[C-14]serotonin uptake and [O-methyl-C-11]venlafaxine kinetics in porcine brain

As part of our program of developing PET tracers for neuroimaging of psycho tropic compounds, venlafaxine. an antidepressant drug, was evaluated. First , we measured in vitro rates of serotonin uptake in synaptosomes prepared f rom selected regions of porcine brain. Then, we determined the pharmacokine tics of venlafaxine, [O-methyl-C-11]-labeled for PET. Synaptosomal studies showed that the active uptake of [C-14]5-HT differed markedly between brain regions, with highest rates in hypothalamus, raphe region, and thalamus, a nd lowest rates in cortex and cerebellum. PET studies showed that the unidi rectional rate of uptake of [O-methyl-(11)'C]venlafaxine from blood to brai n was highest in the hypothalamus, raphe region, thalamus and basal ganglia and lowest in the cortex and cerebellum. Under normal physiological condit ions, the capillary permeability-surface area (PS) product for [O-methyl-C- 11]venlafaxine could not be estimated, because of complete flow-limitation of the cerebral uptake. Nevertheless, a correlation occurred between the ap parent partition volume of the radiotracer and the rate of active uptake of 5-HT in selected regions of the porcine brain. During hypercapnia, limitat ions of blood-brain transfer were observed, giving PS-products for water th at were only ca. 50% higher than those of venlafaxine. Thus, under normal p hysiological conditions, the rate of uptake of venlafaxine from blood into brain is completely flow-limited. (C) 2001 Elsevier Science Inc. All rights reserved.