Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleDrug Discovery and Translational Medicine

Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676

Katarina Varnäs, Anders Juréus, Peter Johnström, Charlotte Ahlgren, Pär Schött, Magnus Schou, Susanne Gruber, Eva Jerning, Jonas Malmborg, Christer Halldin, Lovisa Afzelius and Lars Farde
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 464-471; DOI: https://doi.org/10.1124/jpet.116.234146
Katarina Varnäs
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anders Juréus
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Peter Johnström
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charlotte Ahlgren
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pär Schött
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Magnus Schou
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susanne Gruber
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eva Jerning
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonas Malmborg
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christer Halldin
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lovisa Afzelius
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lars Farde
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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.

Footnotes

    • 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.

  • dx.doi.org/10.1124/jpet.116.234146.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Integrated Strategy for Use of Positron Emission Tomography in Nonhuman Primates to Confirm Multitarget Occupancy of Novel Psychotropic Drugs: An Example with AZD3676
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleDrug Discovery and Translational Medicine

Use of PET for Confirmation of Multitarget Occupancy

Katarina Varnäs, Anders Juréus, Peter Johnström, Charlotte Ahlgren, Pär Schött, Magnus Schou, Susanne Gruber, Eva Jerning, Jonas Malmborg, Christer Halldin, Lovisa Afzelius and Lars Farde
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 464-471; DOI: https://doi.org/10.1124/jpet.116.234146

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleDrug Discovery and Translational Medicine

Use of PET for Confirmation of Multitarget Occupancy

Katarina Varnäs, Anders Juréus, Peter Johnström, Charlotte Ahlgren, Pär Schött, Magnus Schou, Susanne Gruber, Eva Jerning, Jonas Malmborg, Christer Halldin, Lovisa Afzelius and Lars Farde
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 464-471; DOI: https://doi.org/10.1124/jpet.116.234146
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Midazolam compared with tezampanel-caramiphen against soman
  • ERR agonist reduces obesity
  • Mechanistic Modeling of Humoral Immunity in NHPs
Show more Drug Discovery and Translational Medicine

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics