AUTOMATED CHEMOENZYMATIC SYNTHESIS OF NO-CARRIER-ADDED [CARBONYL-C-11]PROPIONYL L-CARNITINE FOR PHARMACOKINETIC STUDIES

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 th e preparation of [C-11]propionyl chloride as labelling agent via C-11- carboxylation of ethylmagnesium bromide with cyclotron-produced [C-11] carbon dioxide and subsequent chlorination. Reaction of carrier-added [C-11]propionyl chloride with L-carnitine in trifluoroacetic acid gave [C-11]PLC in 12% radiochemical yield (decay-corrected) from cyclotron -produced [C-11]carbon dioxide. However, the radiosynthesis was unsucc essful at the no-carrier-added (NCA) level of specific radioactivity. [C-11]Propionate, as a radioactive precursor for chemoenzymatic routes , was prepared via carboxylation of ethylmagnesium bromide with [C-11] carbon dioxide and hydrolysis. NCA [C-11]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [C-11]propionate via s equential conversions catalysed by acetate kinase, phosphotransacetyla se and carnitine acetyltransferase. A superior chemoenzymatic synthesi s of NCA [C-11]PLC was developed, based on the use of a novel supporte d Grignard reagent for the synthesis of [C-11]propionate and conversio ns by S-acetyl-CoA synthetase and carnitine acetyltransferase. This ga ve an overall radiochemical yield of 30-48% (decay-corrected). This sy nthesis was automated for radiation safety and provides pure NCA [C-11 ]PLC in high radioactivities ready for intravenous administration with in 25 min from radionuclide production. The [C-11]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. (C) 1997 Elsevier Science Ltd.