[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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Veröffentlicht in:Synapse (New York, N.Y.) N.Y.), 1998-11, Vol.30 (3), p.263-274
Hauptverfasser: Mulholland, G. Keith, Wieland, Donald M., Kilbourn, Michael R., Frey, Kirk A., Sherman, Phillip S., Carey, James E., Kuhl, David E.
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container_start_page 263
container_title Synapse (New York, N.Y.)
container_volume 30
creator Mulholland, G. Keith
Wieland, Donald M.
Kilbourn, Michael R.
Frey, Kirk A.
Sherman, Phillip S.
Carey, James E.
Kuhl, David E.
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.
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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><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. 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(−)‐[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. 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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. 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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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