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Abstract
We have developed 18F-fluoxetine as a radiotracer analog of the antidepressant drug
fluoxetine (Prozac). In vitro saturation experiments of 18F-fluoxetine were carried
out on rat midbrain tissue and citalopram was used for measuring nonspecific binding.
A saturation curve for the binding of 18F-fluoxetine was not obtained. Even when fluoxetine
(10 microM) was used for measurements of nonspecific binding, a saturation curve was
difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and
reserpine were also not able to reduce the binding of 18F-fluoxetine. Ex vivo autoradiographic
experiments with 18F-fluoxetine did not reveal any specific uptake in various brain
regions. In vivo administration of 18F-fluoxetine in rats showed similar uptake in
all the brain regions with little regional selectivity. A subcellular analysis of
rat brain tissue after intravenous (IV) administration of 18F-fluoxetine indicated
significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro
experiments with 18F-fluoxetine indicate little specific binding. Binding to the serotonin
transporter was not identifiable. High nonspecific binding of the tracer resulting
from its subcellular nature in the brain masks the ability to detect binding to the
serotonin uptake sites in vivo. These findings indicate that a large portion of the
binding of 18F-fluoxetine in rat brains is subcellular and clears slowly out of the
cells. Other sites, such as monoamine oxidase, may also play a significant role in
the action of fluoxetine.