Serotonin 2A Receptor Agonist Binding in the Human Brain with [11C]Cimbi-36

• Published in: Journal of cerebral blood flow and metabolism Vol. 34; no. 7; pp. 1188 - 1196
• Main Authors: Ettrup, Anders, da Cunha-Bang, Sophie, McMahon, Brenda, Lehel, Szabolcs, Dyssegaard, Agnete, Skibsted, Anine W, Jørgensen, Louise M, Hansen, Martin, Baandrup, Anders O, Bache, Søren, Svarer, Claus, Kristensen, Jesper L, Gillings, Nie, Madsen, Jacob, Knudsen, Gitte M
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.07.2014; Sage Publications Ltd; Nature Publishing Group
• Subjects: Benzylamines - pharmacokinetics; Brain - diagnostic imaging; Female; Humans; Male; Original; Phenethylamines - pharmacokinetics; Positron-Emission Tomography - methods; Radiopharmaceuticals - pharmacokinetics; Receptor, Serotonin, 5-HT2A - analysis; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin 5-HT2 Receptor Agonists - pharmacokinetics; Young Adult; clinical; 5-HT2A receptor; agonist; positron emission tomography; kinetic modeling
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2014.68

[11C]Cimbi-36 was recently developed as a selective serotonin 2A (5-HT2A) receptor agonist radioligand for positron emission tomography (PET) brain imaging. Such an agonist PET radioligand may provide a novel, and more functional, measure of the serotonergic system and agonist binding is more likely than antagonist binding to reflect 5-HT levels in vivo. Here, we show data from a first-in-human clinical trial with [11C]Cimbi-36. In 29 healthy volunteers, we found high brain uptake and distribution according to 5-HT2A receptors with [11C]Cimbi-36 PET. The two-tissue compartment model using arterial input measurements provided the most optimal quantification of cerebral [11C]Cimbi-36 binding. Reference tissue modeling was feasible as it induced a negative but predictable bias in [11C]Cimbi-36 PET outcome measures. In five subjects, pretreatment with the 5-HT2A receptor antagonist ketanserin before a second PET scan significantly decreased [11C]Cimbi-36 binding in all cortical regions with no effects in cerebellum. These results confirm that [11C]Cimbi-36 binding is selective for 5-HT2A receptors in the cerebral cortex and that cerebellum is an appropriate reference tissue for quantification of 5-HT2A receptors in the human brain. Thus, we here describe [11C]Cimbi-36 as the first agonist PET radioligand to successfully image and quantify 5-HT2A receptors in the human brain.