Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

PET Imaging Studies in Rhesus Monkey with the Cannabinoid-1 (CB1) Receptor Ligand [11C]CB-119

  • 196 Accesses

  • 10 Citations

Abstract

Purpose

The in vitro and in vivo evaluation of the selective, high affinity (human CB1 IC50 0.49 nM) inverse agonist CB1R tracer [11C]CB-119, a close analog of the previously disclosed [18F]MK-9470, was undertaken.

Procedures

[11C]CB-119 was synthesized with high specific activity by alkylation of a phenolic precursor with [11C]methyl iodide. In vitro autoradiographic studies using rhesus brain slices were carried out using [3H]CB-119, and in vivo imaging studies were carried out using [11C]CB-119 in rhesus monkeys under baseline and blocked conditions.

Results

Autoradiographic studies in rhesus brain showed the expected distribution pattern for CB1R with highest binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Lower binding was seen in the posterior hypothalamus, ventral tegmental area, and periventricular gray area, and the lowest binding was in the thalamic nuclei. The binding of [3H]CB-119 was fully blocked by the addition of 10 μM CB-119. Rhesus positron emission tomography imaging studies showed very good brain uptake and a distribution pattern consistent with that seen in the autoradiographic studies. The kinetics of tracer uptake was slow. The brain uptake was blocked by pretreatment with taranabant, a CB1R inverse agonist. The specific signal (total/nonspecific) in rhesus putamen at 90 min was ~6:1.

Conclusions

[11C]CB-119 is a suitable tracer for imaging central CB1 receptors.

This is a preview of subscription content, log in to check access.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6

References

  1. 1.

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

  2. 2.

    Lindsey KP, Glaser ST, Gatley SJ (2005) Imaging of the brain cannabinoid system (edited by Pertwee RG). Handb Exp Pharmacol 168:425–443

  3. 3.

    Fan H, Revert HT, Holt DP, Dannals RF, Horti AG (2006) Synthesis of 1-(2,4-dichlorophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide ([11C]JHU75528) and 1-(2-bromophenyl)-4-cyano-5-(4-[11C]methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide ([11C]JHU75575) as potential radioligands for PET imaging of cerebral cannabinoid receptor. J Labelled Comp Radiopharm 49:1021–1036

  4. 4.

    Horti AG, Fan H, Kuwabara H et al (2006) 11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. J Nucl Med 47(10):1689–1696

  5. 5.

    Yasuno F, Brown AK, Zoghbi SS et al (2008) The PET radioligand [11C]MePPEP binds reversibly and with high specific signal to cannabinoid CB1 receptors in nonhuman primate brain. Neuropsychopharmacology 33(2):259–269

  6. 6.

    Terry G, Liow J-S, Chernet E et al (2008) Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents. NeuroImage 41:690–698

  7. 7.

    Burns HD, Van Laere K, Sanabria-Bohorquez S et al (2007) [18F]MK-9470: a tracer for in vivo human PET brain imaging of the cannabinoid-type 1 receptor. Proc Natl Acad Sci U S A 104(23):9800–9805

  8. 8.

    Addy C, Wright H, Laere KV et al (2008) The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake. Cell Metab 7(1):68–78

  9. 9.

    Liu P, Lin LS, Hamill TG et al (2007) 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 50(15):3427–3430

  10. 10.

    Lin LS, Lanza Jr TJ, Jewell JP et al (2006) Discovery of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (taranabant), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity. J Med Chem 49(26):7584–7587

  11. 11.

    Glass M, Dragunow M, Faull RLM (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77(2):299–318

  12. 12.

    Herkenham M, Lynn AB, Little M et al (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 87(5):1932–1936

Download references

Acknowledgments

The authors wish to thank Mangay Williams for performing the in vivo metabolism studies.

Author information

Correspondence to Terence G. Hamill.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hamill, T.G., Lin, L.S., Hagmann, W. et al. PET Imaging Studies in Rhesus Monkey with the Cannabinoid-1 (CB1) Receptor Ligand [11C]CB-119. Mol Imaging Biol 11, 246–252 (2009). https://doi.org/10.1007/s11307-008-0194-8

Download citation

Key words

  • Cannabinoid-1 receptor
  • CB1
  • PET
  • Carbon-11
  • Autoradiography
  • Rhesus