The possible deployment of organophosphate (OP) nerve agents by terrorists, rogue organizations, or by government agencies is of immediate concern and has prompted new investigations to better understand the properties of OP agents so that new therapeutics can be developed to combat and reverse the ill effects of OPs. These research endeavors are producing new approaches and molecular countermeasures to ameliorate the short- and long-term neurotoxicity associated with OPs. The objectives in this application are: (1) to provide quantitative and visual accounts of three OP structure types (VX, sarin and paraoxon) exposures in rats, guinea pigs and primates to advance our understanding of OP biodistribution; and (2) to provide quantitative and visual accounts of three oxime subtypes (cation, neutral and zwitterion) in rats, guinea pigs and primates to advance our understanding of oxime biodistribution; and (c) to develop new dynamic assays that evaluate, measure and validate new therapeutic agents in live subjects over time by employing positron emission tomography (PET) imaging. The approach will assess key pharmacokinetic (PK) and pharmacodynamic (PD) parameters and thus, this application will generate new 18F- and 11C-labeled organophosphate and oxime PET imaging tracers to demonstrate their functional imaging utility in live rodent/primate subjects, and validate their performance qualities in the presence of specific countermeasures. To accomplish these goals, rationally designed methylphosphonate PET radioligands will be prepared with the following progressive specific aims defined by two operational phases: Phase I (Specific Aims 1-2). Design and Synthesis of OP and Countermeasure PET Imaging Tracers and Phase II (Specific Aims 3-6). Establish and Confirm the Countermeasure Molecular Imaging Animal Platforms.
Specific aims 1 and 2 will synthesize and validate the mechanism of action and pharmacology of the 18F- and 11C-labeled OP and oximes tracers.
Specific Aims 3 -4 will determine the PK/PD profiles of the 18F- and 11C-labeled OP and oxime tracers in rat and guinea pig.
Specific aims 5 -6 will advance the experimentation to combination approaches and evaluate the diagnostic capabilities of the 18F- and 11C-labeled tracers and use a candidate OP and oxime tracer in non-human primates.
Specific aims 3 -6 will collectively afford imaging platforms in each species.
Military personnel and citizens remain vulnerable to acts of terrorism using chemical weapons including highly toxic nerve agents like organophosphates, which are relatively inexpensive to produce and deploy. The relevance of this investigation is to develop novel positron emission tomography (PET) tissue imaging agents based on organophosphate structures and their antidotes (oximes) that can be used to demonstrate the in vivo action and distribution of organophosphates, and serve to validate and assess new therapeutic drugs and approaches for clinical use in the event of an attack.
|Neumann, Kiel D; Blecha, Joseph E; Hayes, Thomas R et al. (2018) Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [11C]2-Pyridinealdoxime Methiodide ([11C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication. ACS Chem Neurosci :|
|Chao, Chih-Kai; Balasubramanian, Narayanaganesh; Gerdes, John M et al. (2018) The inhibition, reactivation and mechanism of VX-, sarin-, fluoro-VX and fluoro-sarin surrogates following their interaction with HuAChE and HuBuChE. Chem Biol Interact 291:220-227|
|Neumann, Kiel D; Thompson, Charles M; Blecha, Joseph E et al. (2017) An improved radiosynthesis of O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate: A first-in-class cholinesterase PET tracer. J Labelled Comp Radiopharm 60:337-342|
|Chao, Chih-Kai; Ahmed, S Kaleem; Gerdes, John M et al. (2016) Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases. Chem Res Toxicol 29:1810-1817|