ABSTRACT
BACKGROUND:
We have explored the possibility that the
serotonin 1B receptor radioligand [(11)C]AZ10419369 is a substrate for
adenosine triphosphate (
ATP)-binding cassette (ABC) transporters, such as
P-glycoprotein (P-gp), Mrp4, and Bcrp, in
rodents and whether there is a species difference regarding its
blood-brain barrier (BBB) penetration.
METHODS:
In a series of preclinical
positron emission tomography measurements, we have administered [(11)C]AZ10419369 to
mice,
rats, and
guinea pigs under baseline conditions and, on separate experimental days, after
administration of the
ABC transporter inhibitor,
cyclosporin A (CsA).
RESULTS:
During baseline conditions, the
brain uptake was low in
mice and
rats, but not in
guinea pigs. After CsA pretreatment, the peak whole
brain uptake values of [(11)C]AZ10419369 increased by 207% in
mice, 94% in
rats, and 157% in
guinea pigs. Binding potentials (BPND) could not be estimated during baseline conditions in
mice and
rats. After CsA pretreatment, the highest BPND values were obtained in the striatum and
thalamus (BPND ≈ 0.4) in
mice, while in
rats, the highest binding areas were the striatum,
thalamus,
hypothalamus, and
periaqueductal gray (BPND ≈ 0.5). In
guinea pigs, we did not find any significant changes in BPND between baseline and CsA pretreatment, except in the striatum.
CONCLUSIONS:
The results indicate that BBB penetration of [(11)C]AZ10419369 was hindered by
ABC transporter activity in
mouse,
rat, and
guinea pig. This study highlights the importance of
ABC transporters in the design of preclinical
positron emission tomography (
PET) studies.