This study was
conducted to develop a new positron emission tomography (PET) method to
visualize neurokinin-1 (NK(1)) receptor systems in the human brain in
vivo in order to examine their neuroanatomical distribution and
facilitate investigations of the role of substance P, NK(1) receptors,
and NK(1) receptor antagonists in central nervous system (CNS) function
and dysfunction.

PET
studies were conducted in 10 healthy male volunteers using a novel
selective, high-affinity NK(1) receptor antagonist labeled with
fluorine-18 to very high specific radioactivity (up to 2000
GBq/micromol) [F-18]SPA-RQ. Data were collected in 3D mode for greatest
sensitivity. Different modeling methods were compared and regional
receptor distributions determined for comparison with in vitro
autoradiographic studies using postmortem human brain slices with
[F-18]SPA-RQ.

The
studies showed that the highest uptake of [F-18]SPA-RQ was observed in
the caudate and putamen. Lower binding was found in globus pallidus and
substantia nigra. [F-18]SPA-RQ uptake was also widespread throughout the
neocortex and limbic cortex including amygdala and hippocampus. There
was very low specific uptake of the tracer in the cerebellar cortex. The
distribution pattern was confirmed using in vitro receptor
autoradiography with [F-18]SPA-RQ on postmortem human brain slices.
Kinetic modeling of the [F-18]SPA-RQ uptake data indicated a binding
potential between 4 and 5 in the basal ganglia and between 1.5 and 2.5
in the cortical regions.

[F-18]SPA-RQ
is a novel tool for exploration of the functions of NK(1) receptors in
man. [F-18]SPA-RQ can be used to define receptor pharmacodynamics and
focus dose selection of novel NK(1) receptor antagonists in clinical
trials thereby ensuring adequate proof of concept testing particularly
in therapeutic applications related to CNS dysfunction.