Positron emission tomography (PET) is widely applied in central nervous system (CNS) drug development for assessment of target engagement in vivo. As the majority of PET investigations have addressed drug interaction at a single binding site, findings of multitarget engagement have been less frequently reported and have often been inconsistent with results obtained in vitro. AZD3676 [N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl) benzofuran-2-carboxamide] is a novel combined serotonin (5-hydroxytryptamine) 5-HT1A and 5-HT1B receptor antagonist that was developed for the treatment of cognitive impairment in Alzheimer’s disease. Here, we evaluated the properties of AZD3676 as a CNS drug by combining in vitro and ex vivo radioligand binding techniques, behavioral pharmacology in rodents, and PET imaging in nonhuman primates. Target engagement in the nonhuman primate brain was assessed in PET studies by determination of drug-induced occupancy using receptor-selective radioligands. AZD3676 showed preclinical properties consistent with CNS drug potential, including nanomolar receptor affinity and efficacy in rodent models of learning and memory. In PET studies of the monkey brain, AZD3676 inhibited radioligand binding in a dose-dependent manner with similar affinity at both receptors. The equally high affinity at 5-HT1A and 5-HT1B receptors as determined in vivo was not predicted from corresponding estimates obtained in vitro, suggesting more than 10-fold selectivity for 5-HT1A versus 5-HT1B receptors. These findings support the further integrated use of PET for confirmation of multitarget occupancy of CNS drugs. Importantly, earlier introduction of PET studies in nonhuman primates may reduce future development costs and the requirement for animal experiments in preclinical CNS drug development programs.
- Received May 11, 2016.
- Accepted July 6, 2016.
↵1 Current affiliation: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
↵2 Current affiliation: Patientsäkerhetsenheten, Landstinget Sörmland, Nyköping, Sweden.
↵3 Current affiliation: Science for Life Laboratory (SciLifeLab), KTH Royal Institute of Technology, Stockholm, Sweden.
↵4 Current affiliation: BioArctic Neuroscience, Stockholm, Sweden.
↵5 Current affiliation: Chemistry and Technology, National Forensic Centre, Linköping, Sweden.
↵6 Current affiliation: Computational Precision Medicine, Inflammation & Immunology Research Unit, Pfizer, Cambridge, Massachusetts, US.
Supported by AstraZeneca Pharmaceuticals.
- Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics