In vitro permeability, pharmacokinetics and brain uptake of WAY-100635 and FCWAY in rats using liquid chromatography electrospray ionization tandem mass spectrometry.
Positron emission tomography (PET) is a sensitive non-invasive imaging technique. To reduce imaging measurements of defects, there is a demand for proper LC-ESI-MS/MS method to carry out with its specificity and sensitivity. This study describes a rapid and simple liquid chromatography electrospray ionization tandem-MS/MS (LC-ESI-MS/MS) method for determination of both PET tracers: N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY-100635) and 4-fluoro-N-[2-[4-(2-methoxylphenyl)-1-piperazino]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (FCWAY). Both target compounds were prepared by one-step protein precipitation with acetonitrile and methanol (1:1, v/v), and analyzed using a C18 column. This simple method has an excellent linearity, selectivity and sensitivity. Precision and accuracy values for the intra-day and inter-day validation were below 12%. The limit of quantification (LOQ) for both target compounds was defined as 1 ng/mL in plasma and 5 ng/mL in brain homogenate. The stability of both compounds is considered stable under a various experimental conditions. The in vitro MDR-MDCK cell permeability showed the both compounds have high permeability (Papp, A→B ≥ 20 × 10(-6 )cm/s) and low efflux ratio (≤2.0). Brain to blood (AUCbrain/AUCblood) distribution ratios in rats were 3.15 ± 0.42 for WAY-100635 and 2.20 ± 0.34 for FCWAY, respectively, and these results suggest that LC-ESI-MS/MS method might be a supplementary way for the identifying and understanding of radiopharmaceuticals.
Department of Drug Discovery Platform Technology, Korea Research Institute of Chemical Technology (KRICT), Yuseong-gu, Daejeon, 305-343, Korea.
Zhi
Z
Zheng
So Hee
SH
Im
Byung Hoi
BH
Lee
Hyewon
H
Seo
Myung Ae
MA
Bae
Sung-Hoon
SH
Ahn
D000818:Animals; D001921:Brain / Q000378:metabolism; D002463:Cell Membrane Permeability; D002851:Chromatography, High Pressure Liquid; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D004285:Dogs; D007202:Indicators and Reagents; D061985:Madin Darby Canine Kidney Cells; D010879:Piperazines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry
D003510:Cyclohexanes; D007202:Indicators and Reagents; C493883:N-(2-(4-(2-methoxyphenyl)piperazino))-N-(2-pyridinyl) trans-4-fluorocyclohexanecarboxamide; D010879:Piperazines; D011725:Pyridines; D019275:Radiopharmaceuticals; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide