title: The stability of methyl-, ethyl- and fluoroethylesters against carboxylesterases in vitro: there is no difference.
abstract: BACKGROUND
  Carboxylesterases (CES) play a very important role in the hydrophilic biotransformation of a huge number of structurally diverse drugs and especially play a leading part in the catabolic pathway of carboxylesters or thioesters. Hence, the aim of the present study was the comparison of the in vitro stability of methyl- and ethylesters with fluoroethylesters.
  
  
  METHODS
  We incubated methyl 3β-(4-iodophenyl)tropane-2β-carboxylate (β-CIT)/2-fluoroethyl 3β-(4-iodophenyl)tropane-2β-carboxylate (FE@CIT), methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (MTO)/ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (ETO)/2-fluoroethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate (FETO), ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4]diazepine-3-carboxylate (FMZ)/2-fluoroethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-benzo-[f]imidazo[1,5-a]-[1,4]diazepine-3-carboxylate (FFMZ), methyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (CFN)/2-fluoroethyl 1-phenylethyl-4-(N-propanoylanilino)piperidine-4-carboxylate (FE@CFN) and methyl 2,4-diethyl-3-methylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate [(Me)(2)@SUPPY]/2-fluorethyl 2,4-diethyl-3-ethylsulfanylcarbonyl-6-phenylpyridine-5-carboxylate (FE@SUPPY) under physiological conditions. The enzymatic reactions were stopped at different time points and analyzed by a standard protocol.
  
  
  RESULTS
  The Michaelis-Menten constants (K(M)) and limiting velocities (V(max)) are comparable. The statistical K(M) values were as follows: β-CIT/FE@CIT, P>.05; MTO/FETO, P>.06; ETO/FETO, P>.09; FMZ/FFMZ, P>.05; CFN/FE@CFN, P>.9; (Me)(2)@SUPPY/FE@SUPPY, P>.07.
  
  
  CONCLUSIONS
  We found no statistical difference in stability against CES in vitro. These findings support the strategy to translate C-11-methyl-/ethylesters into their longer-lived F-18-fluoroethyl analogues.
authors.affiliation: Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Nics
authors.forename: Daniela
authors.initials: D
authors.lastname: Haeusler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wagner
authors.forename: Robert
authors.initials: R
authors.lastname: Dudczak
authors.forename: Kurt
authors.initials: K
authors.lastname: Kletter
authors.forename: Markus
authors.initials: M
authors.lastname: Mitterhauser
mesh_terms: D043182:Carboxylesterase / Q000378:metabolism*; D002264:Carboxylic Acids / Q000737:chemistry* / Q000378:metabolism*; D004355:Drug Stability; D004952:Esters; D007700:Kinetics; D011849:Radioactive Tracers; D013379:Substrate Specificity
chemical_list: D002264:Carboxylic Acids; D004952:Esters; D011849:Radioactive Tracers; D043182:Carboxylesterase