Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase
Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the bra...
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| Veröffentlicht in: | European journal of medicinal chemistry 2025-01, Vol.285, p.117246 |
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| creator | Li, Yinlong Mori, Wakana Chaudhary, Ahmad Zhao, Chunyu Yamasaki, Tomoteru Zhang, Zachary Feng, Siyan Ware, Tim Rong, Jian Fujinaga, Masayuki Chen, Jiahui Kumata, Katsushi Zhang, Yiding Hu, Kuan Xie, Lin Zhou, Xin Song, Zhendong Gao, Yabiao Sun, Zhenkun Patel, Jimmy S Zhai, Chuangyan Yuan, Katherine Y Collier, Thomas L Ran, Chongzhao Collin, Ludovic Haider, Achi Grether, Uwe Wittwer, Matthias B Cravatt, Benjamin F Zhang, Ming-Rong Liang, Steven H |
| description | Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC
= 18.6 nM and (S)-6, IC
= 1.6 nM). In vitro autoradiography studies of [
F](R)-6 (codenamed [
F]MAGL-2304) and [
F](S)-6 (codenamed [
F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [
F](S)-6. Dynamic PET imaging studies revealed that [
F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [
F](S)-6 uptake in the brain, suggesting that [
F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds. |
| doi_str_mv | 10.1016/j.ejmech.2025.117246 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed</sourceid><recordid>TN_cdi_pubmed_primary_39793441</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>39793441</sourcerecordid><originalsourceid>FETCH-pubmed_primary_397934413</originalsourceid><addsrcrecordid>eNqFzrsKwkAQheFFEOPtDUTmBYy7uWotiqWIvYzJJNkw2Q1ZFfL2ptDa6jQfh1-IlZK-kirZ1j7VDWWVH8gg9pVKgygZialKk90mDOLIEzPnaillnEg5EV64T_dhFKmpyK6Ya-t686zIaQdocqA38guf2hqwBRj7Jga1gxMwPogph8vxBqzLwToobAe6wVKbEhprLGY9l9xn1FkeUIuOFmJcIDtafncu1qfj7XDetK9HQ_m97YaDrr__qsK_4ANAQUou</addsrcrecordid><sourcetype>Index Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase</title><source>Elsevier ScienceDirect Journals</source><creator>Li, Yinlong ; Mori, Wakana ; Chaudhary, Ahmad ; Zhao, Chunyu ; Yamasaki, Tomoteru ; Zhang, Zachary ; Feng, Siyan ; Ware, Tim ; Rong, Jian ; Fujinaga, Masayuki ; Chen, Jiahui ; Kumata, Katsushi ; Zhang, Yiding ; Hu, Kuan ; Xie, Lin ; Zhou, Xin ; Song, Zhendong ; Gao, Yabiao ; Sun, Zhenkun ; Patel, Jimmy S ; Zhai, Chuangyan ; Yuan, Katherine Y ; Collier, Thomas L ; Ran, Chongzhao ; Collin, Ludovic ; Haider, Achi ; Grether, Uwe ; Wittwer, Matthias B ; Cravatt, Benjamin F ; Zhang, Ming-Rong ; Liang, Steven H</creator><creatorcontrib>Li, Yinlong ; Mori, Wakana ; Chaudhary, Ahmad ; Zhao, Chunyu ; Yamasaki, Tomoteru ; Zhang, Zachary ; Feng, Siyan ; Ware, Tim ; Rong, Jian ; Fujinaga, Masayuki ; Chen, Jiahui ; Kumata, Katsushi ; Zhang, Yiding ; Hu, Kuan ; Xie, Lin ; Zhou, Xin ; Song, Zhendong ; Gao, Yabiao ; Sun, Zhenkun ; Patel, Jimmy S ; Zhai, Chuangyan ; Yuan, Katherine Y ; Collier, Thomas L ; Ran, Chongzhao ; Collin, Ludovic ; Haider, Achi ; Grether, Uwe ; Wittwer, Matthias B ; Cravatt, Benjamin F ; Zhang, Ming-Rong ; Liang, Steven H</creatorcontrib><description>Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC
= 18.6 nM and (S)-6, IC
= 1.6 nM). In vitro autoradiography studies of [
F](R)-6 (codenamed [
F]MAGL-2304) and [
F](S)-6 (codenamed [
F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [
F](S)-6. Dynamic PET imaging studies revealed that [
F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [
F](S)-6 uptake in the brain, suggesting that [
