Distribution of the 5-HT(1A) receptor antagonist [ (18)F]FPWAY in blood and brain of the rat with and without isoflurane anesthesia.
OBJECTIVE
To determine whether brain and plasma equilibrium of a proposed PET tracer for 5-HT(1A), [(18)F]FPWAY, can be achieved in a sufficiently short time for practical use of the brain to plasma equilibrium distribution ratio (DR) to monitor receptor availability with and without isoflurane anesthesia.


METHODS
Awake (n=4) and isoflurane-anesthetized (n=4) rats were administered a continuous 60 min intravenous infusion of [(18)F]FPWAY with timed arterial blood sampling. Brains of the isoflurane-anesthetized rats were scanned with the ATLAS small animal PET scanner; awake rats were not. All rats were killed at 60 min and scanned postmortem for 15 min, followed by brain slicing for autoradiography. Several regions of interest (ROIs) were defined in the PET images as well as in the autoradiographic images. Regional DRs were calculated as total activity in the brain ROI divided by plasma [(18)F]FPWAY activity.


RESULTS
DRs in the anesthetized animals were constant between 30 and 60 min, indicating that near equilibrium between brain and plasma had been achieved by approximately 30 min. DRs determined from postmortem PET data were higher in the isoflurane-anesthetized rats by 24% (not significant) and 33% (p=0.065) in whole brain and hippocampus, respectively. DRs determined from autoradiographic data were greater in isoflurane-anesthetized rats in medial hippocampus, lateral hippocampus, and cerebellum by 33% (p=0.054), 63% (p<0.01), and 32% (p<0.05), respectively.


CONCLUSIONS
[(18)F]FPWAY could be an appropriate ligand for monitoring changes in receptor availability in the serotonergic system using a bolus/infusion paradigm. One possible explanation for higher DRs in anesthetized rats may be a reduction in endogenous 5-HT secretion under isoflurane anesthesia.
Tokugawa
Joji
J
Positron Emission Tomography Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Ravasi
Laura
L
Nakayama
Toshiyuki
T
Lang
Lixin
L
Schmidt
Kathleen C
KC
Seidel
Jurgen
J
Green
Michael V
MV
Sokoloff
Louis
L
Eckelman
William C
WC
D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D004347:Drug Interactions; D007530:Isoflurane / Q000008:administration & dosage*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D058829:Serotonin 5-HT1 Receptor Antagonists; D014018:Tissue Distribution / Q000187:drug effects
C520057:4-fluoro-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyrimidinyl)benzamide; D018685:Anesthetics, Inhalation; D010879:Piperazines; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D058829:Serotonin 5-HT1 Receptor Antagonists; D007530:Isoflurane