Imaging the 5-HT _2C receptor with PET: Evaluation of 5-HT _2C and 5-HT _2A affinity of pimavanserin in the primate brain

Two complimentary techniques were used to estimate occupancy of pimavanserin (a selective 5-HT_2A/2C inverse agonist) to 5-HT_2A and 5-HT_2C receptors in non-human primate brains. One employed the 5-HT_2A/2C selective radioligand [¹¹C]CIMBI-36 combined with quantification of binding potentials in brain regions known to be enriched in 5-HT_2A (cortex) or 5-HT_2C (choroid plexus) receptors to estimate occupancy. Pimavanserin was 6-10 fold more potent displacing [¹¹C]CIMBI-36 from cortex (ED₅₀ = 0.007 mg/kg; EC₅₀ = 0.6 ng/ml) than from choroid plexus (ED₅₀ =0.046 mg/kg; EC₅₀ = 6.0 ng/ml). The assignment of [¹¹C]CIMBI-36 binding to 5-HT_2A and 5-HT_2C receptors by anatomical brain structure was confirmed using the 5-HT_2A selective inverse agonist MDL 100,907 and the 5-HT_2C selective antagonist SB 242584 to displace [¹¹C]CIMBI-36. The second technique employed a novel, 5-HT_2C selective tracer called [¹¹C]AC1332. [¹¹C]AC1332 bound robustly to choroid plexus, moderately to hippocampus, and minimally to cortex. Pimavanserin displaced [¹¹C]AC1332 with similar potency (ED₅₀ = 0.062 mg/kg; EC₅₀ = 2.5 ng/ml) as its potency displacing [¹¹C]CIMBI-36 binding from choroid plexus. These results demonstrate the feasibility of simultaneously estimating drug occupancy of 5-HT_2A and 5-HT_2C receptors in vivo, and the utility of a novel 5-HT_2C receptor selective tracer ligand.