The pyridinyl-6 position of WAY-100635 as a site for radiofluorination--effect on 5-HT1A receptor radioligand behavior in vivo.
OBJECTIVE
We aimed to evaluate radiofluorination at the pyridinyl-6 position of the selective 5-HT(1A) receptor antagonist, WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide)], on 5-HT(1A) receptor radioligand behavior in vivo.


METHODS
The pyridinyl-6 [(18)F]fluoro derivative of WAY-100635 ([(18)F]6FPWAY) was obtained by direct nucleophilic substitution with [(18)F]fluoride ion in a bromo precursor. After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into brain regions was assessed with positron emission tomography (PET) and blood samples analyzed by high performance liquid chromatography (HPLC) for parent radioligand and radioactive metabolites. The experiment was repeated after pretreatment of the monkey with a dose of WAY-100635 that blocks brain 5-HT(1A) receptors.


RESULTS
After intravenous injection of [(18)F]6FPWAY into Cynomolgus monkey, the uptake of radioactivity into whole brain reached 4.33% of injected dose at 7.5 min. Uptake was highest in 5-HT(1A) receptor-rich regions. Pretreatment with WAY-100635 reduced uptake in these regions to near the levels in receptor-devoid cerebellum. [(18)F]6FPWAY was rapidly metabolized in vivo, as evidenced by the rapid appearance of radioactive metabolites in plasma.


CONCLUSIONS
[(18)F]6FPWAY is selective and moderately useful for imaging brain 5-HT(1A) receptors in vivo. The pyridinyl-6 position is resistant to defluorination and may be an attractive site for the (18)F-labeling of 6FPWAY analogs that resist hydrolysis.
McCarron
Julie A
JA
PET Radiopharmaceutical Sciences Section, Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. mccarroj@intra.nimh.nih.gov
Pike
Victor W
VW
Halldin
Christer
C
Sandell
Johan
J
Sóvágó
Judit
J
Gulyas
Balàsz
B
Cselényi
Zsolt
Z
Wikström
Hakan V
HV
Marchais-Oberwinkler
Sandrine
S
Nowicki
Bartek
B
Dollé
Frédéric
F
Farde
Lars
L
D000631:Aminopyridines / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D008252:Macaca fascicularis; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000032:analysis*; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000737:chemistry / Q000493:pharmacokinetics*; D014055:Tomography, Emission-Computed
D000631:Aminopyridines; D005462:Fluorine Radioisotopes; C431268:N-(2-(1-(4-(2-methoxyphenyl)-piperazinyl)ethyl))-N-(2-(6-fluoropyridinyl))cyclohexanecarboxamide; D010879:Piperazines; D011725:Pyridines; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide