Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor
As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. T...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-05, Vol.58 (10), p.4266-4277 |
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| container_title | Journal of medicinal chemistry |
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| creator | Slavik, Roger Grether, Uwe Müller Herde, Adrienne Gobbi, Luca Fingerle, Jürgen Ullmer, Christoph Krämer, Stefanie D Schibli, Roger Mu, Linjing Ametamey, Simon M |
| description | As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([11C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. It might serve as a tool for the investigation of CB2 receptor expression levels in healthy tissues and different neuroinflammatory disorders in humans. |
| doi_str_mv | 10.1021/acs.jmedchem.5b00283 |
| format | Article |
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A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([11C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. 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Med. Chem</addtitle><description>As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([11C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. It might serve as a tool for the investigation of CB2 receptor expression levels in healthy tissues and different neuroinflammatory disorders in humans.</description><subject>Animals</subject><subject>Azetidines - chemistry</subject><subject>Azetidines - pharmacokinetics</subject><subject>CHO Cells</subject><subject>Contrast Media - chemistry</subject><subject>Contrast Media - pharmacokinetics</subject><subject>Cricetulus</subject><subject>Drug Discovery</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Drug Stability</subject><subject>Humans</subject><subject>Male</subject><subject>Mice, Inbred Strains</subject><subject>Picolinic Acids - chemistry</subject><subject>Picolinic Acids - pharmacokinetics</subject><subject>Positron-Emission Tomography - methods</subject><subject>Pyridines - chemistry</subject><subject>Rats, Wistar</subject><subject>Receptor, Cannabinoid, CB1 - analysis</subject><subject>Receptor, Cannabinoid, CB1 - genetics</subject><subject>Receptor, Cannabinoid, CB1 - metabolism</subject><subject>Receptor, Cannabinoid, CB2 - analysis</subject><subject>Receptor, Cannabinoid, CB2 - genetics</subject><subject>Receptor, Cannabinoid, CB2 - metabolism</subject><subject>Tissue Distribution</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctO3DAUhi3UCgbaN6gqL7vJ4FsuXo6Gq4RUVIZ15DjHGaPEDnYGKe_BA2OYgWVXPvL5_mPrfAj9omRJCaPnSsfl0wCt3sKwzBtCWMWP0ILmjGSiIuIbWqQ7lrGC8RN0GuMTIYRTxo_RCctlTiQVC_R6YaP2LxBm7A1W-MZ2W7wyxjo7zVi5Fj9AD3qyL4Dv52Bb6wCvnOp9h1VMgXs_gZus6lMV7RS8w5eDjdGmYuMH3wU1bmd8O6jOug6vukRj4wNeK-dUY523Ld7MI2CG_4GGcfLhB_puVB_h5-E8Q49Xl5v1TXb39_p2vbrLFBfVlGnNmSiZqQxlUDalkTKvpFEFMVyaAmjJRMtkIwoBikIB0uQtSFqVJSspKfkZ-rOfOwb_vIM41ennGvpeOfC7WNOiEoJTSnlCxR7VwccYwNRjsIMKc01J_e6jTj7qTx_1wUeK_T68sGtS7yv0KSABZA98xP0upNXG_898A3flmzQ</recordid><startdate>20150528</startdate><enddate>20150528</enddate><creator>Slavik, Roger</creator><creator>Grether, Uwe</creator><creator>Müller Herde, Adrienne</creator><creator>Gobbi, Luca</creator><creator>Fingerle, Jürgen</creator><creator>Ullmer, Christoph</creator><creator>Krämer, Stefanie D</creator><creator>Schibli, Roger</creator><creator>Mu, Linjing</creator><creator>Ametamey, Simon M</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>20150528</creationdate><title>Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor</title><author>Slavik, Roger ; Grether, Uwe ; Müller Herde, Adrienne ; Gobbi, Luca ; Fingerle, Jürgen ; Ullmer, Christoph ; Krämer, Stefanie D ; Schibli, Roger ; Mu, Linjing ; Ametamey, Simon M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-cc32472f8f12e7b7f99589fa60f39f6e1724d29b464ea1e6e9f5de91877271073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Azetidines - chemistry</topic><topic>Azetidines - pharmacokinetics</topic><topic>CHO Cells</topic><topic>Contrast Media - chemistry</topic><topic>Contrast Media - pharmacokinetics</topic><topic>Cricetulus</topic><topic>Drug Discovery</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Drug Stability</topic><topic>Humans</topic><topic>Male</topic><topic>Mice, Inbred Strains</topic><topic>Picolinic Acids - chemistry</topic><topic>Picolinic Acids - pharmacokinetics</topic><topic>Positron-Emission Tomography - methods</topic><topic>Pyridines - chemistry</topic><topic>Rats, Wistar</topic><topic>Receptor, Cannabinoid, CB1 - analysis</topic><topic>Receptor, Cannabinoid, CB1 - genetics</topic><topic>Receptor, Cannabinoid, CB1 - metabolism</topic><topic>Receptor, Cannabinoid, CB2 - analysis</topic><topic>Receptor, Cannabinoid, CB2 - genetics</topic><topic>Receptor, Cannabinoid, CB2 - metabolism</topic><topic>Tissue Distribution</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Slavik, Roger</creatorcontrib><creatorcontrib>Grether, Uwe</creatorcontrib><creatorcontrib>Müller Herde, Adrienne</creatorcontrib><creatorcontrib>Gobbi, Luca</creatorcontrib><creatorcontrib>Fingerle, Jürgen</creatorcontrib><creatorcontrib>Ullmer, Christoph</creatorcontrib><creatorcontrib>Krämer, Stefanie D</creatorcontrib><creatorcontrib>Schibli, Roger</creatorcontrib><creatorcontrib>Mu, Linjing</creatorcontrib><creatorcontrib>Ametamey, Simon M</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>Slavik, Roger</au><au>Grether, Uwe</au><au>Müller Herde, Adrienne</au><au>Gobbi, Luca</au><au>Fingerle, Jürgen</au><au>Ullmer, Christoph</au><au>Krämer, Stefanie D</au><au>Schibli, Roger</au><au>Mu, Linjing</au><au>Ametamey, Simon M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-05-28</date><risdate>2015</risdate><volume>58</volume><issue>10</issue><spage>4266</spage><epage>4277</epage><pages>4266-4277</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([11C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. 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| subjects | Animals Azetidines - chemistry Azetidines - pharmacokinetics CHO Cells Contrast Media - chemistry Contrast Media - pharmacokinetics Cricetulus Drug Discovery Drug Evaluation, Preclinical - methods Drug Stability Humans Male Mice, Inbred Strains Picolinic Acids - chemistry Picolinic Acids - pharmacokinetics Positron-Emission Tomography - methods Pyridines - chemistry Rats, Wistar Receptor, Cannabinoid, CB1 - analysis Receptor, Cannabinoid, CB1 - genetics Receptor, Cannabinoid, CB1 - metabolism Receptor, Cannabinoid, CB2 - analysis Receptor, Cannabinoid, CB2 - genetics Receptor, Cannabinoid, CB2 - metabolism Tissue Distribution |
| title | Discovery of a High Affinity and Selective Pyridine Analog as a Potential Positron Emission Tomography Imaging Agent for Cannabinoid Type 2 Receptor |
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