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

Yingfang He; Uwe Grether; Marco f. Taddio; Carla Meier; Claudia Keller; Martin r. Edelmann; Michael Honer; Sylwia Huber; Matthias b. Wittwer; Dominik Heer; Hans Richter; Ludovic Collin; Melanie n. Hug; Manuel Hilbert; Annemarieke g.j. Postmus; Anna floor Stevens; Mario Van der stelt; Stefanie d. Krämer; Roger Schibli; Linjing Mu; Luca c. Gobbi

doi:10.1016/j.ejmech.2022.114750

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

Yingfang He, Uwe Grether, Marco f. Taddio, Carla Meier, Claudia Keller, Martin r. Edelmann, Michael Honer, Sylwia Huber, Matthias b. Wittwer, Dominik Heer, Hans Richter, Ludovic Collin, Melanie n. Hug, Manuel Hilbert, Annemarieke g.j. Postmus, Anna floor Stevens, Mario Van der stelt, Stefanie d. Krämer, Roger Schibli, Linjing MuLuca c. Gobbi

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

8 Citations (SciVal)

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. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]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 [11C]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 [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C]RO7284390) showed promising results warranting further clinical evaluation.

Original language	English
Article number	114750
Journal	European Journal of Medicinal Chemistry
Volume	243
Early online date	9 Sept 2022
DOIs	https://doi.org/10.1016/j.ejmech.2022.114750
Publication status	Published - 5 Dec 2022

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https://linkinghub.elsevier.com/retrieve/pii/S0223523422006523

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He, Y., Grether, U., Taddio, M. F., Meier, C., Keller, C., Edelmann, M. R., Honer, M., Huber, S., Wittwer, M. B., Heer, D., Richter, H., Collin, L., Hug, M. N., Hilbert, M., Postmus, A. G. J., Stevens, A. F., Van der stelt, M., Krämer, S. D., Schibli, R., ... Gobbi, L. C. (2022). 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, 243, Article 114750. https://doi.org/10.1016/j.ejmech.2022.114750

He, Y, Grether, U, Taddio, MF, Meier, C, Keller, C, Edelmann, MR, Honer, M, Huber, S, Wittwer, MB, Heer, D, Richter, H, Collin, L, Hug, MN, Hilbert, M, Postmus, AGJ, Stevens, AF, Van der stelt, M, Krämer, SD, Schibli, R, Mu, L & Gobbi, LC 2022, '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, 114750. https://doi.org/10.1016/j.ejmech.2022.114750

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

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. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]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 [11C]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 [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C]RO7284390) showed promising results warranting further clinical evaluation.",

author = "Yingfang He and Uwe Grether and Taddio, {Marco f.} and Carla Meier and Claudia Keller and Edelmann, {Martin r.} and Michael Honer and Sylwia Huber and Wittwer, {Matthias b.} and Dominik Heer and Hans Richter and Ludovic Collin and Hug, {Melanie n.} and Manuel Hilbert and Postmus, {Annemarieke g.j.} and Stevens, {Anna floor} and {Van der stelt}, Mario and Kr{\"a}mer, {Stefanie d.} and Roger Schibli and Linjing Mu and Gobbi, {Luca c.}",

year = "2022",

month = dec,

day = "5",

doi = "10.1016/j.ejmech.2022.114750",

language = "English",

volume = "243",

journal = "European Journal of Medicinal Chemistry",

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TY - JOUR

T1 - Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain

AU - He, Yingfang

AU - Grether, Uwe

AU - Taddio, Marco f.

AU - Meier, Carla

AU - Keller, Claudia

AU - Edelmann, Martin r.

AU - Honer, Michael

AU - Huber, Sylwia

AU - Wittwer, Matthias b.

AU - Heer, Dominik

AU - Richter, Hans

AU - Collin, Ludovic

AU - Hug, Melanie n.

AU - Hilbert, Manuel

AU - Postmus, Annemarieke g.j.

AU - Stevens, Anna floor

AU - Van der stelt, Mario

AU - Krämer, Stefanie d.

AU - Schibli, Roger

AU - Mu, Linjing

AU - Gobbi, Luca c.

PY - 2022/12/5

Y1 - 2022/12/5

N2 - 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. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]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 [11C]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 [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C]RO7284390) showed promising results warranting further clinical evaluation.

AB - 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. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]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 [11C]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 [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C]RO7284390) showed promising results warranting further clinical evaluation.

U2 - 10.1016/j.ejmech.2022.114750

DO - 10.1016/j.ejmech.2022.114750

M3 - Article

SN - 0223-5234

VL - 243

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 114750

ER -

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

Abstract

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