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Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain

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@article{ab682c8f33024843941c19bb71572c8c,
title = "Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain",
abstract = "Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2A receptor agonist PET radioligand, [(11)C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [(11)C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [(11)C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [(11)C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2A receptor occupancy indicates that [(11)C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.",
author = "J{\o}rgensen, {Louise M} and Pia Weikop and Jonas Villadsen and Tanel Visnapuu and Anders Ettrup and Hansen, {Hanne D} and Baandrup, {Anders O} and {Littrup Andersen}, Flemming and Bjarkam, {Carsten R} and Carsten Thomsen and Bo Jespersen and Knudsen, {Gitte M}",
note = "{\textcopyright} The Author(s) 2016.",
year = "2017",
doi = "10.1177/0271678X16629483",
language = "English",
volume = "37",
pages = "425--436",
journal = "Journal of Cerebral Blood Flow and Metabolism",
issn = "0271-678X",
publisher = "Nature Publishing Group",
number = "2",

}

RIS

TY - JOUR

T1 - Cerebral 5-HT release correlates with [11C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain

AU - Jørgensen, Louise M

AU - Weikop, Pia

AU - Villadsen, Jonas

AU - Visnapuu, Tanel

AU - Ettrup, Anders

AU - Hansen, Hanne D

AU - Baandrup, Anders O

AU - Littrup Andersen, Flemming

AU - Bjarkam, Carsten R

AU - Thomsen, Carsten

AU - Jespersen, Bo

AU - Knudsen, Gitte M

N1 - © The Author(s) 2016.

PY - 2017

Y1 - 2017

N2 - Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2A receptor agonist PET radioligand, [(11)C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [(11)C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [(11)C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [(11)C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2A receptor occupancy indicates that [(11)C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.

AB - Positron emission tomography (PET) can, when used with appropriate radioligands, non-invasively generate temporal and spatial information about acute changes in brain neurotransmitter systems. We for the first time evaluate the novel 5-HT2A receptor agonist PET radioligand, [(11)C]Cimbi-36, for its sensitivity to detect changes in endogenous cerebral 5-HT levels, as induced by different pharmacological challenges. To enable a direct translation of PET imaging data to changes in brain 5-HT levels, we calibrated the [(11)C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular 5-HT levels with microdialysis and [(11)C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram + pindolol, fenfluramine). In a subset of pigs, para-chlorophenylalanine pretreatment was given to deplete cerebral 5-HT. The interventions increased the cerebral extracellular 5-HT levels to 2-11 times baseline, with fenfluramine being the most potent pharmacological enhancer of 5-HT release, and induced a varying degree of decline in [(11)C]Cimbi-36 binding in the brain, consistent with the occupancy competition model. The observed correlation between changes in the extracellular 5-HT level in the pig brain and the 5-HT2A receptor occupancy indicates that [(11)C]Cimbi-36 binding is sensitive to changes in endogenous 5-HT levels, although only detectable with PET when the 5-HT release is sufficiently high.

U2 - 10.1177/0271678X16629483

DO - 10.1177/0271678X16629483

M3 - Journal article

C2 - 26825776

VL - 37

SP - 425

EP - 436

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 2

ER -

ID: 49663283