Preparation of carbon-11-labeled surrogates of VX and sarin: Divergent radiosynthesis of 11C-tracers by modification of reaction conditions

186 Objectives: Organophosphates (OP) are a class of compounds used as insecticides and chemical nerve agents that are known as potent cholinesterase inhibitors. As part of our ongoing program to investigate in vivo acetylcholinesterase (AChE) inhibitor tissue and blood profiles, we synthesized 11C-VX and 11C-sarin surrogate tracers. Structurally, the surrogate tracers differ by the presence of either an ethyl or isopropyl phospho-ester component. Herein, we report the preparation of 11C-VX and 11C-sarin surrogate tracers from 11C-carbon dioxide (11CO2) and identical chemical reagents, utilizing unique reaction conditions for each tracer. Methods: 11CO2 was prepared using a GE PETtrace by the 14N(p,α)11C reaction. The 11C-VX and 11C-sarin surrogate tracers were synthesized using a loop Methods: A Teflon loop (40 cm x 0.03” ID) was coated with a 1 M solution of MeMgBr in diethyl ether and then dried with N2. 11CO2 was transferred in a stream of N2 through the loop at a temperature of 0 °C or 0°C warmed to 25°C. Ethyl derivatives were formed preferentially at 0 °C while increased isopropyl intermediates formed at 25 °C. Reduction of the respective radiointermediates with 0.2 M LiAlH4 and iodination with HI gave the corresponding ethyl- and isopropyl-iodides. The iodides were distilled through P2O5 and ascarite and delivered into a reactor vessel containing a common phosphonic acid precursor to produce the desired 11C-VX or 11C-sarin surrogate tracers at 120 °C. The 11C-tracers were purified by semi-preparative reversed phase HPLC and formulated in 10% acetonitrile/pH 6.8 PBS. Results: Temperature control of the loop at 0 °C yielded primarily ethyl derivatives, while warming to 25 °C gave a mixture of [11C]ethyl and [11C]isopropyl derivatives. This corroborates previous reports for the preparation of [11C]alkyl iodides [1]. [11C]-VX and -sarin surrogates were prepared in radiochemical purities of >95%. [11C]-VX was obtained in decay corrected yields of 2.8 ± 1.4% while [11C]-sarin was obtained in 0.19 ± 0.04%. Molar activity of [11C]-VX and -sarin were 42 ± 16 and 264 ± 130 Ci/mmol, respectively. Isolated surrogates were stable for > 1h in the pH 6.8 formulation buffer. Conclusions: We have developed a viable and reproducible radiosynthesis of [11C]VX and sarin surrogate tracers for in vivo imaging and ex vivo tissue evaluations. This novel radiosynthesis exemplifies an efficient approach to prepare two radiotracers using identical reagents by varying reaction conditions thereby enabling enhanced formations of either [11C]-VX or [11C]-sarin surrogate tracers. The versatile qualities of the radiosynthetic approach are thought useful for the generation of other 11C-labeled tracers. Research Support: This work was supported by NIH U01NS092495-01. Reference [1] Zhang, Ming-Rong, Ogawa, Masanao, Yoshida, Yuichiro, Suzuki, Kazutoshi. Applied Radiation and Isotopes. 64, 2006. 216-222.