Abstract
Positron emission tomography (PET) is widely applied in 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 multi-target engagement have been less frequently reported and have often been inconsistent with results obtained in vitro. AZD3676 is a novel, combined serotonin 5-HT1A and 5-HT1B receptor antagonist, 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 non-human primates. Target engagement in the non-human 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 vs. 5-HT1B receptors. These findings support the further integrated use of PET for confirmation of multi-target occupancy of CNS drugs. Importantly, earlier introduction of PET studies in non-human primates may reduce future development costs and requirement for animal experiments in preclinical CNS drug development programs.
- The American Society for Pharmacology and Experimental Therapeutics