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A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates
- Source :
- Neuropharmacology. 101:519-530
- Publication Year :
- 2016
- Publisher :
- Elsevier BV, 2016.
-
Abstract
- There is a medical need for safe and efficacious anti-obesity drugs with acceptable side effect profiles. To mitigate the challenge posed by translating target interaction across species and balancing beneficial vs. adverse effects, a positron emission tomography (PET) approach could help guide clinical dose optimization. Thus, as part of a compound differentiation effort, three novel selective CB1 receptor (CB1R) antagonists, developed by AstraZeneca (AZ) for the treatment of obesity, were compared with two clinically tested reference compounds, rimonabant and taranabant, with regard to receptor occupancy relative to dose and exposure. A total of 42 PET measurements were performed in 6 non-human primates using the novel CB1R antagonist radioligand [(11)C]SD5024. The AZ CB1R antagonists bound in a saturable manner to brain CB1R with in vivo affinities similar to that of rimonabant and taranabant, compounds with proven weight loss efficacy in clinical trials. Interestingly, it was found that exposures corresponding to those needed for optimal clinical efficacy of rimonabant and taranabant resulted in a CB1R occupancy typically around ∼20-30%, thus much lower than what would be expected for classical G-protein coupled receptor (GPCR) antagonists in other therapeutic contexts. These findings are also discussed in relation to emerging literature on the potential usefulness of 'neutral' vs. 'classical' CB1R (inverse agonist) antagonists. The study additionally highlighted the usefulness of the radioligand [(11)C]SD5024 as a specific tracer for CB1R in the primate brain, though an arterial input function would ideally be required in future studies to further assure accurate quantitative analysis of specific binding.
- Subjects :
- 0301 basic medicine
Time Factors
Cannabinoid receptor
Side effect
Pharmacology
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
Taranabant
Receptor, Cannabinoid, CB1
Rimonabant
In vivo
Radioligand
medicine
Animals
Inverse agonist
Cannabinoid Receptor Antagonists
Carbon Isotopes
Sulfonamides
Radiochemistry
Dose-Response Relationship, Drug
Chemistry
Brain
Macaca fascicularis
030104 developmental biology
Area Under Curve
Positron-Emission Tomography
Pyrazoles
Cannabinoid receptor antagonist
Female
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 101
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....392a14c581d716809aa60ebb19e1eb0d