Dose Formulation, Biodistribution and PET Imaging Studies of a First-in-Class Fluorine-18 Organophosphorus Cholinesterase Inhibitor Tracer in Rat

Abstract

To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 [18F] radiolabeled Positron Emission Tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. We sought to evaluate the PET tracer in vivo using a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivo tracer performance to previous data collected using a CH3CN:PBS formulation. A high molar activity [18F]tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included a tracer and a single metabolite. The ex vivo biodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we found that the i.v. dose formulation changed the in vivo profile of an organophosphorus PET tracer that is considered an important finding for future organophosphorus PET tracer studies.