Cerebral 5-HT release correlates with [C-11]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain
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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, [11C]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 [11C]Cimbi-36 PET signal in the pig brain by simultaneous measurements of extracellular
5-HT levels with microdialysis and [11C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram þ 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[11C]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 [11C]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.
5-HT levels with microdialysis and [11C]Cimbi-36 PET after various acute interventions (saline, citalopram, citalopram þ 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[11C]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 [11C]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.
Original language | English |
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Journal | Journal of Cerebral Blood Flow and Metabolism |
Volume | 37 |
Issue number | 2 |
Pages (from-to) | 425-434 |
ISSN | 0271-678X |
DOIs | |
Publication status | Published - Feb 2017 |
- Positron emission tomography, 5-HT, brain imaging, kinetic modelling, neurosurgery
Research areas
Links
- http://europepmc.org/articles/pmc5381441?pdf=render
Final published version
ID: 174664492