A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates

Neuropharmacology
Stephan HjorthL Farde

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 (G...Continue Reading

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Citations

Dec 18, 2020·Frontiers in Neuroanatomy·Isabelle MiedererMathias Schreckenberger
Apr 17, 2021·ACS Pharmacology & Translational Science·Nayaab KhanRangan Maitra
Apr 22, 2019·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Agnė StadulytėAdriana Alexandre S Tavares

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