A novel high affinity F-18 organophosphonate tracer for CNS acetylcholinesterase

323 Objectives Acetylcholinesterase (AChE) is a valuable CNS PET imaging target. Organophosphorus (OP) chemical agents are known irreversible inhibitors of AChE. Our overall objective has been to discover and develop a novel OP-based fluorine-18 (18F) AChE PET tracer with reduced toxicity that is suitable for detecting a priori poisonous OP CNS AChE exposures and that serves as an insightful radioprobe for elucidating the biochemical fates of OPs bound to AChE. Methods A panel of OP AChE covalent inhibitors, specifically designed with reduced toxicity, were prepared and evaluated with three in vitro anti-cholinesterase assays. The 2-fluoroethyl 4-nitrophenyl methylphosphonate 1 was selected for further study. F-18 labeled 1 ([18F]1) was produced via microwave assisted coupling of [18F]2-fluoroethyltosylate with 4-nitrophenyl hydrogen methylphosphonate. Intravenous administration of [18F]1 then PET imaging (120 min scans) of rats was conducted using an Inveon PET scanner in the absence and presence of OP AChE blocking agents. Results Ligand 1 showed in vitro AChE inhibition activity similar to the known OP agent paraoxon. [18F]1 was prepared in >99% radiochemical purity; mean specific activity 2.1 mCi/nmol (n=10). [18F]1 displayed high differential regional activity uptake consistent with known distribution of AChE densities in brain and the periphery. [18F]1 brain uptake was fast; peak time of 90% activity 2 h post injection. Loss of >85 % regional activity occurred after pretreatment with 1. Other cold OP challenges (paroxon or ecothiophate) resulted in expected blocked activity profiles. Conclusions In rats radioligand [18F]1 has promising in vivo properties as a first-in-class radiofluorinated OP AChE brain tracer. Nonradioactive OP exposed rats show significantly reduced differential regional activity. Research Support NIH R21-NS072079 & P30-NS055022