The aim of the present study was to develop an experimental paradigm for the study of serotonergic neurotransmission in humans using positron emission tomography and the 5-HT2A selective radioligand [18F]altanserin. [18F]altanserin studies were conducted in seven subjects using the bolus/infusion approach designed for attaining steady state in blood and brain 2 hours after the initial [18F]altanserin administration. Three hours after commencement of radiotracer administration, 0.25 mg/kg of the selective serotonin reuptake inhibitor, citalopram (Lundbeck, Valby, Denmark), was administered to all subjects as a constant infusion for 20 minutes. To reduce 5-HT1A-mediated autoinhibition of cortical 5-HT release, four of the seven subjects were pretreated with the partial 5-HT1A agonist pindolol for 3 days at an increasing oral dose (25 mg on the day of scanning). In each subject, the baseline condition (120 to 180 minutes) was compared with the stimulated condition (195 to 300 minutes). Despite a pronounced increase in plasma prolactin and two subjects reporting hot flushes compatible with an 5-HT-induced adverse effect, cortical [18F]altanserin binding was insensitive to the citalopram challenge, even after pindolol pretreatment. The biochemical and cellular events possibly affecting the unsuccessful translation of the citalopram/pindolol challenge into a change in 5-HT2A receptor binding of [18F]altanserin are discussed.
There are several different experimental systems for screening of in vitro inhibitory potency of drugs under development. In this study we compared three different types of cytochrome P450 (CYP) inhibition tests: the traditional single substrate assays, the fluorescent probe method with recombinant human CYPs, and a novel n-in-one technique. All major hepatic drug-metabolizing CYPs were included (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4). Six compounds (sotalol, propranolol, citalopram, fluoxetine, oxazepam and diazepam) were selected for detailed comparisons. The IC50 values of each of these compounds were measured using the three assay types. The inhibitory potencies of these model drugs were generally within the same order of magnitude and followed similar inhibition profiles in all the assay types. Clinically observed inhibitory interactions, or lack thereof, were predictable with all three assays. Comparison of potencies of 'diagnostic' inhibitors revealed also some notable differences between the assays, especially regarding CYP2E1. The potency of inhibitors towards CYP3A4 was dependent on the substrate and reaction measured. Generally all three assays gave reasonably comparable results, although some unexplained differences were also noted.