Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

Abstract

There is a unique in vivo interplay involving the mechanism of inactivation of acetylcholinesterase (AChE) by toxic organophosphorus (OP) compounds and the restoration of AChE activity by oxime antidotes. OP compounds form covalent adducts to this critical enzyme target and oximes are introduced to directly displace the OP from AChE. For the most part, the in vivo inactivation of AChE leading to neurotoxicity and antidote-based therapeutic reversal of this mechanism are well understood, however, these molecular-level events have not been evaluated by dynamic imaging in living systems at millimeter resolution. A deeper understanding of these critically, time-dependent mechanisms is needed to develop new countermeasures. To address this void and to help accelerate the development of new countermeasures, positron-emission tomography (PET) has been investigated as a unique opportunity to create platform technologies to directly examine the interdependent toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic features of OPs and oximes in real time within live animals. This review will cover two first-in-class PET tracers representing an OP and an oxime antidote, including their preparation, requisite pharmacologic investigations, mechanistic interpretations, bio-distribution and imaging.

[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.…”

“…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.…”

Clinical Assessment of Acute Organophosphorus Pesticide Poisoning in Pediatric Patients Admitted to the Toxicology Emergency Department

“…Decreased serum ChE was observed in all cases of acute organophosphorus pesticide poisoning, mainly due to the suppression of carboxylic ester hydrolases. Organophosphates deactivate AChE by phosphorylating the hydroxyl serine group present in the active site of acetylcholinesterase [ 11 , 36 ]. With the inactivation of acetylcholinesterase, acetylcholine increases in the nervous system causing overstimulation of muscarinic and nicotinic receptors.…”

Supporting Fundamental Chemical Toxicology Research To Inform Medical Countermeasure Developments: The National Institutes of Health Chemical Countermeasures Research Program

“…These advancements in inhalation sulfur mustard toxicology knowledge subsequently led to the breakthrough discovery of “off-the-shelf” fibrinolytics as potential MCMs . Similarly, using real-time positron emission tomography imaging, another CCRP-supported project successfully interrogated the in vivo toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic properties of various toxic organophosphorus (OP) compounds and their interactions with acetylcholinesterase (AChE) and AChE oxime reactivators within the central nervous system . It is possible that this advancement in understanding the interplay among the HTC insult (OP), physiological target (AChE), and antidote (oxime reactivator) could inform the future design of more effective MCMs.…”

“…7 Similarly, using realtime positron emission tomography imaging, another CCRPsupported project successfully interrogated the in vivo toxicokinetic/pharmacokinetic and toxicodynamic/pharmacodynamic properties of various toxic organophosphorus (OP) compounds and their interactions with acetylcholinesterase (AChE) and AChE oxime reactivators within the central nervous system. 8 It is possible that this advancement in understanding the interplay among the HTC insult (OP), physiological target (AChE), and antidote (oxime reactivator) could inform the future design of more effective MCMs. In any event, these are just two examples from the CCRP portfolio where basic research discoveries have led (or will hopefully lead) to candidate MCMs.…”