The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo
We aimed to evaluate radiofluorination at the pyridinyl-6 position of the selective 5-HT(1A) receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide)], on 5-HT(1A) receptor radioligand behavior in vivo. The pyridinyl-6 [(18)F]fluoro deri...
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| Veröffentlicht in: | Molecular imaging and biology 2004-01, Vol.6 (1), p.17-26 |
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| creator | McCarron, Julie A Pike, Victor W Halldin, Christer Sandell, Johan Sóvágó, Judit Gulyas, Balàsz Cselényi, Zsolt Wikström, Hakan V Marchais-Oberwinkler, Sandrine Nowicki, Bartek Dollé, Frédéric Farde, Lars |
| description | We aimed to evaluate radiofluorination at the pyridinyl-6 position of the selective 5-HT(1A) receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide)], on 5-HT(1A) receptor radioligand behavior in vivo.
The pyridinyl-6 [(18)F]fluoro derivative of WAY-100635 ([(18)F]6FPWAY) was obtained by direct nucleophilic substitution with [(18)F]fluoride ion in a bromo precursor. After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into brain regions was assessed with positron emission tomography (PET) and blood samples analyzed by high performance liquid chromatography (HPLC) for parent radioligand and radioactive metabolites. The experiment was repeated after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5-HT(1A) receptors.
After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of injected dose at 7.5 min. Uptake was highest in 5-HT(1A) receptor-rich regions. Pretreatment with WAY-100635 reduced uptake in these regions to near the levels in receptor-devoid cerebellum. [(18)F]6FPWAY was rapidly metabolized in vivo, as evidenced by the rapid appearance of radioactive metabolites in plasma.
[(18)F]6FPWAY is selective and moderately useful for imaging brain 5-HT(1A) receptors in vivo. The pyridinyl-6 position is resistant to defluorination and may be an attractive site for the (18)F-labeling of 6FPWAY analogs that resist hydrolysis. |
| doi_str_mv | 10.1016/j.mibio.2003.12.001 |
| format | Article |
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The pyridinyl-6 [(18)F]fluoro derivative of WAY-100635 ([(18)F]6FPWAY) was obtained by direct nucleophilic substitution with [(18)F]fluoride ion in a bromo precursor. After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into brain regions was assessed with positron emission tomography (PET) and blood samples analyzed by high performance liquid chromatography (HPLC) for parent radioligand and radioactive metabolites. The experiment was repeated after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5-HT(1A) receptors.
After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of injected dose at 7.5 min. Uptake was highest in 5-HT(1A) receptor-rich regions. Pretreatment with WAY-100635 reduced uptake in these regions to near the levels in receptor-devoid cerebellum. [(18)F]6FPWAY was rapidly metabolized in vivo, as evidenced by the rapid appearance of radioactive metabolites in plasma.
[(18)F]6FPWAY is selective and moderately useful for imaging brain 5-HT(1A) receptors in vivo. The pyridinyl-6 position is resistant to defluorination and may be an attractive site for the (18)F-labeling of 6FPWAY analogs that resist hydrolysis.</description><identifier>ISSN: 1536-1632</identifier><identifier>DOI: 10.1016/j.mibio.2003.12.001</identifier><identifier>PMID: 15018825</identifier><language>eng</language><publisher>United States</publisher><subject>Aminopyridines - chemistry ; Aminopyridines - pharmacokinetics ; Animals ; Brain - diagnostic imaging ; Brain - metabolism ; Chromatography, High Pressure Liquid ; Fluorine Radioisotopes ; Macaca fascicularis ; Molecular Structure ; Piperazines - chemistry ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Pyridines - chemistry ; Pyridines - pharmacology ; Radioligand Assay ; Receptor, Serotonin, 5-HT1A - analysis ; Serotonin 5-HT1 Receptor Antagonists ; Serotonin Antagonists - chemistry ; Serotonin Antagonists - pharmacokinetics ; Tomography, Emission-Computed</subject><ispartof>Molecular imaging and biology, 2004-01, Vol.6 (1), p.17-26</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c303t-7c255da6a34fbffe81fce95cdccf4430b97d55ebf4f5df476bbcaabc622a45033</citedby></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/15018825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McCarron, Julie A</creatorcontrib><creatorcontrib>Pike, Victor W</creatorcontrib><creatorcontrib>Halldin, Christer</creatorcontrib><creatorcontrib>Sandell, Johan</creatorcontrib><creatorcontrib>Sóvágó, Judit</creatorcontrib><creatorcontrib>Gulyas, Balàsz</creatorcontrib><creatorcontrib>Cselényi, Zsolt</creatorcontrib><creatorcontrib>Wikström, Hakan V</creatorcontrib><creatorcontrib>Marchais-Oberwinkler, Sandrine</creatorcontrib><creatorcontrib>Nowicki, Bartek</creatorcontrib><creatorcontrib>Dollé, Frédéric</creatorcontrib><creatorcontrib>Farde, Lars</creatorcontrib><title>The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo</title><title>Molecular imaging and biology</title><addtitle>Mol Imaging Biol</addtitle><description>We aimed to evaluate radiofluorination at the pyridinyl-6 position of the selective 5-HT(1A) receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide)], on 5-HT(1A) receptor radioligand behavior in vivo.
