TY - JOUR
T1 - [14C]Serotonin uptake and [O-methyl-11C]venlafaxine kinetics in porcine brain
AU - Smith, D. F.
AU - Hansen, S. B.
AU - Østergaard, L.
AU - Gee, A. D.
AU - Danielsen, E.
AU - Ishizu, K.
AU - Bender, D.
AU - Poulsen, P. H.
AU - Gjedde, A.
PY - 2001/1/1
Y1 - 2001/1/1
N2 - As part of our program of developing PET tracers for neuroimaging of psychotropic compounds, venlafaxine, an antidepressant drug, was evaluated. First, we measured in vitro rates of serotonin uptake in synaptosomes prepared from selected regions of porcine brain. Then, we determined the pharmacokinetics of venlafaxine, [O-methyl-11C]-labeled for PET. Synaptosomal studies showed that the active uptake of [14C]5-HT differed markedly between brain regions, with highest rates in hypothalamus, raphé region, and thalamus, and lowest rates in cortex and cerebellum. PET studies showed that the unidirectional rate of uptake of [O-methyl-11C]venlafaxine from blood to brain was highest in the hypothalamus, raphé region, thalamus and basal ganglia and lowest in the cortex and cerebellum. Under normal physiological conditions, the capillary permeability-surface area (PS) product for [O-methyl-11C]venlafaxine could not be estimated, because of complete flow-limitation of the cerebral uptake. Nevertheless, a correlation occurred between the apparent partition volume of the radiotracer and the rate of active uptake of 5-HT in selected regions of the porcine brain. During hypercapnia, limitations of blood-brain transfer were observed, giving PS-products for water that were only ca. 50% higher than those of venlafaxine. Thus, under normal physiological conditions, the rate of uptake of venlafaxine from blood into brain is completely flow-limited.
AB - As part of our program of developing PET tracers for neuroimaging of psychotropic compounds, venlafaxine, an antidepressant drug, was evaluated. First, we measured in vitro rates of serotonin uptake in synaptosomes prepared from selected regions of porcine brain. Then, we determined the pharmacokinetics of venlafaxine, [O-methyl-11C]-labeled for PET. Synaptosomal studies showed that the active uptake of [14C]5-HT differed markedly between brain regions, with highest rates in hypothalamus, raphé region, and thalamus, and lowest rates in cortex and cerebellum. PET studies showed that the unidirectional rate of uptake of [O-methyl-11C]venlafaxine from blood to brain was highest in the hypothalamus, raphé region, thalamus and basal ganglia and lowest in the cortex and cerebellum. Under normal physiological conditions, the capillary permeability-surface area (PS) product for [O-methyl-11C]venlafaxine could not be estimated, because of complete flow-limitation of the cerebral uptake. Nevertheless, a correlation occurred between the apparent partition volume of the radiotracer and the rate of active uptake of 5-HT in selected regions of the porcine brain. During hypercapnia, limitations of blood-brain transfer were observed, giving PS-products for water that were only ca. 50% higher than those of venlafaxine. Thus, under normal physiological conditions, the rate of uptake of venlafaxine from blood into brain is completely flow-limited.
KW - Antidepressant drug
KW - Cerebral blood flow
KW - PET pharmacokinetics
KW - Porcine brain
KW - Serotonin uptake
KW - Venlafaxine
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U2 - 10.1016/S0969-8051(01)00230-X
DO - 10.1016/S0969-8051(01)00230-X
M3 - Article
C2 - 11518644
AN - SCOPUS:0034742160
VL - 28
SP - 633
EP - 638
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
SN - 0969-8051
IS - 6
ER -