Positron emission tomography studies of organophosphate chemical threats and oxime countermeasures

NEUROBIOLOGY OF DISEASE

卷:133

Review

Thompson, Charles M.¹  Gerdes, John M.¹  VanBrocklin, Henry F.² 

[1] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA

[2] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, 185 Berry St,Suite 350, San Francisco, CA 94107 USA

关键词: Positron emission tomography (PET);    Imaging;    Biodistribution;    Pharmacokinetics/toxicokinetics;    Pharmacodynamics/toxicodynamics;    Organophosphate/organophosphorus;    Oxime;    Fluorine-18;    Carbon-11;    Acetylcholinesterase;    Inhibition;    Reactivation;    Aging;   

DOI  :  10.1016/j.nbd.2019.04.011

来源: Elsevier

【 摘 要 】

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.