The pyridinyl-6 [(18)F]fluoro derivative of WAY-100635 ([(18)F]6FPWAY) was obtained by direct nucleophilic substitution with [(18)F]fluoride ion in a bromo precursor. After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into brain regions was assessed with positron emission tomography (PET) and blood samples analyzed by high performance liquid chromatography (HPLC) for parent radioligand and radioactive metabolites. The experiment was repeated after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5-HT(1A) receptors.
After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of injected dose at 7.5 min. Uptake was highest in 5-HT(1A) receptor-rich regions. Pretreatment with WAY-100635 reduced uptake in these regions to near the levels in receptor-devoid cerebellum. [(18)F]6FPWAY was rapidly metabolized in vivo, as evidenced by the rapid appearance of radioactive metabolites in plasma.
[(18)F]6FPWAY is selective and moderately useful for imaging brain 5-HT(1A) receptors in vivo. The pyridinyl-6 position is resistant to defluorination and may be an attractive site for the (18)F-labeling of 6FPWAY analogs that resist hydrolysis.</description><subject>Aminopyridines - chemistry</subject><subject>Aminopyridines - pharmacokinetics</subject><subject>Animals</subject><subject>Brain - diagnostic imaging</subject><subject>Brain - metabolism</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Fluorine Radioisotopes</subject><subject>Macaca fascicularis</subject><subject>Molecular Structure</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacokinetics</subject><subject>Piperazines - pharmacology</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Receptor, Serotonin, 5-HT1A - analysis</subject><subject>Serotonin 5-HT1 Receptor Antagonists</subject><subject>Serotonin Antagonists - chemistry</subject><subject>Serotonin Antagonists - pharmacokinetics</subject><subject>Tomography, Emission-Computed</subject><issn>1536-1632</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE9LwzAYh3NQ3Jx-AkFy8paaP03bHcdQJwy8TMRTSNLEZbRNTdrBLn52M514euH3Pr_3hQeAG4Izgklxv8tap5zPKMYsIzTDmJyBKeGsQKRgdAIuY9ylsCSUXYAJ4ZhUFeVT8LXZGtgfgqtdd2hQAXsf3eB8B72Fb4t3RDAuGIcyQgnTxkDrAwyydt42ow-uk0caIWOt0QNMRY5WG7KAwWjTD39w4z5kV0NltnLvUug6uHd7fwXOrWyiuT7NGXh9fNgsV2j98vS8XKyRZpgNqNSU81oWkuVWpUcVsdrMua61tnnOsJqXNedG2dzy2uZloZSWUumCUplzzNgM3P3e7YP_HE0cROuiNk0jO-PHKEpS5qxi8wSyX1AHH2MwVvTBtTIcBMHiqFrsxI9qcVQtCBXJamrdns6PqjX1f-fkmX0DJ1N-1w</recordid><startdate>20040101</startdate><enddate>20040101</enddate><creator>McCarron, Julie A</creator><creator>Pike, Victor W</creator><creator>Halldin, Christer</creator><creator>Sandell, Johan</creator><creator>Sóvágó, Judit</creator><creator>Gulyas, Balàsz</creator><creator>Cselényi, Zsolt</creator><creator>Wikström, Hakan V</creator><creator>Marchais-Oberwinkler, Sandrine</creator><creator>Nowicki, Bartek</creator><creator>Dollé, Frédéric</creator><creator>Farde, Lars</creator><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>20040101</creationdate><title>The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo</title><author>McCarron, Julie A ; Pike, Victor W ; Halldin, Christer ; Sandell, Johan ; Sóvágó, Judit ; Gulyas, Balàsz ; Cselényi, Zsolt ; Wikström, Hakan V ; Marchais-Oberwinkler, Sandrine ; Nowicki, Bartek ; Dollé, Frédéric ; Farde, Lars</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c303t-7c255da6a34fbffe81fce95cdccf4430b97d55ebf4f5df476bbcaabc622a45033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Aminopyridines - chemistry</topic><topic>Aminopyridines - pharmacokinetics</topic><topic>Animals</topic><topic>Brain - diagnostic imaging</topic><topic>Brain - metabolism</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Fluorine Radioisotopes</topic><topic>Macaca fascicularis</topic><topic>Molecular Structure</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacokinetics</topic><topic>Piperazines - pharmacology</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Receptor, Serotonin, 5-HT1A - analysis</topic><topic>Serotonin 5-HT1 Receptor Antagonists</topic><topic>Serotonin Antagonists - chemistry</topic><topic>Serotonin Antagonists - pharmacokinetics</topic><topic>Tomography, Emission-Computed</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCarron, Julie A</creatorcontrib><creatorcontrib>Pike, Victor W</creatorcontrib><creatorcontrib>Halldin, Christer</creatorcontrib><creatorcontrib>Sandell, Johan</creatorcontrib><creatorcontrib>Sóvágó, Judit</creatorcontrib><creatorcontrib>Gulyas, Balàsz</creatorcontrib><creatorcontrib>Cselényi, Zsolt</creatorcontrib><creatorcontrib>Wikström, Hakan V</creatorcontrib><creatorcontrib>Marchais-Oberwinkler, Sandrine</creatorcontrib><creatorcontrib>Nowicki, Bartek</creatorcontrib><creatorcontrib>Dollé, Frédéric</creatorcontrib><creatorcontrib>Farde, Lars</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>Molecular imaging and biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCarron, Julie A</au><au>Pike, Victor W</au><au>Halldin, Christer</au><au>Sandell, Johan</au><au>Sóvágó, Judit</au><au>Gulyas, Balàsz</au><au>Cselényi, Zsolt</au><au>Wikström, Hakan V</au><au>Marchais-Oberwinkler, Sandrine</au><au>Nowicki, Bartek</au><au>Dollé, Frédéric</au><au>Farde, Lars</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo</atitle><jtitle>Molecular imaging and biology</jtitle><addtitle>Mol Imaging Biol</addtitle><date>2004-01-01</date><risdate>2004</risdate><volume>6</volume><issue>1</issue><spage>17</spage><epage>26</epage><pages>17-26</pages><issn>1536-1632</issn><abstract>We aimed to evaluate radiofluorination at the pyridinyl-6 position of the selective 5-HT(1A) receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide)], on 5-HT(1A) receptor radioligand behavior in vivo.
The pyridinyl-6 [(18)F]fluoro derivative of WAY-100635 ([(18)F]6FPWAY) was obtained by direct nucleophilic substitution with [(18)F]fluoride ion in a bromo precursor. After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into brain regions was assessed with positron emission tomography (PET) and blood samples analyzed by high performance liquid chromatography (HPLC) for parent radioligand and radioactive metabolites. The experiment was repeated after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5-HT(1A) receptors.
After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of injected dose at 7.5 min. Uptake was highest in 5-HT(1A) receptor-rich regions. Pretreatment with WAY-100635 reduced uptake in these regions to near the levels in receptor-devoid cerebellum. [(18)F]6FPWAY was rapidly metabolized in vivo, as evidenced by the rapid appearance of radioactive metabolites in plasma.
[(18)F]6FPWAY is selective and moderately useful for imaging brain 5-HT(1A) receptors in vivo. The pyridinyl-6 position is resistant to defluorination and may be an attractive site for the (18)F-labeling of 6FPWAY analogs that resist hydrolysis.</abstract><cop>United States</cop><pmid>15018825</pmid><doi>10.1016/j.mibio.2003.12.001</doi><tpages>10</tpages></addata></record> |
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| subjects | Aminopyridines - chemistry Aminopyridines - pharmacokinetics Animals Brain - diagnostic imaging Brain - metabolism Chromatography, High Pressure Liquid Fluorine Radioisotopes Macaca fascicularis Molecular Structure Piperazines - chemistry Piperazines - pharmacokinetics Piperazines - pharmacology Pyridines - chemistry Pyridines - pharmacology Radioligand Assay Receptor, Serotonin, 5-HT1A - analysis Serotonin 5-HT1 Receptor Antagonists Serotonin Antagonists - chemistry Serotonin Antagonists - pharmacokinetics Tomography, Emission-Computed |
| title | The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo |
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