Remotely-controlled production of the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635, via 11C-carboxylation of an immobilized Grignard reagent

Abstract

WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl))-N-(2-pyridyl)-cyclohexanecarboxamide], when labelled in its carbonyl position with carbon-11 (t1/2 = 20.4 min), is an effective radioligand for the study of 5-HT1A receptors in human brain with positron emission tomography (PET). A simple remotely-controlled procedure was developed for the routine synthesis of [carbonyl-11C]WAY-100635. Thus, cyclohexylmagnesium chloride is coated onto the inner surface of a narrow polypropylene tube. Cyclotron-produced [11C]carbon dioxide is passed into the tube in a nitrogen stream. A solution of thionyl chloride in tetrahydrofuran is then passed through the tube to convert the trapped radioactive adduct into [carbonyl-11C]cyclohexanecarbonyl chloride and to release this labelling agent into a vial containing 1-(2-methoxyphenyl)-4-(2-(2-pyridylamino)ethyl)piperazine plus triethylamine. The vial is sealed and heated to 70°C for 5 min. [carbonyl-11C]WAY-100635 is isolated by sample-enrichment and reverse phase HPLC and formulated for human intravenous injection by evaporation of solvent and dissolution in ‘saline for injection’. The novel use of the immobilized Grignard reagent has the advantages that only small quantities of all reagents are required so simplifying product purification. Moreover, the procedure was readily adapted for operation in a shielded hot-cell with remote control for radiation safety. The remotely-controlled radiosynthesis takes 45 min and gives high radioactivities (2.96–5.92 GBq) of formulated [carbonyl-11C]WAY-100635 in > 99% radiochemical purity and high specific radioactivity (average, 192 GBq/μmol).