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The organophosphate O-(2-fluoroethyl)-O-(p-nitrophenyl) methyphosphonate 1 is the first-in-class, fluorine-18 radiolabeled organophosphate inhibitor ([ 18 F]1) of acetylcholinesterase (AChE). In rats, [ 18 F]1 localizes in AChE rich regions of the brain and other tissues where it likely exists as the (CH 3 )( 18 FCH 2 CH 2 O)P(O)-AChE adduct (ChE-1). Characterization of this adduct would define the inhibition mechanism and subsequent postinhibitory pathways and reactivation rates. To validate this adduct, the stability (hydrolysis) of 1 and ChE-1 reactivation rates were determined. Base hydrolysis of 1 yields p-nitrophenol and (CH 3 ) (FCH 2 CH 2 O)P(O)OH with pseudo first order rate constants (k obsd ) at pH 7.4 (PBS) of 3.25 × 10 -4 min -1 (t 1/2 = 35.5 h) at 25 °C and 8.70 × 10 -4 min -1 (t 1/2 = 13.3 h) at 37 °C. Compound 1 was a potent inhibitor of human acetylcholinesterase (HuAChE; k i = 7.5 × 10 5 M -1 min -1 ), electric eel acetylcholinesterase (EEAChE) (k i = 3.0 × 10 6 M -1 min -1 ), and human serum butyrylcholinesterase (HuBChE; 1.95 × 10 5 M -1 min -1 ). Spontaneous and oxime-mediated reactivation rates for the (CH 3 ) (FCH 2 CH 2 O)P(O)-serine ChE adducts using 2-PAM (10 μM) were (a) HuAChE 8.8 × 10 -5 min -1 (t 1/2 = 131.2 h) and 2.41 × 10 -2 min -1 (t 1/2 = 0.48 h), (b) EEAChE 9.32 × 10 -3 min -1 (t 1/2 = 1.24 h) and 3.33 × 10 -2 min -1 (t 1/2 = 0.35 h), and (c) HuBChE 1.16 × 10 -4 min -1 (t 1/2 = 99.6 h) and 4.19 × 10 -2 min -1 (t 1/2 = 0.27 h). All ChE-1 adducts undergo rapid and near complete restoration of enzyme activity following addition of 2-PAM (30 min), and no aging was observed for either reactivation process. The fast reactivation rates and absence of aging of ChE-1 adducts are explained on the basis of the electron-withdrawing fluorine group that favors the nucleophilic reactivation processes but disfavors cation-based dealkylation aging mechanisms. Therefore, the likely fate of radiolabeled compound 1 in vivo is the formation of (CH 3 )(FCH 2 CH 2 O)P(O)-serine adducts and monoacid (CH 3 )(FCH 2 CH 2 O)P(O)OH from hydrolysis and reactivation.

chemical research in toxicology

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(<i>p</i>-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases

Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases