Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain
European Journal of Medicinal Chemistry, vol. 243, pp. 114750
Abstract
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. [ 11 C] 7 was synthesized via direct 11 CO 2 fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [ 11 C] 7 demonstrated its improved kinetic profile compared to the lead structure. Its high specificity in vivo was proved by using MAGL KO mice. Although further studies confirmed that [ 11 C] 7 is a P-glycoprotein (P-gp) substrate in mice, its low P-gp efflux ratio on cells transfected with human protein suggests that it should not be an issue for the clinical translation of [ 11 C] 7 as a novel reversible MAGL PET tracer in human subjects. Overall, [ 11 C] 7 ([ 11 C]RO7284390) showed promising results warranting further clinical evaluation.
Authors 20
-
ETH Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
ETH Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland
-
ETH Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland
-
ETH Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Affiliation as printed
Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland
-
Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, Netherlands
-
Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, Netherlands
-
Leiden University · Oncode Institute
Affiliation as printed
Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, Leiden, Netherlands
-
ETH Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland
-
ETH Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
Center for Radiopharmaceutical Sciences, Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland
-
Linjing Mu corresponding
ETH Zurich · University Hospital Zurich · Institute of Pharmaceutical Sciences
Affiliation as printed
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
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
Cited by 15 stored of 14
15 results
No patents citing this paper on Lens.org (checked 2026-10-11).