A simple synthesis of [11C]carfentanil using an extraction disk instead of HPLC
Introduction
The μ-opioid receptor agonist, carfentanil, is reported to have a potency 7000 times that of morphine [4]. In order to avoid pharmacological effects from [11C]carfentanil in human subjects the introduction of extraneous carbon-12 from all sources must be avoided during the synthesis. In addition, shortening the synthesis time significantly can further improve the specific activity. In the original synthesis of [11C]carfentanil reported by Dannals et al. (1985) the sodium salt of the carboxylate precursor was heated with [11C]methyl iodide to yield the desired methyl ester [2]. The latter was purified by HPLC. These time-consuming steps were avoided in the new synthesis reported below. The carboxylate precursor as the tetrabutylammonium salt was reacted at room temperature with [11C]methyl triflate. The product was trapped on a high performance extraction disk, and starting materials were selectively washed off. [11C]Carfentanil was eluted with a small volume of ethanol into water. Radioactive contaminants were further removed by a small column of fibrous anion exchanger. The synthesis was completed within five minutes after the distillation of the [11C]methyl triflate thus saving approximately one half-life.
Section snippets
Precursor
4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylic acid was obtained as the free amino acid as follows: Benzyl 4-[N-(1-oxopropyl)-N-phenylamino]-1-(2-phenylethyl)-4-piperidinecarboxylate hydrochloride [4] was hydrogenated (2 atm, 24 h) in ethanol in the presence of Pd/carbon (Aldrich 20,569–9). After removal of the solvent the residue was treated with excess aqueous NH4OH. The solution was evaporated to dryness. The resulting solid was taken up in a small amount of
Results and discussion
The purification and formulation of [11C]carfentanil were completed in five minutes after introduction of [11C]methyl triflate. Approximately 250 mCi [11C]carfentanil were obtained from 1600 mCi [11C]CO2. The average specific activity at end of synthesis was 3500 mCi/μmole. The radiochemical purity was 97–98%. The radioactive contaminants eluted before [11C]carfentanil in reversed phase HPLC. Residual precursor was detectable by reversed phase HPLC at low levels (approx. 0.1 ug/mL) in most
Acknowledgements
This research was supported by grants from the Department of Energy (DE-FG02-87ER60561) and from the Pritzker Foundation. The author received important advice from Bob Dannals and Marcian Van Dort.
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