Dose-response relationships of FMISO between trace dose and various macro-doses in rat by ultra-performance liquid chromatography with mass spectrometry and radioactivity analysis.

Screening the pharmacokinetics of candidates using liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) may be efficacious and safe for the research and development of new PET imaging agents. However, the PET imaging agent is administered as trace dose and the sensitivity of LC–MS/MS is often insufficient. If the dose was increased to be quantifiable, it should be necessary to prove whether the pharmacokinetics between trace and macro-doses is consistent or not. In this paper, fluoromisonidazole (FMISO), a tumor PET imaging agent, was chosen to evaluate the dose–response pharmacokinetics by administering various single intravenous doses (0.1, 0.4, 1.6 and 6.4mg/kg) in male Sprague-Dawley rats. The plasma concentration of FMISO was determined by an ultra-performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method, and the blood radioactivity of [18F]FMISO was detected by a gamma counter. By calculating and comparing the pharmacokinetic parameters, the total area under the plasma concentration–time curve from time zero to infinity (AUC0–∞) and peak plasma concentration (Cmax) values increased with the selected FMISO doses, and showing linear dose-dependent. On the other hand, some parameters related to time, such as the elimination half-lives (t1/2) and elimination rate constant (Ke) were dose-independent, and there is no significant deference between trace dose and various macro-doses. The data should be useful to evaluate the novel 2-nitroimidazole derivatives as potential PET tumor imaging agents.