Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET
A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5-a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D4 receptor (D4R) ligands (3a−3h, K i = 1.3–28 nM). The para-fluoroethoxy-substituted der...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1800-1810 |
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| creator | Prante, Olaf Tietze, Rainer Hocke, Carsten Löber, Stefan Hübner, Harald Kuwert, Torsten Gmeiner, Peter |
| description | A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5-a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D4 receptor (D4R) ligands (3a−3h, K i = 1.3–28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D4 subtype selectivity of more than 3 orders of magnitude over both congeners D2 and D3 combined with inverse agonism at D4R. The corresponding 18F-labeled radioligands revealed high serum stability in vitro and log P values of 2–3. In vitro rat brain autoradiography showed specific binding of [18F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65–80%) and the selective D4R antagonist 10 (78–93%). The observed binding pattern was mainly consistent with the known D4R distribution in the rat brain. Thus, [18F]3h (FAUC F41) represents a potential radioligand for studying the D4R in vivo by positron emission tomography (PET). |
| doi_str_mv | 10.1021/jm701375u |
| format | Article |
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The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D4 subtype selectivity of more than 3 orders of magnitude over both congeners D2 and D3 combined with inverse agonism at D4R. The corresponding 18F-labeled radioligands revealed high serum stability in vitro and log P values of 2–3. In vitro rat brain autoradiography showed specific binding of [18F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65–80%) and the selective D4R antagonist 10 (78–93%). The observed binding pattern was mainly consistent with the known D4R distribution in the rat brain. Thus, [18F]3h (FAUC F41) represents a potential radioligand for studying the D4R in vivo by positron emission tomography (PET).</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm701375u</identifier><identifier>PMID: 18307287</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Brain - diagnostic imaging ; Catecholaminergic system ; Contrast media. Radiopharmaceuticals ; Drug Design ; Drug Evaluation, Preclinical ; Female ; Fluorine Radioisotopes - chemistry ; Humans ; Isotope Labeling - methods ; Ligands ; Medical sciences ; Molecular Structure ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Positron-Emission Tomography ; Pyrazoles - chemical synthesis ; Pyrazoles - pharmacology ; Pyridines - chemical synthesis ; Pyridines - pharmacology ; Radioligand Assay ; Radiopharmaceuticals - chemical synthesis ; Radiopharmaceuticals - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Dopamine D4 - drug effects ; Stereoisomerism</subject><ispartof>Journal of medicinal chemistry, 2008-03, Vol.51 (6), p.1800-1810</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm701375u$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm701375u$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20205759$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18307287$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Prante, Olaf</creatorcontrib><creatorcontrib>Tietze, Rainer</creatorcontrib><creatorcontrib>Hocke, Carsten</creatorcontrib><creatorcontrib>Löber, Stefan</creatorcontrib><creatorcontrib>Hübner, Harald</creatorcontrib><creatorcontrib>Kuwert, Torsten</creatorcontrib><creatorcontrib>Gmeiner, Peter</creatorcontrib><title>Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5-a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D4 receptor (D4R) ligands (3a−3h, K i = 1.3–28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D4 subtype selectivity of more than 3 orders of magnitude over both congeners D2 and D3 combined with inverse agonism at D4R. The corresponding 18F-labeled radioligands revealed high serum stability in vitro and log P values of 2–3. In vitro rat brain autoradiography showed specific binding of [18F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65–80%) and the selective D4R antagonist 10 (78–93%). The observed binding pattern was mainly consistent with the known D4R distribution in the rat brain. Thus, [18F]3h (FAUC F41) represents a potential radioligand for studying the D4R in vivo by positron emission tomography (PET).