Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain.

Animals Mice Humans Monoacylglycerol Lipases / metabolism Tomography, X-Ray Computed Positron-Emission Tomography / methods Brain / metabolism Kinetics Enzyme Inhibitors / chemistry
Brain imaging MAGL Morpholin-3-one derivatives PET tracer Structural optimization

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
05 Dec 2022
Historique:
received: 01 07 2022
revised: 23 08 2022
accepted: 04 09 2022
pubmed: 23 9 2022
medline: 2 11 2022
entrez: 22 9 2022
Statut: ppublish

Résumé

Monoacylglycerol lipase (MAGL) is a gatekeeper in regulating endocannabinoid signaling and has gained substantial attention as a therapeutic target for neurological disorders. We recently discovered a morpholin-3-one derivative as a novel scaffold for imaging MAGL via positron emission tomography (PET). However, its slow kinetics in vivo hampered the application. In this study, structural optimization was conducted and eleven novel MAGL inhibitors were designed and synthesized. Based on the results from MAGL inhibitory potency, in vitro metabolic stability and surface plasmon resonance assays, we identified compound 7 as a potential MAGL PET tracer candidate. [

Identifiants

DOI: 10.1016/j.ejmech.2022.114750 PMID: 36137365
pubmed: 36137365
pii: S0223-5234(22)00652-3
doi: 10.1016/j.ejmech.2022.114750
pii:
doi:

Substances chimiques

Monoacylglycerol Lipases EC 3.1.1.23
Enzyme Inhibitors 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114750

Informations de copyright

Copyright © 2022 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yingfang He reports financial support was provided by China Scholarship Council. COLLIN LUDOVIC, EDELMANN MARTIN, GOBBI LUCA, GRETHER UWE, HE YINGFANG, HONER MICHAEL, MU LINJING, RICHTER HANS has patent RADIOLABELED COMPOUNDS issued to ETH Zurich, F. Hoffmann-La Roche Ltd.

Auteurs

Yingfang He (Y)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland.

Uwe Grether (U)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Marco F Taddio (MF)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland.

Carla Meier (C)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland.

Claudia Keller (C)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland.

Martin R Edelmann (MR)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Michael Honer (M)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Sylwia Huber (S)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Matthias B Wittwer (MB)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Dominik Heer (D)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Hans Richter (H)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Ludovic Collin (L)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Melanie N Hug (MN)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Manuel Hilbert (M)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

Annemarieke G J Postmus (AGJ)

Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, Netherlands.

Anna Floor Stevens (AF)

Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, Netherlands.

Mario van der Stelt (M)

Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, Netherlands.

Stefanie D Krämer (SD)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland.

Roger Schibli (R)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland.

Linjing Mu (L)

Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland; Department of Nuclear Medicine, University Hospital Zurich, CH-8091, Zurich, Switzerland. Electronic address: linjing.mu@pharma.ethz.ch.

Luca C Gobbi (LC)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland.

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Classifications MeSH

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questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Multi-parameter optimization: Development of a...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Carboxylic ester hydrolases › Acylglycerol lipase › Multi-parameter optimization: Development of a...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Imagerie diagnostique › Tomographie › Tomographie à rayons X › Tomodensitométrie › Multi-parameter optimization: Development of a...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Techniques de diagnostic radioisotopique › Scintigraphie › Tomoscintigraphie › Tomographie par émission de positons › Multi-parameter optimization: Development of a...
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questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Cinétique › Multi-parameter optimization: Development of a...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Multi-parameter optimization: Development of a...