A radiolabeled agonist tracer, (11)C-CIMBI-5, was developed for PET imaging of the serotonin 2A (5-HT2A) receptor in the brain. In vitro assays showed CIMBI-5 is a high-affinity agonist at the 5-HT2A receptor. Ex vivo rat studies demonstrated a specific binding ratio of 0.77 ± 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, indicating selective binding. PET studies in pigs revealed a cortical binding potential of 0.46 ± 0.12 and a target-to-background ratio similar to the antagonist tracer (18)F-altanserin. Ketanserin treatment reduced cortical binding to cerebellar levels, confirming selective in vivo binding. (11)C-CIMBI-5 is a promising tool for investigating 5-HT2A agonist binding in the living human brain.
Subchronic administration of phencyclidine (PCP) to mice increases the sensitivity of serotonin 2A receptors (5-HT2A Rs) in the frontal cortex. Mice treated with PCP (10 mg/kg) for 10 days, followed by a 5-day washout, showed a stronger head-twitch response and greater expression of immediate-early genes (Arc, c-fos, egr-2) after a challenge with the 5-HT2A R agonist DOI, compared to saline-treated mice. These functional changes occurred without alterations in 5-HT2A R binding or in binding of the 5-HT1A receptor or serotonin transporter. Basal Arc mRNA levels were also elevated in the prefrontal cortex. The findings suggest that PCP-induced changes enhance 5-HT2A R-mediated neurotransmission, which may contribute to behavioral deficits in this schizophrenia model.