Chao_2016_Chem.Res.Toxicol_29_1810

Reference

Title : Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases - Chao_2016_Chem.Res.Toxicol_29_1810
Author(s) : Chao CK , Ahmed SK , Gerdes JM , Thompson CM
Ref : Chemical Research in Toxicology , 29 :1810 , 2016
Abstract :

The organophosphate O-(2-fluoroethyl)-O-(p-nitrophenyl) methyphosphonate 1 is the first-in-class, fluorine-18 radiolabeled organophosphate inhibitor ([18F]1) of acetylcholinesterase (AChE). In rats, [18F]1 localizes in AChE rich regions of the brain and other tissues where it likely exists as the (CH3)(18FCH2CH2O)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 (CH3) (FCH2CH2O)P(O)OH with pseudo first order rate constants (kobsd) at pH 7.4 (PBS) of 3.25 x 10-4 min-1 (t1/2 = 35.5 h) at 25 degrees C and 8.70 x 10-4 min-1 (t1/2 = 13.3 h) at 37 degrees C. Compound 1 was a potent inhibitor of human acetylcholinesterase (HuAChE; ki = 7.5 x 105 M-1 min-1), electric eel acetylcholinesterase (EEAChE) (ki = 3.0 x 106 M-1 min-1), and human serum butyrylcholinesterase (HuBChE; 1.95 x 105 M-1 min-1). Spontaneous and oxime-mediated reactivation rates for the (CH3) (FCH2CH2O)P(O)-serine ChE adducts using 2-PAM (10 muM) were (a) HuAChE 8.8 x 10-5 min-1 (t1/2 = 131.2 h) and 2.41 x 10-2 min-1 (t1/2 = 0.48 h), (b) EEAChE 9.32 x 10-3 min-1 (t1/2 = 1.24 h) and 3.33 x 10-2 min-1 (t1/2 = 0.35 h), and (c) HuBChE 1.16 x 10-4 min-1 (t1/2 = 99.6 h) and 4.19 x 10-2 min-1 (t1/2 = 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 (CH3)(FCH2CH2O)P(O)-serine adducts and monoacid (CH3)(FCH2CH2O)P(O)OH from hydrolysis and reactivation.

PubMedSearch : Chao_2016_Chem.Res.Toxicol_29_1810
PubMedID: 27551891

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Citations formats

Chao CK, Ahmed SK, Gerdes JM, Thompson CM (2016)
Novel Organophosphate Ligand O-(2-Fluoroethyl)-O-(p-Nitrophenyl)Methylphosphonate: Synthesis, Hydrolytic Stability and Analysis of the Inhibition and Reactivation of Cholinesterases
Chemical Research in Toxicology 29 :1810

Chao CK, Ahmed SK, Gerdes JM, Thompson CM (2016)
Chemical Research in Toxicology 29 :1810