinoid receptor imaging of a transgenic rat model in the early phase of Huntington disease. Exp Neurol. 2011;229(2):440–9.

    Article  CAS  PubMed  Google Scholar 

  16. Gerard N, Ceccarini J, Bormans G, Vanbilloen B, Casteels C, Goffin K, et al. Influence of chronic nicotine administration on cerebral type 1 cannabinoid receptor binding: an in vivo micro-PET study in the rat using [18F]MK-9470. J Mol Neurosci. 2010;42(2):162–7.

    Article  CAS  PubMed  Google Scholar 

  17. Goffin K, Bormans G, Casteels C, Bosier B, Lambert DM, Grachev ID, et al. An in vivo [18F]MK-9470 microPET study of type 1 cannabinoid receptor binding in Wistar rats after chronic administration of valproate and levetiracetam. Neuropharmacology. 2008;54(7):1103–6.

    Article  CAS  PubMed  Google Scholar 

  18. Vandeputte C, Casteels C, Struys T, Koole M, van Veghel D, Evens N, et al. Small-animal PET imaging of the type 1 and type 2 cannabinoid receptors in a photothrombotic stroke model. Eur J Nucl Med Mol Imaging. 2012;39(11):1796–806.

    Article  CAS  PubMed  Google Scholar 

  19. Verdurand M, Nguyen V, Stark D, Zahra D, Gregoire MC, Greguric I, et al. Comparison of cannabinoid CB(1) receptor binding in adolescent and adult rats: a positron emission tomography study using [F]MK-9470. Int J Mol Imaging. 2011;2011:548123.

    PubMed  Google Scholar 

  20. Casteels C, Koole M, Celen S, Bormans G, Van Laere K. Preclinical evaluation and quantification of [18F]MK-9470 as a radioligand for PET imaging of the type 1 cannabinoid receptor in rat brain. Eur J Nucl Med Mol Imaging. 2012;39(9):1467–77.

    Google Scholar 

  21. Burns HD, Van Laere K, Sanabria-Bohórquez 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(23):9800–5.

    Article  CAS  PubMed  Google Scholar 

  22. Liu P, Lin LS, Hamill TG, Jewell JP, Lanza Jr TJ, 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(15):3427–30.

    Article  CAS  PubMed  Google Scholar 

  23. Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418(6897):530–4.

    Article  CAS  PubMed  Google Scholar 

  24. Altman DG, Bland JM. Measurement in medicine: the analysis of method comparison studies. The Statistician. 1983;32:307–17.

    Article  Google Scholar 

  25. Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics. 1989;45(1):255–68.

    Article  CAS  PubMed  Google Scholar 

  26. 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(5):1932–6.

    Article  CAS  PubMed  Google Scholar 

  27. Dupont P, Warwick J. Kinetic modelling in small animal imaging with PET. Methods. 2009;48(2):98–103.

    Article  CAS  PubMed  Google Scholar 

  28. Steffens M, Zentner J, Honegger J, Feuerstein TJ. Binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical CB1 receptor. Biochem Pharmacol. 2005;69(1):169–78.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We were grateful to Prof. Volker Böhmer (Institute of Organic Chemistry, Johannes Gutenberg University Mainz), who allowed us to use the laboratory for the chemical syntheses. We also acknowledge the work of our colleagues Nicole Bausbacher, Nuse Afahaene and Barbara Biesalski for their excellent technical assistance in data acquisition and Alejandro Aparisi Rey for his help in preparation of rimonabant. This work was supported by the Focus Program Translational Neuroscience (FTN) of the Johannes Gutenberg University Mainz.

Conflicts of Interest

None.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    I. Miederer, S. Maus & M. Schreckenberger

  2. Institute of Medical Biostatistics, Epidemiology & Informatics, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Straße 69, 55131, Mainz, Germany

    I. Zwiener

  3. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Duesbergweg 6, 55128, Mainz, Germany

    G. Podoprygorina, D. Meshcheryakov & B. Lutz

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  1. I. Miederer
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  2. S. Maus
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  3. I. Zwiener
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  4. G. Podoprygorina
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  5. D. Meshcheryakov
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  6. B. Lutz
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  7. M. Schreckenberger
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Corresponding author

Correspondence to I. Miederer.

Additional information

B. Lutz and M. Schreckenberger contributed equally to this work.

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Miederer, I., Maus, S., Zwiener, I. et al. Evaluation of cannabinoid type 1 receptor expression in the rat brain using [18F]MK-9470 microPET. Eur J Nucl Med Mol Imaging 40, 1739–1747 (2013). https://doi.org/10.1007/s00259-013-2483-y

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  • DOI: https://doi.org/10.1007/s00259-013-2483-y

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