Synthesis, Evaluation, and Radiolabeling of New Potent Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2 as Potential Tracers for Positron Emission Tomography Imaging
The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metab...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-10, Vol.55 (20), p.8685-8699 |
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| creator | Andrés, José-Ignacio Alcázar, Jesús Cid, José María De Angelis, Meri Iturrino, Laura Langlois, Xavier Lavreysen, Hilde Trabanco, Andrés A Celen, Sofie Bormans, Guy |
| description | The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [35S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC50 values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [11C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain. |
| doi_str_mv | 10.1021/jm300912k |
| format | Article |
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The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [35S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC50 values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [11C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300912k</identifier><identifier>PMID: 22992024</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Allosteric Regulation ; Allosteric Site ; Animals ; Binding, Competitive ; Brain - metabolism ; Carbon Radioisotopes ; CHO Cells ; Cricetinae ; Cricetulus ; Humans ; Male ; Positron-Emission Tomography ; Pyridines - chemical synthesis ; Pyridines - pharmacokinetics ; Pyridines - pharmacology ; Radioligand Assay ; Radiopharmaceuticals - chemical synthesis ; Radiopharmaceuticals - pharmacokinetics ; Radiopharmaceuticals - pharmacology ; Rats ; Rats, Wistar ; Receptors, Metabotropic Glutamate - metabolism ; Thiazoles - chemical synthesis ; Thiazoles - pharmacokinetics ; Thiazoles - pharmacology ; Tissue Distribution</subject><ispartof>Journal of medicinal chemistry, 2012-10, Vol.55 (20), p.8685-8699</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a296t-f50e4b62d1665372244ebfe731f92eace762dbd512680c233d20e2f961e7a2503</citedby><cites>FETCH-LOGICAL-a296t-f50e4b62d1665372244ebfe731f92eace762dbd512680c233d20e2f961e7a2503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm300912k$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300912k$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22992024$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Andrés, José-Ignacio</creatorcontrib><creatorcontrib>Alcázar, Jesús</creatorcontrib><creatorcontrib>Cid, José María</creatorcontrib><creatorcontrib>De Angelis, Meri</creatorcontrib><creatorcontrib>Iturrino, Laura</creatorcontrib><creatorcontrib>Langlois, Xavier</creatorcontrib><creatorcontrib>Lavreysen, Hilde</creatorcontrib><creatorcontrib>Trabanco, Andrés A</creatorcontrib><creatorcontrib>Celen, Sofie</creatorcontrib><creatorcontrib>Bormans, Guy</creatorcontrib><title>Synthesis, Evaluation, and Radiolabeling of New Potent Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2 as Potential Tracers for Positron Emission Tomography Imaging</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [35S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC50 values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [11C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.</description><subject>Allosteric Regulation</subject><subject>Allosteric Site</subject><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Brain - metabolism</subject><subject>Carbon Radioisotopes</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Humans</subject><subject>Male</subject><subject>Positron-Emission Tomography</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Radiopharmaceuticals - chemical synthesis</subject><subject>Radiopharmaceuticals - pharmacokinetics</subject><subject>Radiopharmaceuticals - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Metabotropic Glutamate - metabolism</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - pharmacokinetics</subject><subject>Thiazoles - pharmacology</subject><subject>Tissue