Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O‐(2‐[¹⁸F]fluoroethyl)‐O‐(p‐nitrophenyl)methylphosphonate [¹⁸F]‐VXS

Abstract

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 [ 18 F]-VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [ 18 F]-VXS was evaluated after an LD 50 dose (250 µg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [ 18 F]-VXS tracer alone had significantly higher radioactivity (two-to threefold) in the heart and lung than rats given LD 50 POX at 20 or 60 min prior to [ 18 F]-VXS. When rats were given LD 50 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 [ 18 F]-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.

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

“…Most tissues decreased in radioactivity from 5 to 30 minutes except lung. The larger levels in lung at 30 minutes were attributed to elevated amounts of carboxylesterases found in rat lung tissue and similar to a previous finding using a fluorine-18 OP tracer ( Hayes et al, 2020 , 2021 ; Thompson et al, 2020 ). As expected, heart radioactivity levels closely paralleled blood levels at both the 5- and 30-minute time points.…”

“…Given the shared mechanism of enzyme inactivation by OPs and the high concentration of AChE in the CNS, imaging time-activity curves were compared in brain between [ 11 C]POX and previously reported OP-based PET imaging tracers ( Fig. 14 ) ( Neumann et al, 2017 , 2018 ; Hayes et al, 2018 , 2019 , 2020 , 2021 ). The rat brain SUV activity data for [ 11 C]POX (blue curve) is significantly higher but similar in profile to brain TACs from other OP tracers.…”

“…This work describes for the first time the synthesis and pharmacokinetics of carbon-11–labeled paraoxon [ 11 C]POX, a PET tracer of one of the most widely used compounds to study the biochemistry, in vivo biodistribution, and toxicity of reactive organophosphate compounds. Prior PET imaging OP tracer studies used [ 18 F]fluorine-labeled and/or leaving group analogs of OP chemical agents ( James et al, 2014 ; Neumann et al, 2017 , 2018 ; Hayes et al, 2018 , 2019 , 2020 , 2021 ; Thompson et al, 2020 ). [ 11 C]POX is an exact isotopic replica of a reactive OP in which the in vivo data accurately reflects that of nonradioactive paraoxon.…”

“…Whereas prior PET imaging OP tracer studies used [ 18 F]fluorine-labeled and/or leaving group analogs of OP chemical agents (James et al, 2014;Neumann et al, 2017;Hayes et al, 2018;Neumann et al, 2018;Hayes et al, 2019;Hayes et al, 2020;Thompson et al, 2020;Hayes et al, 2021).…”

“…Therefore, for the non-radioactive POX pretreatment scenario after the increase in brain radioactivity at 60 min relative to 20 min is most likely due to an increase in available functional target proteins (e.g., reactivated) allowing OP-based PET imaging tracers (Figure 14) (Neumann et al, 2017;Hayes et al, 2018;Neumann et al, 2018;Hayes et al, 2019;Hayes et al, 2020;Hayes et al, 2021). The rat brain SUV activity data for [ 11 C]POX (blue curve) is significantly higher but similar in profile to brain TACs from other OP tracers.…”