A Highly Selective and Versatile Probe Platform for Visualization of Monoacylglycerol Lipase

Angewandte Chemie, vol. 137

Abstract

Abstract Monoacylglycerol lipase (MAGL) is a key enzyme for signal termination in the endocannabinoid system (ECS). MAGL inhibition results in indirect activation of the cannabinoid receptors, which offers unique advantages for the treatment of, e.g., multiple sclerosis, epilepsy, and other neurological disorders. Molecular imaging techniques are valuable tools to overcome the current poor understanding of MAGL's distribution and role in patho‐ and physiological processes within ECS signaling. Herein, we report the design, synthesis, and validation of highly selective versatile fluorescent and click‐chemistry probes for MAGL. Structure‐based design combined with a reverse‐design approach allowed the development of a structural unit that selectively and effectively recognizes MAGL while offering a versatile platform to attach different fluorophores and further reporter units. In this way, labeled probes with sub‐nanomolar potency carrying diverse fluorescent dyes were obtained. Probe affinity and selectivity remained invariant to changes in the fluorophore subunit, showing the remarkable robustness of this platform in delivering tailor‐made probes. Highly consistent inhibition across species supports pharmacological model translatability. Extensive profiling and validation in various cellular systems shows the ability of these highly potent and selective probes to elucidate the complex role of MAGL in ECS cellular signaling, inflammatory processes, and disease progression.

Authors 19

1. Axel Hentsch

   Leibniz-Forschungsinstitut für Molekulare Pharmakologie

   Affiliation as printed

   Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER

2. Mónica Guberman

   Leibniz-Forschungsinstitut für Molekulare Pharmakologie

   Affiliation as printed

   Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER

3. Silke Radetzki

   Leibniz-Forschungsinstitut für Molekulare Pharmakologie

   Affiliation as printed

   Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER

4. Mirjam C. W. Huizenga Aachen

   Leiden University

   Affiliation as printed

   Leiden Institute of Chemistry (LIC) Universiteit Leiden Einsteinweg 55 2333 CC Leiden NL

5. Jérôme Paul

   Leibniz-Forschungsinstitut für Molekulare Pharmakologie

   Affiliation as printed

   Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER

6. Jörg Benz

   Roche (Switzerland)

   Affiliation as printed

   Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

7. Bernd Kuhn

   Roche (Switzerland)

   Affiliation as printed

   Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

8. Dominik Heer

   Roche (Switzerland)

   Affiliation as printed

   Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

9. Andreas Topp

   Roche (Switzerland)

   Affiliation as printed

   Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

10. Ludivine Esteves Gloria

    Roche (Switzerland)

    Affiliation as printed

    Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

11. Remo Hochstrasser

    Roche (Switzerland)

    Affiliation as printed

    Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

12. Matthias Wittwer

    Roche (Switzerland)

    Affiliation as printed

    Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

13. Jens Peter von Kries

    Leibniz-Forschungsinstitut für Molekulare Pharmakologie

    Affiliation as printed

    Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER

14. Ludovic Collin

    Roche (Switzerland)

    Affiliation as printed

    Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

15. Julie Blaising

    Roche (Switzerland)

    Affiliation as printed

    Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

16. Mario van der Stelt Aachen

    Leiden University

    Affiliation as printed

    Leiden Institute of Chemistry (LIC) Universiteit Leiden Einsteinweg 55 2333 CC Leiden NL

17. Noa Lipstein

    Leibniz-Forschungsinstitut für Molekulare Pharmakologie

    Affiliation as printed

    Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER

18. Uwe Grether

    Roche (Switzerland)

    Affiliation as printed

    Pharma Research & Early Development (pRED) F. Hoffmann-La Roche Ltd Grenzacherstrasse 124 CH-4070 Basel CH

19. Marc Nazaré

    Leibniz-Forschungsinstitut für Molekulare Pharmakologie

    Affiliation as printed

    Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) Robert-Roessle-Strasse 10 13125 Berlin GER