Cerebral 5-HT release correlates with [ 11 C]Cimbi36 PET measures of 5-HT2A receptor occupancy in the pig brain
Open accessAbstract
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-HT 2A 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-HT 2A 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.
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Fenfluramine challenge transiently increased the interstitial serotonin content in cortex ten-fold according to microdialysis.
“transiently increased the interstitial serotonin content in cortex ten-fold according to microdialysis [104].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [104]
Jorgensen et al. argued that occupancy of 5HT2A sites labelled with [11C]-Cimbi-36 by endogenous serotonin in anesthetized pig increased from 17% at baseline to 44% after fenfluramine treatment, which transiently increased interstitial serotonin content in cortex ten-fold according to microdialysis.
“Nonetheless, Jorgensen et al. argued that the occupancy of 5HT2A sites labelled with [11C]-Cimbi-36 (38) by endogenous serotonin in anesthetized pig increased from 17% at baseline to 44% after fenfluramine treatment, which transiently increased the interstitial serotonin content in cortex ten-fold according to microdialysis [104].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [104]
The sensitivity of [11C]-Cimbi-36 binding to fenfluramine challenge seemed to exceed that reported earlier for [18F]-altanersin in healthy human volunteers, albeit at a lower dose of fenfluramine in humans.
“This sensitivity of [11C]-Cimbi-36 (38) binding to fenfluramine challenge seemed to exceed that reported earlier for [18F]-altanersin (39) in healthy human volunteers, albeit at a lower relatively lower dose of fenfluramine in human [104].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [104]
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Self-citation
- Authors
- Jørgensen, L. M., Weikop, P., Villadsen, J., Visnapuu, T., Ettrup, A., Hansen, H. D., Baandrup, A. O., Andersen, F. L., Bjarkam, C. R., Thomsen, C., Jespersen, B., & Knudsen, G. M.
- Affiliations
- University of Copenhagen (DK)
- Rigshospitalet (DK)
- Roskilde Sygehus (DK)
- Aalborg University Hospital (DK)
- Corresponding author
- Knudsen, Gitte M
- ORCID
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2016-07-20
- Volume
- 37
- Issue
- 2
- Pages
- 425-434
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC5381441
- OpenAlex
- W2273847960
- Cited by
- 44
- References
- 59
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 1 · 2022: 8 · 2021: 3 · 2020: 3 · 2019: 10 · 2018: 2 · 2017: 6 · 2016: 1
- FWCI
- 3.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- VBN Forskningsportal (Aalborg Universitet) (submittedVersion, other-oa)
- Funders
- Lundbeckfonden (R183 2014 3836, R170-2014-994)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Keywords
- 5-HT2A receptor, serotonin release, PET radiotracer, receptor occupancy, fenfluramine, citalopram, pindolol, p-chlorophenylalanine, microdialysis, pig brain
- MeSH terms
- Animals, Benzylamines, Brain, Carbon Radioisotopes, Female, Fenfluramine, Phenethylamines, Serotonin, Swine, Serotonin Agents, Receptor, Serotonin, 5-HT2A, Positron-Emission Tomography, Serotonin 5-HT2 Receptor Agonists
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