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Oxime antidotes regenerate organophosphate‐inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [18F]‐VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [18F]‐VXS was evaluated after an LD50 dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [18F]‐VXS tracer alone had significantly higher radioactivity (two‐ to threefold) in the heart and lung than rats given LD50 POX at 20 or 60 min prior to [18F]‐VXS. When rats were given LD50 POX followed by 2‐PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI‐6 or MMB‐4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX‐treated rats. This new in vivo dynamic platform using [18F]‐VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats. [ABSTRACT FROM AUTHOR]