In vivo receptor occupancy method that simultaneously quantifies four tracers: raclopride, pirenzepine, MDL‐100907, and SB‐221284

Abstract

The atypical antipsychotics share the common attributes of working on serotonin and dopamine receptors. However, a comprehensive mechanism of action of these agents is unknown. In order to better elucidate the mechanism by which these drugs produce their therapeutic and the undesired effects, a robust method for measuring in vivo receptor binding is needed. The authors developed a liquid chromatography/triple quad mass spectral detectors (LC/MS/MS) method to measure the brain distribution of receptor occupancy using tracers targeting dopamine D2, serotonin 5‐HT2A, 5‐HT2C and muscarinic M1 receptors. The tracers are raclopride, MDL‐100907, SB‐221284 and pirenzepine, respectively. All four non‐radiolabeled tracers were detectable in discrete rat brain areas after intravenous administration. These tracers demonstrated a differential brain distribution corresponding to the regional differences in their respective receptor densities. Oral pretreatment of various antipsychotic agents that occupy these receptors decreased this differential distribution in a dose‐dependent manner. Our results demonstrate the utility of LC/MS/MS to quantify the in vivo receptor occupancy of antipsychotic and other agents acting in the CNS.