title: Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676.
abstract: 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.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden katarina.varnas@ki.se.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Juréus
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Johnström
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahlgren
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Schött
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Schou
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Gruber
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Jerning
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Malmborg
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Afzelius
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (K.V., P.J., M.S., C.H., L.F.); AstraZeneca Translational Science Centre at Karolinska Institutet, PET CoE, Stockholm (P.J., M.S., L.F.); AstraZeneca R&D, Södertälje (A.J., C.A., P.S., S.G., E.J., J.M., L.A.), Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000378:metabolism* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008252:Macaca fascicularis; D008568:Memory / Q000187:drug effects; D051379:Mice; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011619:Psychotropic Drugs / Q000378:metabolism* / Q000494:pharmacology*; D011799:Quinazolines / Q000378:metabolism* / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology
chemical_list: C000604577:AZD3759; D001572:Benzofurans; D001798:Blood Proteins; C000619375:N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide; D010879:Piperazines; D011619:Psychotropic Drugs; D011799:Quinazolines; D044302:Receptor, Serotonin, 5-HT1B; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A