[18F]fluoroethoxy‐benzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses
Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]...
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description | Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (−)‐[18F]FEOBV, (−)‐(2R,3R)‐trans‐2‐hydroxy‐3‐(4‐phenylpiperidino)‐5‐(2‐[18F]fluoroethoxy)‐1,2,3,4‐tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (−)‐[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare‐like effects of FEOBV were associated with the “(−)”‐enantiomer exclusively. (−)‐[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)‐3‐PPP, or E‐2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or σ receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (−)‐[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (−)‐[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET. Synapse 30:263–274, 1998. © 1998 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/(SICI)1098-2396(199811)30:3<263::AID-SYN4>3.0.CO;2-9 |
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Keith ; Wieland, Donald M. ; Kilbourn, Michael R. ; Frey, Kirk A. ; Sherman, Phillip S. ; Carey, James E. ; Kuhl, David E.</creator><creatorcontrib>Mulholland, G. Keith ; Wieland, Donald M. ; Kilbourn, Michael R. ; Frey, Kirk A. ; Sherman, Phillip S. ; Carey, James E. ; Kuhl, David E.</creatorcontrib><description>Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (−)‐[18F]FEOBV, (−)‐(2R,3R)‐trans‐2‐hydroxy‐3‐(4‐phenylpiperidino)‐5‐(2‐[18F]fluoroethoxy)‐1,2,3,4‐tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (−)‐[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare‐like effects of FEOBV were associated with the “(−)”‐enantiomer exclusively. (−)‐[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)‐3‐PPP, or E‐2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or σ receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (−)‐[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (−)‐[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET. Synapse 30:263–274, 1998. © 1998 Wiley‐Liss, Inc.</description><identifier>ISSN: 0887-4476</identifier><identifier>EISSN: 1098-2396</identifier><identifier>DOI: 10.1002/(SICI)1098-2396(199811)30:3<263::AID-SYN4>3.0.CO;2-9</identifier><identifier>PMID: 9776130</identifier><language>eng</language><publisher>New York: John Wiley & Sons, Inc</publisher><subject>Acetylcholine - metabolism ; Animals ; autoradiography ; Autoradiography - methods ; Brain - drug effects ; Brain - metabolism ; Calibration ; Carrier Proteins - metabolism ; cholinergic ; Cholinesterase Inhibitors - pharmacology ; Dopamine Agonists - pharmacology ; dosimetry ; Female ; Fluorine Radioisotopes - pharmacokinetics ; Haloperidol - pharmacology ; Humans ; imaging ; Indans - pharmacology ; Kinetics ; Male ; Membrane Transport Proteins ; Mice ; Organ Specificity ; PET ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; synapse ; Synapses - drug effects ; Synapses - metabolism ; Tissue Distribution ; Tomography, Emission-Computed ; vesamicol ; Vesicular Acetylcholine Transport Proteins ; Vesicular Transport Proteins</subject><ispartof>Synapse (New York, N.Y.), 1998-11, Vol.30 (3), p.263-274</ispartof><rights>Copyright © 1998 Wiley‐Liss, Inc.</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://onlinelibrary.wiley.com/doi/pdf/10.1002%2F%28SICI%291098-2396%28199811%2930%3A3%3C263%3A%3AAID-SYN4%3E3.0.CO%3B2-9$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2F%28SICI%291098-2396%28199811%2930%3A3%3C263%3A%3AAID-SYN4%3E3.0.CO%3B2-9$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9776130$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mulholland, G. Keith</creatorcontrib><creatorcontrib>Wieland, Donald M.</creatorcontrib><creatorcontrib>Kilbourn, Michael R.</creatorcontrib><creatorcontrib>Frey, Kirk A.</creatorcontrib><creatorcontrib>Sherman, Phillip S.</creatorcontrib><creatorcontrib>Carey, James E.</creatorcontrib><creatorcontrib>Kuhl, David E.</creatorcontrib><title>[18F]fluoroethoxy‐benzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses</title><title>Synapse (New York, N.Y.)</title><addtitle>Synapse</addtitle><description>Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (−)‐[18F]FEOBV, (−)‐(2R,3R)‐trans‐2‐hydroxy‐3‐(4‐phenylpiperidino)‐5‐(2‐[18F]fluoroethoxy)‐1,2,3,4‐tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (−)‐[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare‐like effects of FEOBV were associated with the “(−)”‐enantiomer exclusively. (−)‐[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)‐3‐PPP, or E‐2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or σ receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (−)‐[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (−)‐[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET. Synapse 30:263–274, 1998. © 1998 Wiley‐Liss, Inc.</description><subject>Acetylcholine - metabolism</subject><subject>Animals</subject><subject>autoradiography</subject><subject>Autoradiography - methods</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Calibration</subject><subject>Carrier Proteins - metabolism</subject><subject>cholinergic</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Dopamine Agonists - pharmacology</subject><subject>dosimetry</subject><subject>Female</subject><subject>Fluorine Radioisotopes - pharmacokinetics</subject><subject>Haloperidol - pharmacology</subject><subject>Humans</subject><subject>imaging</subject><subject>Indans - pharmacology</subject><subject>Kinetics</subject><subject>Male</subject><subject>Membrane Transport Proteins</subject><subject>Mice</subject><subject>Organ Specificity</subject><subject>PET</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Stereoisomerism</subject><subject>synapse</subject><subject>Synapses - drug effects</subject><subject>Synapses - metabolism</subject><subject>Tissue Distribution</subject><subject>Tomography, Emission-Computed</subject><subject>vesamicol</subject><subject>Vesicular Acetylcholine Transport Proteins</subject><subject>Vesicular Transport Proteins</subject><issn>0887-4476</issn><issn>1098-2396</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd9q1EAUh4ModVt9BGGupAWznpNJ5s9ahBJbXSiu0PVCRIZJMutGspk4k1TTKx_BZ_RJnLhLb70azvl9c-CcL4rOEeYIkLw8vVnmyzMEKeKESnaKUgrEMwoLep4wulhcLN_EN5_ep6_pHOb56lUSywfR7P7Dw2gGQvA4TTl7HB17_w0AKEJ6FB1JzhlSmEV3n1Fcfdk0g3XW9Fv7c_zz63dh2jt7a7ze1aVtXhBNPlyuidNVbXunS-PIxjrSbw0JUF0OjXYktPuxKbe2qVtDAtb6zro-sLqtyKHvvtYl8WOrO2_8k-jRRjfePD28J9HHq8t1_i6-Xr1d5hfXcUcxTWMhgINgWcEzXhXAKM8SicAzlJvEYCrKjUZWZIJqBJ1VzFRhT0y4yJAXSUZPouf7uZ2z3wfje7WrfWmaRrfGDl4xKVkKVPwXRI7hZnya-OwADsXOVKpz9U67UR2uGvL1Pv9RN2a8jxHUJFZNXtWkSU2a1N6roqCoCl5V0KomraEEla9UouS_mv4Fu9OcOw</recordid><startdate>199811</startdate><enddate>199811</enddate><creator>Mulholland, G. 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Keith</creatorcontrib><creatorcontrib>Wieland, Donald M.</creatorcontrib><creatorcontrib>Kilbourn, Michael R.</creatorcontrib><creatorcontrib>Frey, Kirk A.</creatorcontrib><creatorcontrib>Sherman, Phillip S.</creatorcontrib><creatorcontrib>Carey, James E.</creatorcontrib><creatorcontrib>Kuhl, David E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Synapse (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mulholland, G. Keith</au><au>Wieland, Donald M.</au><au>Kilbourn, Michael R.</au><au>Frey, Kirk A.</au><au>Sherman, Phillip S.</au><au>Carey, James E.</au><au>Kuhl, David E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>[18F]fluoroethoxy‐benzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses</atitle><jtitle>Synapse (New York, N.Y.)</jtitle><addtitle>Synapse</addtitle><date>1998-11</date><risdate>1998</risdate><volume>30</volume><issue>3</issue><spage>263</spage><epage>274</epage><pages>263-274</pages><issn>0887-4476</issn><eissn>1098-2396</eissn><abstract>Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (−)‐[18F]FEOBV, (−)‐(2R,3R)‐trans‐2‐hydroxy‐3‐(4‐phenylpiperidino)‐5‐(2‐[18F]fluoroethoxy)‐1,2,3,4‐tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (−)‐[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare‐like effects of FEOBV were associated with the “(−)”‐enantiomer exclusively. (−)‐[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)‐3‐PPP, or E‐2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or σ receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (−)‐[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (−)‐[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET. Synapse 30:263–274, 1998. © 1998 Wiley‐Liss, Inc.</abstract><cop>New York</cop><pub>John Wiley & Sons, Inc</pub><pmid>9776130</pmid><doi>10.1002/(SICI)1098-2396(199811)30:3<263::AID-SYN4>3.0.CO;2-9</doi><tpages>12</tpages></addata></record> |
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subjects | Acetylcholine - metabolism Animals autoradiography Autoradiography - methods Brain - drug effects Brain - metabolism Calibration Carrier Proteins - metabolism cholinergic Cholinesterase Inhibitors - pharmacology Dopamine Agonists - pharmacology dosimetry Female Fluorine Radioisotopes - pharmacokinetics Haloperidol - pharmacology Humans imaging Indans - pharmacology Kinetics Male Membrane Transport Proteins Mice Organ Specificity PET Piperidines - pharmacokinetics Piperidines - pharmacology Rats Rats, Sprague-Dawley Stereoisomerism synapse Synapses - drug effects Synapses - metabolism Tissue Distribution Tomography, Emission-Computed vesamicol Vesicular Acetylcholine Transport Proteins Vesicular Transport Proteins |
title | [18F]fluoroethoxy‐benzovesamicol, a PET radiotracer for the vesicular acetylcholine transporter and cholinergic synapses |
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