Visualization and quantification of neurokinin-1 (NK1) receptors in the human brain.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
[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.
Hietala
Jarmo
J
Neuropsychiatric Imaging, Turku PET Centre, Turku University Central Hospital, Finland.
Nyman
Mikko J
MJ
Eskola
Olli
O
Laakso
Aki
A
Grönroos
Tove
T
Oikonen
Vesa
V
Bergman
Jörgen
J
Haaparanta
Merja
M
Forsback
Sarita
S
Marjamäki
Päivi
P
Lehikoinen
Pertti
P
Goldberg
Michael
M
Burns
Donald
D
Hamill
Terence
T
Eng
Wai-Si
WS
Coimbra
Alexandre
A
Hargreaves
Richard
R
Solin
Olof
O
D000328:Adult; D001158:Arteries / Q000378:metabolism; D001345:Autoradiography; D001479:Basal Ganglia / Q000378:metabolism; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D008297:Male; D008636:Mesencephalon / Q000033:anatomy & histology / Q000378:metabolism; D008954:Models, Biological; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000032:analysis* / Q000378:metabolism*; D012015:Reference Standards; D012886:Skull / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
D005462:Fluorine Radioisotopes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1