[11C]Paraoxon: Radiosynthesis, Biodistribution and In Vivo Positron Emission Tomography (PET) Imaging in Rat

Synthesis of the acetylcholinesterase inhibitor paraoxon (POX) as a carbon-11 positron emission tomography tracer ([11C]POX) and profiling in live rats is reported. Naive rats intravenously injected with [11C]POX showed a rapid decrease in parent tracer to-1%, with an increase in radiolabeled serum proteins to 87% and red blood cells (RBCs) to 9%. Protein and RBC leveled over 60 mi-nutes, reflecting covalent modification of proteins by [11C]POX. Ex vivo biodistribution and imaging profiles in naive rats had the highest radioactivity levels in lung followed by heart and kidney, and brain and liver the lowest. Brain radioactivity levels were low but observed immediately after injection and persisted over the 60-minute experiment. This showed for the first time that even low POX exposures (-200 ng tracer) can rapidly enter brain. Rats given an LD50 dose of nonradioactive paraoxon at the LD50 20 or 60 minutes prior to [11C]POX tracer revealed that protein pools were blocked. Blood radioactivity at 20 minutes was markedly lower than naive levels due to rapid protein modification by non-radioactive POX; however, by 60 minutes the blood radioactivity returned to near naive levels. Live rat tissue imaging-derived ra-dioactivity values were 10%-37% of naive levels in nonradioac-tive POX pretreated rats at 20 minutes, but by 60 minutes the area under the curve (AUC) values had recovered to 25%-80% of naive. The live rat imaging supported blockade by nonradioactive POX pretreatment at 20 minutes and recovery of proteins by 60 minutes.