Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain
Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-c...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-09, Vol.67 (18), p.16403-16415 |
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| container_title | Journal of medicinal chemistry |
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| creator | Li, Wanqing Zhang, Xiaojun Ma, Jie Zhou, Jingyin Di, Xuan Huang, Donglan Zhou, Kaixiang Zhang, Jinming Wang, Lu Fu, Hualong Cui, Mengchao |
| description | Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1–3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK′547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands. |
| doi_str_mv | 10.1021/acs.jmedchem.4c01263 |
| format | Article |
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In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1–3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK′547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c01263</identifier><identifier>PMID: 39259669</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Brain - diagnostic imaging ; Brain - metabolism ; Fluorine Radioisotopes - chemistry ; Humans ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Positron-Emission Tomography - methods ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - metabolism ; Pyrazoles - pharmacokinetics ; Pyrazoles - pharmacology ; Radiopharmaceuticals - chemical synthesis ; Radiopharmaceuticals - chemistry ; Radiopharmaceuticals - pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism ; Systemic Inflammatory Response Syndrome - diagnostic imaging ; Systemic Inflammatory Response Syndrome - metabolism ; Tissue Distribution</subject><ispartof>Journal of medicinal chemistry, 2024-09, Vol.67 (18), p.16403-16415</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a227t-7d2044984769376fba2476a1b60e90faff8cac97ca67f50e367312f338be6cf83</cites><orcidid>0000-0002-7197-8087 ; 0000-0002-3488-7864 ; 0000-0003-4210-6711 ; 0000-0002-8049-1991</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.4c01263$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01263$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2764,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39259669$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Wanqing</creatorcontrib><creatorcontrib>Zhang, Xiaojun</creatorcontrib><creatorcontrib>Ma, Jie</creatorcontrib><creatorcontrib>Zhou, Jingyin</creatorcontrib><creatorcontrib>Di, Xuan</creatorcontrib><creatorcontrib>Huang, Donglan</creatorcontrib><creatorcontrib>Zhou, Kaixiang</creatorcontrib><creatorcontrib>Zhang, Jinming</creatorcontrib><creatorcontrib>Wang, Lu</creatorcontrib><creatorcontrib>Fu, Hualong</creatorcontrib><creatorcontrib>Cui, Mengchao</creatorcontrib><title>Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1–3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK′547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.</description><subject>Animals</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - metabolism</subject><subject>Fluorine Radioisotopes - chemistry</subject><subject>Humans</subject><subject>Ligands</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Positron-Emission Tomography - methods</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - metabolism</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Radiopharmaceuticals - chemical synthesis</subject><subject>Radiopharmaceuticals - chemistry</subject><subject>Radiopharmaceuticals - pharmacokinetics</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor-Interacting Protein Serine-Threonine Kinases - metabolism</subject><subject>Systemic Inflammatory Response Syndrome - diagnostic imaging</subject><subject>Systemic Inflammatory Response Syndrome - metabolism</subject><subject>Tissue Distribution</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-O0zAQxi0EYrsLb4CQj91Duv5XJzlC6UK1lYiWco5cZ9x4ldjBTpDKe_F-uLTLkdOMxr_vs2Y-hN5RsqCE0Tul4-Kph0a30C-EJpRJ_gLN6JKRTBREvEQzQhjLmGT8Cl3H-EQI4ZTx1-iKl2xZSlnO0O8qgO6ss1p1eP1TdZMarXfYG_zJtscm-OEY1C_fQbbyARpc-WjHkIh1b2M8oTvf-0NQQ3vE82q9u8Vbe1Cuidj4gDe9Olh3OPk9goZh9CHbuBGC0uNp_g2CdXC3awN4lzpcBT-CdfjBOhUBUzx_3FQP9Ban2dgC_hiUdW_QK6O6CG8v9QZ9v1_vVl-y7dfPm9WHbaYYy8csbxgRoixELkueS7NXLLWK7iWBkhhlTKGVLnOtZG6WBLjM04EM58UepDYFv0Hzs-8Q_I8J4linpTV0nXLgp1hzSrgQyVMkVJxRHXyMAUw9BNurcKwpqU-B1Smw-jmw-hJYkr2__DDt09s_0XNCCSBn4K_cT8Glhf_v-QcELKcc</recordid><startdate>20240926</startdate><enddate>20240926</enddate><creator>Li, Wanqing</creator><creator>Zhang, Xiaojun</creator><creator>Ma, Jie</creator><creator>Zhou, Jingyin</creator><creator>Di, Xuan</creator><creator>Huang, Donglan</creator><creator>Zhou, Kaixiang</creator><creator>Zhang, Jinming</creator><creator>Wang, Lu</creator><creator>Fu, Hualong</creator><creator>Cui, Mengchao</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7197-8087</orcidid><orcidid>https://orcid.org/0000-0002-3488-7864</orcidid><orcidid>https://orcid.org/0000-0003-4210-6711</orcidid><orcidid>https://orcid.org/0000-0002-8049-1991</orcidid></search><sort><creationdate>20240926</creationdate><title>Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain</title><author>Li, Wanqing ; Zhang, Xiaojun ; Ma, Jie ; Zhou, Jingyin ; Di, Xuan ; Huang, Donglan ; Zhou, Kaixiang ; Zhang, Jinming ; Wang, Lu ; Fu, Hualong ; Cui, Mengchao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a227t-7d2044984769376fba2476a1b60e90faff8cac97ca67f50e367312f338be6cf83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Brain - diagnostic imaging</topic><topic>Brain - metabolism</topic><topic>Fluorine Radioisotopes - chemistry</topic><topic>Humans</topic><topic>Ligands</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Positron-Emission Tomography - methods</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - metabolism</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - pharmacology</topic><topic>Radiopharmaceuticals - chemical synthesis</topic><topic>Radiopharmaceuticals - chemistry</topic><topic>Radiopharmaceuticals - pharmacokinetics</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor-Interacting Protein Serine-Threonine Kinases - metabolism</topic><topic>Systemic Inflammatory Response Syndrome - diagnostic imaging</topic><topic>Systemic Inflammatory Response Syndrome - metabolism</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Wanqing</creatorcontrib><creatorcontrib>Zhang, Xiaojun</creatorcontrib><creatorcontrib>Ma, Jie</creatorcontrib><creatorcontrib>Zhou, Jingyin</creatorcontrib><creatorcontrib>Di, Xuan</creatorcontrib><creatorcontrib>Huang, Donglan</creatorcontrib><creatorcontrib>Zhou, Kaixiang</creatorcontrib><creatorcontrib>Zhang, Jinming</creatorcontrib><creatorcontrib>Wang, Lu</creatorcontrib><creatorcontrib>Fu, Hualong</creatorcontrib><creatorcontrib>Cui, Mengchao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Wanqing</au><au>Zhang, Xiaojun</au><au>Ma, Jie</au><au>Zhou, Jingyin</au><au>Di, Xuan</au><au>Huang, Donglan</au><au>Zhou, Kaixiang</au><au>Zhang, Jinming</au><au>Wang, Lu</au><au>Fu, Hualong</au><au>Cui, Mengchao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-09-26</date><risdate>2024</risdate><volume>67</volume><issue>18</issue><spage>16403</spage><epage>16415</epage><pages>16403-16415</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Receptor-interacting serine/threonine protein kinase 1 (RIPK1) has emerged as an important regulator of pathologic cell death and inflammation and is implicated in the pathologies of various central nervous system diseases. In this study, we reported the development of three potent dihydropyrazole-cored RIPK1 positron emission tomography (PET) ligands [18F]WL1–3. Among these, [18F]WL1 showed specific binding to RIPK1 in mouse brain sections in vitro through autoradiography and exhibited favorable brain kinetics in mice, characterized by a high initial uptake (brain2 min = 4.89% ID/g) and rapid washout (brain60 min = 0.21% ID/g). PET studies in rat brains revealed that [18F]WL1 could readily penetrate the brain with specific binding confirmed by inhibition effects of unlabeled WL1 and GSK′547. Notably, [18F]WL1 showed significant potential in imaging the alterations of RIPK1 in a rat brain of tumor necrosis factor α-induced systemic inflammatory response syndrome model. These findings may pave the way for the future design of potent RIPK1 PET ligands.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>39259669</pmid><doi>10.1021/acs.jmedchem.4c01263</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-7197-8087</orcidid><orcidid>https://orcid.org/0000-0002-3488-7864</orcidid><orcidid>https://orcid.org/0000-0003-4210-6711</orcidid><orcidid>https://orcid.org/0000-0002-8049-1991</orcidid></addata></record> |
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| subjects | Animals Brain - diagnostic imaging Brain - metabolism Fluorine Radioisotopes - chemistry Humans Ligands Male Mice Mice, Inbred C57BL Positron-Emission Tomography - methods Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - metabolism Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Radiopharmaceuticals - chemical synthesis Radiopharmaceuticals - chemistry Radiopharmaceuticals - pharmacokinetics Rats Rats, Sprague-Dawley Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Systemic Inflammatory Response Syndrome - diagnostic imaging Systemic Inflammatory Response Syndrome - metabolism Tissue Distribution |
| title | Preclinical Evaluation of Dihydropyrazole-Cored Positron Emission Tomography (PET) Ligands for Imaging of Receptor-Interacting Serine/Threonine Protein Kinase 1 (RIPK1) in the Brain |
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