</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Brain - diagnostic imaging</subject><subject>Catecholaminergic system</subject><subject>Contrast media. Radiopharmaceuticals</subject><subject>Drug Design</subject><subject>Drug Evaluation, Preclinical</subject><subject>Female</subject><subject>Fluorine Radioisotopes - chemistry</subject><subject>Humans</subject><subject>Isotope Labeling - methods</subject><subject>Ligands</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Positron-Emission Tomography</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Radiopharmaceuticals - chemical synthesis</subject><subject>Radiopharmaceuticals - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Dopamine D4 - drug effects</subject><subject>Stereoisomerism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFks1uEzEQx1cIREPhwAsgX-CUhbG9H15ubROgIoioDVwQsiZZuzjdtRd7t2J5Ih4Tpwnh5BnNz__5TJLnFF5TYPTNti2B8jIfHiQTmjNIMwHZw2QCwFjKCsZPkichbAGAU8YfJydUcCiZKCfJn-vR9j9UMGFKrrA2TjeD88Zib5ydErQ1ubTkq-m9I_M7bIb7AHGaLEePv13jvtFpnuL3bvSmNlal5xhUTWauwza6ZJaRK7VRXe88WZibKBjekpkJG3en_LgTQhtTRCcocnbjrAn9vpLmniY6flzOV0-TRxqboJ4d3tPky7v56uJDuvj8_vLibJEiE6JPeaXFei24FkpQ4JohVlVR8Qx0oUVJo5kj8rriSpW0VpkuVFGoNQchgKuKnyav9rqddz8HFXrZxmJV06BVbgiyEFCxPBMRfHEAh3Wratl506If5b_ZRuDlAcCwwUZ7tBsTjhwDBnmZ7zKmey52rn4d4-hvZVHGrcrV8lryTzksi4_ncvVfFzdBbt3gbZyHpCB3tyCPt8D_ApVro44</recordid><startdate>20080327</startdate><enddate>20080327</enddate><creator>Prante, Olaf</creator><creator>Tietze, Rainer</creator><creator>Hocke, Carsten</creator><creator>Löber, Stefan</creator><creator>Hübner, Harald</creator><creator>Kuwert, Torsten</creator><creator>Gmeiner, Peter</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20080327</creationdate><title>Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET</title><author>Prante, Olaf ; Tietze, Rainer ; Hocke, Carsten ; Löber, Stefan ; Hübner, Harald ; Kuwert, Torsten ; Gmeiner, Peter</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a288t-39f8bb83f8e8103f2aa9969340f6f8716935aa3d93ee71de4f6e66eb308803e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Brain - diagnostic imaging</topic><topic>Catecholaminergic system</topic><topic>Contrast media. Radiopharmaceuticals</topic><topic>Drug Design</topic><topic>Drug Evaluation, Preclinical</topic><topic>Female</topic><topic>Fluorine Radioisotopes - chemistry</topic><topic>Humans</topic><topic>Isotope Labeling - methods</topic><topic>Ligands</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Positron-Emission Tomography</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Radiopharmaceuticals - chemical synthesis</topic><topic>Radiopharmaceuticals - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Dopamine D4 - drug effects</topic><topic>Stereoisomerism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Prante, Olaf</creatorcontrib><creatorcontrib>Tietze, Rainer</creatorcontrib><creatorcontrib>Hocke, Carsten</creatorcontrib><creatorcontrib>Löber, Stefan</creatorcontrib><creatorcontrib>Hübner, Harald</creatorcontrib><creatorcontrib>Kuwert, Torsten</creatorcontrib><creatorcontrib>Gmeiner, Peter</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Prante, Olaf</au><au>Tietze, Rainer</au><au>Hocke, Carsten</au><au>Löber, Stefan</au><au>Hübner, Harald</au><au>Kuwert, Torsten</au><au>Gmeiner, Peter</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-03-27</date><risdate>2008</risdate><volume>51</volume><issue>6</issue><spage>1800</spage><epage>1810</epage><pages>1800-1810</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of fluoro-substituted analogs structurally derived from the aminomethyl-substituted pyrazolo[1,5-a]pyridine lead compounds 9 (FAUC 113) and 10 (FAUC 213) were synthesized and evaluated as high-affinity D4 receptor (D4R) ligands (3a−3h, K i = 1.3–28 nM). The para-fluoroethoxy-substituted derivatives 3f and 3h revealed an outstanding D4 subtype selectivity of more than 3 orders of magnitude over both congeners D2 and D3 combined with inverse agonism at D4R. The corresponding 18F-labeled radioligands revealed high serum stability in vitro and log P values of 2–3. In vitro rat brain autoradiography showed specific binding of [18F]3h in distinct brain regions, including the gyrus dentate of the hippocampus, that were inhibited by both eticlopride (65–80%) and the selective D4R antagonist 10 (78–93%). The observed binding pattern was mainly consistent with the known D4R distribution in the rat brain. Thus, [18F]3h (FAUC F41) represents a potential radioligand for studying the D4R in vivo by positron emission tomography (PET).</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18307287</pmid><doi>10.1021/jm701375u</doi><tpages>11</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Brain - diagnostic imaging Catecholaminergic system Contrast media. Radiopharmaceuticals Drug Design Drug Evaluation, Preclinical Female Fluorine Radioisotopes - chemistry Humans Isotope Labeling - methods Ligands Medical sciences Molecular Structure Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Positron-Emission Tomography Pyrazoles - chemical synthesis Pyrazoles - pharmacology Pyridines - chemical synthesis Pyridines - pharmacology Radioligand Assay Radiopharmaceuticals - chemical synthesis Radiopharmaceuticals - pharmacology Rats Rats, Sprague-Dawley Receptors, Dopamine D4 - drug effects Stereoisomerism |
| title | Synthesis, Radiofluorination, and In Vitro Evaluation of Pyrazolo[1,5-a]pyridine-Based Dopamine D4 Receptor Ligands: Discovery of an Inverse Agonist Radioligand for PET |
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