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Positron emission tomography evaluation of oxime countermeasures in live rats using the tracer O ‐(2‐[ 18 F]fluoroethyl)‐ O ‐( p‐ nitrophenyl)methylphosphonate [ 18 F]‐VXS
Author(s) -
Hayes Thomas R.,
Blecha Joseph E.,
Chao ChihKai,
Huynh Tony L.,
VanBrocklin Henry F.,
Zinn Kurt R.,
Taylor Palmer W.,
Gerdes John M.,
Thompson Charles M.
Publication year - 2020
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14363
Subject(s) - oxime , paraoxon , chemistry , acetylcholinesterase , in vivo , organophosphate , radiochemistry , medicinal chemistry , biochemistry , enzyme , biology , microbiology and biotechnology , pesticide , agronomy
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.