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

• Published in: Journal of cerebral blood flow and metabolism Vol. 37; no. 2; pp. 425 - 434
• Main Authors: Jørgensen, Louise M, Weikop, Pia, Villadsen, Jonas, Visnapuu, Tanel, Ettrup, Anders, Hansen, Hanne D, Baandrup, Anders O, Andersen, Flemming L, Bjarkam, Carsten R, Thomsen, Carsten, Jespersen, Bo, Knudsen, Gitte M
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.02.2017
• Subjects: Animals; Benzylamines - analysis; Benzylamines - metabolism; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Carbon Radioisotopes - analysis; Carbon Radioisotopes - metabolism; Female; Fenfluramine - pharmacology; Original; Phenethylamines - analysis; Phenethylamines - metabolism; Positron-Emission Tomography - methods; Receptor, Serotonin, 5-HT2A - analysis; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin - metabolism; Serotonin 5-HT2 Receptor Agonists - analysis; Serotonin 5-HT2 Receptor Agonists - metabolism; Serotonin Agents - pharmacology; Swine; brain imaging; kinetic modelling; 5-HT; neurosurgery; Positron emission tomography
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1177/0271678X16629483

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 + 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.