F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.</description><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2025.117246</identifier><identifier>PMID: 39793441</identifier><language>eng</language><publisher>France</publisher><ispartof>European journal of medicinal chemistry, 2025-01, Vol.285, p.117246</ispartof><rights>Copyright © 2025 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39793441$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yinlong</creatorcontrib><creatorcontrib>Mori, Wakana</creatorcontrib><creatorcontrib>Chaudhary, Ahmad</creatorcontrib><creatorcontrib>Zhao, Chunyu</creatorcontrib><creatorcontrib>Yamasaki, Tomoteru</creatorcontrib><creatorcontrib>Zhang, Zachary</creatorcontrib><creatorcontrib>Feng, Siyan</creatorcontrib><creatorcontrib>Ware, Tim</creatorcontrib><creatorcontrib>Rong, Jian</creatorcontrib><creatorcontrib>Fujinaga, Masayuki</creatorcontrib><creatorcontrib>Chen, Jiahui</creatorcontrib><creatorcontrib>Kumata, Katsushi</creatorcontrib><creatorcontrib>Zhang, Yiding</creatorcontrib><creatorcontrib>Hu, Kuan</creatorcontrib><creatorcontrib>Xie, Lin</creatorcontrib><creatorcontrib>Zhou, Xin</creatorcontrib><creatorcontrib>Song, Zhendong</creatorcontrib><creatorcontrib>Gao, Yabiao</creatorcontrib><creatorcontrib>Sun, Zhenkun</creatorcontrib><creatorcontrib>Patel, Jimmy S</creatorcontrib><creatorcontrib>Zhai, Chuangyan</creatorcontrib><creatorcontrib>Yuan, Katherine Y</creatorcontrib><creatorcontrib>Collier, Thomas L</creatorcontrib><creatorcontrib>Ran, Chongzhao</creatorcontrib><creatorcontrib>Collin, Ludovic</creatorcontrib><creatorcontrib>Haider, Achi</creatorcontrib><creatorcontrib>Grether, Uwe</creatorcontrib><creatorcontrib>Wittwer, Matthias B</creatorcontrib><creatorcontrib>Cravatt, Benjamin F</creatorcontrib><creatorcontrib>Zhang, Ming-Rong</creatorcontrib><creatorcontrib>Liang, Steven H</creatorcontrib><title>Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC
= 18.6 nM and (S)-6, IC
= 1.6 nM). In vitro autoradiography studies of [
F](R)-6 (codenamed [
F]MAGL-2304) and [
F](S)-6 (codenamed [
F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [
F](S)-6. Dynamic PET imaging studies revealed that [
F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [
F](S)-6 uptake in the brain, suggesting that [
F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.</description><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNqFzrsKwkAQheFFEOPtDUTmBYy7uWotiqWIvYzJJNkw2Q1ZFfL2ptDa6jQfh1-IlZK-kirZ1j7VDWWVH8gg9pVKgygZialKk90mDOLIEzPnaillnEg5EV64T_dhFKmpyK6Ya-t686zIaQdocqA38guf2hqwBRj7Jga1gxMwPogph8vxBqzLwToobAe6wVKbEhprLGY9l9xn1FkeUIuOFmJcIDtafncu1qfj7XDetK9HQ_m97YaDrr__qsK_4ANAQUou</recordid><startdate>20250104</startdate><enddate>20250104</enddate><creator>Li, Yinlong</creator><creator>Mori, Wakana</creator><creator>Chaudhary, Ahmad</creator><creator>Zhao, Chunyu</creator><creator>Yamasaki, Tomoteru</creator><creator>Zhang, Zachary</creator><creator>Feng, Siyan</creator><creator>Ware, Tim</creator><creator>Rong, Jian</creator><creator>Fujinaga, Masayuki</creator><creator>Chen, Jiahui</creator><creator>Kumata, Katsushi</creator><creator>Zhang, Yiding</creator><creator>Hu, Kuan</creator><creator>Xie, Lin</creator><creator>Zhou, Xin</creator><creator>Song, Zhendong</creator><creator>Gao, Yabiao</creator><creator>Sun, Zhenkun</creator><creator>Patel, Jimmy S</creator><creator>Zhai, Chuangyan</creator><creator>Yuan, Katherine Y</creator><creator>Collier, Thomas L</creator><creator>Ran, Chongzhao</creator><creator>Collin, Ludovic</creator><creator>Haider, Achi</creator><creator>Grether, Uwe</creator><creator>Wittwer, Matthias B</creator><creator>Cravatt, Benjamin F</creator><creator>Zhang, Ming-Rong</creator><creator>Liang, Steven H</creator><scope>NPM</scope></search><sort><creationdate>20250104</creationdate><title>Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase</title><author>Li, Yinlong ; Mori, Wakana ; Chaudhary, Ahmad ; Zhao, Chunyu ; Yamasaki, Tomoteru ; Zhang, Zachary ; Feng, Siyan ; Ware, Tim ; Rong, Jian ; Fujinaga, Masayuki ; Chen, Jiahui ; Kumata, Katsushi ; Zhang, Yiding ; Hu, Kuan ; Xie, Lin ; Zhou, Xin ; Song, Zhendong ; Gao, Yabiao ; Sun, Zhenkun ; Patel, Jimmy S ; Zhai, Chuangyan ; Yuan, Katherine Y ; Collier, Thomas L ; Ran, Chongzhao ; Collin, Ludovic ; Haider, Achi ; Grether, Uwe ; Wittwer, Matthias B ; Cravatt, Benjamin F ; Zhang, Ming-Rong ; Liang, Steven H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_397934413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yinlong</creatorcontrib><creatorcontrib>Mori, Wakana</creatorcontrib><creatorcontrib>Chaudhary, Ahmad</creatorcontrib><creatorcontrib>Zhao, Chunyu</creatorcontrib><creatorcontrib>Yamasaki, Tomoteru</creatorcontrib><creatorcontrib>Zhang, Zachary</creatorcontrib><creatorcontrib>Feng, Siyan</creatorcontrib><creatorcontrib>Ware, Tim</creatorcontrib><creatorcontrib>Rong, Jian</creatorcontrib><creatorcontrib>Fujinaga, Masayuki</creatorcontrib><creatorcontrib>Chen, Jiahui</creatorcontrib><creatorcontrib>Kumata, Katsushi</creatorcontrib><creatorcontrib>Zhang, Yiding</creatorcontrib><creatorcontrib>Hu, Kuan</creatorcontrib><creatorcontrib>Xie, Lin</creatorcontrib><creatorcontrib>Zhou, Xin</creatorcontrib><creatorcontrib>Song, Zhendong</creatorcontrib><creatorcontrib>Gao, Yabiao</creatorcontrib><creatorcontrib>Sun, Zhenkun</creatorcontrib><creatorcontrib>Patel, Jimmy S</creatorcontrib><creatorcontrib>Zhai, Chuangyan</creatorcontrib><creatorcontrib>Yuan, Katherine Y</creatorcontrib><creatorcontrib>Collier, Thomas L</creatorcontrib><creatorcontrib>Ran, Chongzhao</creatorcontrib><creatorcontrib>Collin, Ludovic</creatorcontrib><creatorcontrib>Haider, Achi</creatorcontrib><creatorcontrib>Grether, Uwe</creatorcontrib><creatorcontrib>Wittwer, Matthias B</creatorcontrib><creatorcontrib>Cravatt, Benjamin F</creatorcontrib><creatorcontrib>Zhang, Ming-Rong</creatorcontrib><creatorcontrib>Liang, Steven H</creatorcontrib><collection>PubMed</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yinlong</au><au>Mori, Wakana</au><au>Chaudhary, Ahmad</au><au>Zhao, Chunyu</au><au>Yamasaki, Tomoteru</au><au>Zhang, Zachary</au><au>Feng, Siyan</au><au>Ware, Tim</au><au>Rong, Jian</au><au>Fujinaga, Masayuki</au><au>Chen, Jiahui</au><au>Kumata, Katsushi</au><au>Zhang, Yiding</au><au>Hu, Kuan</au><au>Xie, Lin</au><au>Zhou, Xin</au><au>Song, Zhendong</au><au>Gao, Yabiao</au><au>Sun, Zhenkun</au><au>Patel, Jimmy S</au><au>Zhai, Chuangyan</au><au>Yuan, Katherine Y</au><au>Collier, Thomas L</au><au>Ran, Chongzhao</au><au>Collin, Ludovic</au><au>Haider, Achi</au><au>Grether, Uwe</au><au>Wittwer, Matthias B</au><au>Cravatt, Benjamin F</au><au>Zhang, Ming-Rong</au><au>Liang, Steven H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2025-01-04</date><risdate>2025</risdate><volume>285</volume><spage>117246</spage><pages>117246-</pages><eissn>1768-3254</eissn><abstract>Monoacylglycerol lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC
= 18.6 nM and (S)-6, IC
= 1.6 nM). In vitro autoradiography studies of [
F](R)-6 (codenamed [
F]MAGL-2304) and [
F](S)-6 (codenamed [
F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [
F](S)-6. Dynamic PET imaging studies revealed that [
F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [
F](S)-6 uptake in the brain, suggesting that [
F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.</abstract><cop>France</cop><pmid>39793441</pmid><doi>10.1016/j.ejmech.2025.117246</doi></addata></record> |
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| title | Radiosynthesis and evaluation of novel 18 F labeled PET ligands for imaging monoacylglycerol lipase |
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