Novel 6-alkyl-and 6-alkenyl-3-fluoro-2-pyridinaldoximes have been synthesisedb yu sing amild and efficient chemoselective hydrogenation of 6-alkynyl-3-fluoro-2pyridinaldoximes caffolds, withouta lteringt he reducible, unprotected, sensitive oxime functionality and the CÀFb ond. These novel 6-alkyl-3-fluoro-2-pyridinaldoximesmay find medicinal application as antidotes to organophosphate poisoning. Indeed, one low-molecular-weight compound exhibited increased affinity for sarin-inhibited acetylcholinesterase (hAChE) and greater reactivation efficiency or resurrection for sarin-inhibited hAChE, compared with those of 2-pyridin-aldoxime (2-PAM) and 1-({[4-(aminocarbonyl)pyridinio]meth-oxy}methyl)-2-[(hydroxyimino)methyl]pyridiniumchloride (HI-6), two pyridiniums alts currently used as antidote by several countries. In addition, the uncharged 3-fluorinated bifunctional hybrid showedi ncreased in vitro blood-brain barrier permeability compared with those of 2-PAM, HI-6 and obidoxime. These promisingf eatures of novel low-molecular-weight alkylfluoropyridinaldoxime open up an ew era for the design, synthesis and discovery of central non-quaternary broad spectrumr eactivators for organophosphate-inhibitedc holinesterases.