Characterization of [(11)C]Cimbi-36 as an agonist PET radioligand for the 5-HT(2A) and 5-HT(2C) receptors in the nonhuman primate brain

Only recently the first successful serotonin 2A (5-HT2A) receptor agonist PET radioligands have been described, with [(11)C]Cimbi-36 reported as the most promising in the pig brain so far. Agonist radioligands may target specifically the G protein-coupled state of the receptors and thereby provide a more meaningful assessment of available receptors than antagonist radioligands. In the current study we characterized [(11)C]Cimbi-36 receptor binding in the primate brain. On five experimental days, a total of 14 PET measurements were conducted in three female rhesus monkeys. On each day, PET measurements were conducted after intravenous injection of [(11)C]Cimbi-36 during baseline conditions and after intravenous infusion of the 5-HT2 receptor antagonist ketanserin (n=3) or the 5-HT2C receptor antagonist SB 242084 (n=2). On four of the experimental days an additional baseline PET measurement was conducted after injection of [(11)C]MDL 100907. All PET measurements were performed for 2h in a HRRT PET system and arterial blood was obtained for measurement of the [(11)C]Cimbi-36 input function. Quantification of [(11)C]Cimbi-36 receptor binding was performed using kinetic and graphical analysis. After injection of [(11)C]Cimbi-36 the regional distribution of radioactivity in brain was in accordance with the known 5-HT2 receptor distribution. The two-tissue compartment model was superior for the description of the time-radioactivity curves of all examined brain regions. BPND values obtained with reference tissue models correlated with corresponding values obtained with kinetic modeling. Administration of ketanserin decreased the binding in all brain regions but did not affect the cerebellar distribution volume. The BPND of [(11)C]Cimbi-36 was 56±8% of [(11)C]MDL 100907 across cortical regions, but higher in other brain regions including choroid plexus. After administration of SB 242084, [(11)C]Cimbi-36 binding was nearly completely inhibited in the choroid plexus, partly reduced in several subcortical regions (e.g. hippocampus), but not affected in the cortical regions. In conclusion, the receptor binding of [(11)C]Cimbi-36 can be quantified using kinetic modeling and the cerebellum was found to be a suitable reference region. The difference between [(11)C]Cimbi-36 and [(11)C]MDL 100907 binding in the choroid plexus is related to 5-HT2C receptor binding of [(11)C]Cimbi-36. [(11)C]Cimbi-36 is the first agonist radioligand suitable for examination of 5-HT2A receptors in the cortical regions and of 5-HT2C receptors in the choroid plexus of the primate brain.