PET imaging of brain 5-HT1A receptors in rat in vivo with 18F-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole.
18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities.


METHODS
PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis.


RESULTS
PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment.


CONCLUSIONS
Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.
Tipre
Dnyanesh N
DN
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-0135, USA. dnyanesht@yahoo.com
Zoghbi
Sami S
SS
Liow
Jeih-San
JS
Green
Michael V
MV
Seidel
Jurgen
J
Ichise
Masanori
M
Innis
Robert B
RB
Pike
Victor W
VW
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D005461:Fluorine / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007089:Image Enhancement / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008825:Miconazole; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects
D003510:Cyclohexanes; D005462:Fluorine Radioisotopes; C493883:N-(2-(4-(2-methoxyphenyl)piperazino))-N-(2-pyridinyl) trans-4-fluorocyclohexanecarboxamide; D010879:Piperazines; D019275:Radiopharmaceuticals; D044282:Receptor, Serotonin, 5-HT1A; D005461:Fluorine; D008825:Miconazole