Abstract
495
Objectives Dopamine D2/D3 receptors agonist radioligands have been shown more sensitive to changes in dopamine level, than antagonist radioligands. Very recently, the first 5-HT2A receptor agonist PET radioligands have been developed, and [11C]CIMBI-36 was found the most promising in pig brain so far. In this pilot study we characterized [11C]CIMBI-36 receptor binding in the primate brain and performed a serotonin-challenge study with (±)-fenfluramine.
Methods A total of 6 PET measurements were performed in 2 female cynomolgus monkeys. On 3 experimental days, a baseline measurement was followed by a pretreatment measurement with the 5-HT2A receptor selective antagonist ketanserin (1.5 mg/kg, n=2) or the serotonin releaser (±)-fenfluramine (5.0 mg/kg). After i.v. bolus injection of [11C]CIMBI-36, PET measurements were performed for 2 hours in the HRRT PET system. Blood samples were collected for measurement of radioactivity and for HPLC-analysis of radiometabolism. Specific binding and binding ratios (mean of 81-123 min) were calculated with the cerebellum as reference region.
Results Baseline PET measurements showed high uptake of radioactivity in 5-HT2A receptor rich regions. Specific binding in cortical regions reached a plateau ~80 minutes after [11C]CIMBI-36 injection and binding ratios of the cortical regions were ~3.0. Administration of ketanserin and (±)-fenfluramine significantly decreased cortical binding ratios to ~1.5 and ~1.9, respectively. Radiometabolism of [11C]CIMBI-36 was found relatively fast, with 10-15% remaining after 30 minutes until the end of the PET measurements.
Conclusions This preliminary work indicates that [11C]CIMBI-36 provides a regional distribution and binding ratios similar as previously reported for the 5-HT2A receptor antagonist [11C]MDL 100907. The pilot (±)-fenfluramine study suggests that [11C]CIMBI-36 receptor binding is sensitive to endogenous serotonin concentration