Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents
Open accessAbstract
[11C]MePPEP is an inverse agonist and a radioligand developed to image cannabinoid CB1 receptors with positron emission tomography (PET). It provides reversible, high specific signal in monkey brain. We assessed [11C]MePPEP in rodent brain with regard to receptor selectivity, susceptibility to transport by P-glycoprotein (P-gp), sensitivity to displacement by agonists, and accumulation of radiometabolites. We used CB1 receptor knockout mice and P-gp knockout mice to assess receptor selectivity and sensitivity to efflux transport, respectively. Using serial measurements of PET brain activity and plasma concentrations of [11C]MePPEP, we estimated CB1 receptor density in rat brain as distribution volume. CB1 knockout mice showed only nonspecific brain uptake, and [11C]MePPEP was not a substrate for P-gp. Direct acting agonists anandamide (10 mg/kg), methanandamide (10 mg/kg), CP 55,940 (1 mg/kg), and indirect agonist URB597 (0.3 and 0.6 mg/kg) failed to displace [11C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg) displaced >65% of [11C]MePPEP. Radiometabolites represented ~13% of total radioactivity in brain between 30 and 120 min. [11C]MePPEP was selective for the CB1 receptor, was not a substrate for P-gp, and was more potently displaced by inverse agonists than agonists. The low potency of agonists suggests either a large receptor reserve or non-overlapping binding sites for agonists and inverse agonists. Radiometabolites of [11C]MePPEP in brain caused distribution volume to be overestimated by approximately 13%.
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Increased [11C]OMAR VT values are explained to the most part by receptor up-regulation in response to low anandamide levels rather than low receptor occupancy by anandamide.
“The lack of displacement of CB1 radioligands by agonists42–44 which has been attributed to a large receptor reserve45 suggests that increased [11C]OMAR VT values are explained to the most part by receptor up-regulation in response to low anandamide levels rather than low receptor occupancy by anandamide.”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [42]
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Hirvonen, J., Goodwin, R. S., Li, C.-T., Terry, G. E., Zoghbi, S. S., Morse, C., Pike, V. W., Volkow, N. D., Huestis, M. A., & Innis, R. B. (2012) · Molecular Psychiatry · doi:10.1038/mp.2011.82 · Cited by 587 · see citing works
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- Authors
- Terry, G., Liow, J.-S., Chernet, E., Zoghbi, S. S., Phebus, L., Felder, C. C., Tauscher, J., Schaus, J. M., Pike, V. W., Halldin, C., & Innis, R. B.
- Affiliations
- National Institutes of Health (US)
- Eli Lilly (United States) (US)
- Karolinska Institutet (SE)
- Corresponding author
- Innis, Robert B.
- ORCID
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 41
- Issue
- 3
- Pages
- 690-698
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC2474463
- OpenAlex
- W2096441983
- Cited by
- 51
- References
- 35
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 3 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 3 · 2013: 9 · 2012: 6
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- National Institute of Mental Health (Z01-MH-002795-04)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Keywords
- CB1 receptor, receptor selectivity, CB1 knockout mice, receptor reserve, rodent brain imaging
- MeSH terms
- Animals, Arachidonic Acids, Binding, Competitive, Brain Chemistry, Carbon Radioisotopes, Male, Pyrrolidinones, Mass Spectrometry, Rats, Sprague-Dawley, Radiopharmaceuticals, Receptor, Cannabinoid, CB1, Positron-Emission Tomography, Mice, Rats, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids
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