Automated chemoenzymatic synthesis of no-carrier-added [carbonyl-11C]propionyl L-carnitine for pharmacokinetic studies.

Abstract Propionyl- l -carnitine (PLC) is under development as a therapeutic for the treatment of peripheral artery disease, coronary heart disease and chronic heart failure. Three methods were examined for labelling PLC in its propionyl group with positron-emitting carbon-11 ( t 1 2 = 20.3 min ), one chemical and two chemoenzymatic. The former was based on the preparation of [ 11 C]propionyl chloride as labelling agent via 11 C-carboxylation of ethylmagnesium bromide with cyclotron-produced [ 11 C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [ 11 C]propionyl chloride with l -carnitine in trifluoroacetic acid gave [ 11 C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [ 11 ]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier-added (NCA) level of specific radioactivity. [ 11 C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [ 11 C]carbon dioxide and hydrolysis. NCA [ 11 C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [ 11 C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [ 11 C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [ 11 C]propionate and conversions by S -acetyl-CoA synthetase and carnitine acetyltransferase. This gave an overall radiochemical yield of 30–48% (decay-corrected). This synthesis was automated for radiation safety and provides pure NCA [ 11 C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [ 11 C]PLC is suitable for pharmacokinetic studies in human subjects with PET and the elucidation of the fate of the propionyl group of PLC in vivo .