A Novel Fluorine-18 β-Fluoroethoxy OrganophosphatePositron Emission Tomography Imaging Tracer Targeted to Central NervousSystem Acetylcholinesterase

摘要

Radiosynthesis of a fluorine-18 labeled organophosphate (OP) inhibitor of acetylcholinesterase (AChE) and subsequent positron emission tomography (PET) imaging using the tracer in the rat central nervous system are reported. The tracer structure, which contains a novel β-fluoroethoxy phosphoester moiety, was designed as an insecticide-chemical nerve agent hybrid to optimize handling and the desired target reactivity. Radiosynthesis of the β-fluoroethoxy tracer is described that utilizes a [¹⁸F]prosthetic group coupling approach. The imaging utility of the [¹⁸F]tracer is demonstrated in vivo within rats by the evaluation of its brain penetration and cerebral distribution qualities in the absence and presence of a challenge agent. The tracer effectively penetrates brain and localizes to cerebral regions known to correlate with the expression of the AChE target. Brain pharmacokinetic properties of the tracer are consistent with the formation of an OP-adducted acetylcholinesterase containing the fluoroethoxy tracer group. Based on the initial favorable in vivoqualities found in rat, additional [¹⁸F]tracer studiesare ongoing to exploit the technology to dynamically probe organophosphatemechanisms of action in mammalian live tissues.