Distribution</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU9v00AQxVeoiIbCgS-A9oIEUg27s_4TH6MqtJFSQCWcrbE9Tjesve7uuijfjQ_XLQk99TSH95s3b_QYeyfFZylAftn1SohSwu8XbCYzEEk6F-kJmwkBkEAO6pS99n4nhFAS1Ct2ClCWICCdsb8_90O4Ja_9OV_eo5kwaDuccxxafoOttgZrMnrYctvxb_SH_7CBhhCH10HfE18YY30gpxt-bdvJYLDOP8LRlV9TwNoGZ8coX5opYI-B-A01NEaOA0d_dNRo-MZhQ3G7i9K_A84OfNlr72MmvrG93Tocb_d81eM2ZnrDXnZoPL09zjP26-tyc3GVrL9fri4W6wShzEPSZYLSOodW5nmmCoA0pbqjQsmuBIoni6jVbSYhn4sGlGpBEHRlLqlAyIQ6Yx8PvqOzdxP5UMVMDRmDA9nJV1LKLIOikPOIfjqgjbPeO-qq0eke3b6Sonosq3oqK7Lvj7ZT3VP7RP5vJwIfDgA2vtrZyQ3xy2eMHgAsaJ6L</recordid><startdate>20121025</startdate><enddate>20121025</enddate><creator>Andrés, José-Ignacio</creator><creator>Alcázar, Jesús</creator><creator>Cid, José María</creator><creator>De Angelis, Meri</creator><creator>Iturrino, Laura</creator><creator>Langlois, Xavier</creator><creator>Lavreysen, Hilde</creator><creator>Trabanco, Andrés A</creator><creator>Celen, Sofie</creator><creator>Bormans, Guy</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></search><sort><creationdate>20121025</creationdate><title>Synthesis, Evaluation, and Radiolabeling of New Potent Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2 as Potential Tracers for Positron Emission Tomography Imaging</title><author>Andrés, José-Ignacio ; Alcázar, Jesús ; Cid, José María ; De Angelis, Meri ; Iturrino, Laura ; Langlois, Xavier ; Lavreysen, Hilde ; Trabanco, Andrés A ; Celen, Sofie ; Bormans, Guy</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a296t-f50e4b62d1665372244ebfe731f92eace762dbd512680c233d20e2f961e7a2503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Allosteric Regulation</topic><topic>Allosteric Site</topic><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Brain - metabolism</topic><topic>Carbon Radioisotopes</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Humans</topic><topic>Male</topic><topic>Positron-Emission Tomography</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Radiopharmaceuticals - chemical synthesis</topic><topic>Radiopharmaceuticals - pharmacokinetics</topic><topic>Radiopharmaceuticals - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, Metabotropic Glutamate - metabolism</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - pharmacokinetics</topic><topic>Thiazoles - pharmacology</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Andrés, José-Ignacio</creatorcontrib><creatorcontrib>Alcázar, Jesús</creatorcontrib><creatorcontrib>Cid, José María</creatorcontrib><creatorcontrib>De Angelis, Meri</creatorcontrib><creatorcontrib>Iturrino, Laura</creatorcontrib><creatorcontrib>Langlois, Xavier</creatorcontrib><creatorcontrib>Lavreysen, Hilde</creatorcontrib><creatorcontrib>Trabanco, Andrés A</creatorcontrib><creatorcontrib>Celen, Sofie</creatorcontrib><creatorcontrib>Bormans, Guy</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>Andrés, José-Ignacio</au><au>Alcázar, Jesús</au><au>Cid, José María</au><au>De Angelis, Meri</au><au>Iturrino, Laura</au><au>Langlois, Xavier</au><au>Lavreysen, Hilde</au><au>Trabanco, Andrés A</au><au>Celen, Sofie</au><au>Bormans, Guy</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Evaluation, and Radiolabeling of New Potent Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2 as Potential Tracers for Positron Emission Tomography Imaging</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-10-25</date><risdate>2012</risdate><volume>55</volume><issue>20</issue><spage>8685</spage><epage>8699</epage><pages>8685-8699</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [35S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC50 values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [11C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22992024</pmid><doi>10.1021/jm300912k</doi><tpages>15</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2012-10, Vol.55 (20), p.8685-8699 |
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| subjects | Allosteric Regulation Allosteric Site Animals Binding, Competitive Brain - metabolism Carbon Radioisotopes CHO Cells Cricetinae Cricetulus Humans Male Positron-Emission Tomography Pyridines - chemical synthesis Pyridines - pharmacokinetics Pyridines - pharmacology Radioligand Assay Radiopharmaceuticals - chemical synthesis Radiopharmaceuticals - pharmacokinetics Radiopharmaceuticals - pharmacology Rats Rats, Wistar Receptors, Metabotropic Glutamate - metabolism Thiazoles - chemical synthesis Thiazoles - pharmacokinetics Thiazoles - pharmacology Tissue Distribution |
| title | Synthesis, Evaluation, and Radiolabeling of New Potent Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2 as Potential Tracers for Positron Emission Tomography Imaging |
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