title: A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.
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.
authors: Biosciences, CVMD Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Stephan
authors: S
authors: Hjorth
authors: CVMD Translational Medicine Unit, Early Clinical Development, Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden. Electronic address: Cecilia.Karlsson@astrazeneca.com.
authors: Cecilia
authors: C
authors: Karlsson
authors: AstraZeneca Translational Science Centre and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Aurelija
authors: A
authors: Jucaite
authors: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Katarina
authors: K
authors: Varnäs
authors: Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca R&D, Mölndal, Sweden.
authors: Ulrika
authors: U
authors: Wählby Hamrén
authors: AstraZeneca Translational Science Centre and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Peter
authors: P
authors: Johnström
authors: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Balázs
authors: B
authors: Gulyás
authors: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Sean R
authors: SR
authors: Donohue
authors: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Victor W
authors: VW
authors: Pike
authors: Centre for Psychiatric Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Christer
authors: C
authors: Halldin
authors: AstraZeneca Translational Science Centre and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors: Lars
authors: L
authors: Farde
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000000981:diagnostic imaging; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000494:pharmacology; D011854:Radiochemistry; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D063387:Cannabinoid Receptor Antagonists; D002247:Carbon Isotopes; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C000611210:SD5024; D013449:Sulfonamides
keywords: Cannabinoid 1 receptor (CB(1)R) antagonists; Obesity; Positron emission tomography (PET); Receptor occupancy; Rimonabant; Taranabant; [(11)C]SD5024