title: 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 (t12 = 20.3 min), one chemical and two chemoenzymatic. The former was based on the preparation of [11C]propionyl chloride as labelling agent via 11C-carboxylation of ethylmagnesium bromide with cyclotron-produced [11C]carbon dioxide and subsequent chlorination. Reaction of carrier-added [11C]propionyl chloride with L-carnitine in trifluoroacetic acid gave [11C]PLC in 12% radiochemical yield (decay-corrected) from cyclotron-produced [11C]carbon dioxide. However, the radiosynthesis was unsuccessful at the no-carrier-added (NCA) level of specific radioactivity. [11C]Propionate, as a radioactive precursor for chemoenzymatic routes, was prepared via carboxylation of ethylmagnesium bromide with [11C]carbon dioxide and hydrolysis. NCA [11C]PLC was prepared in 68 min in 14% radiochemical yield (decay-corrected) from [11C]propionate via sequential conversions catalysed by acetate kinase, phosphotransacetylase and carnitine acetyltransferase. A superior chemoenzymatic synthesis of NCA [11C]PLC was developed, based on the use of a novel supported Grignard reagent for the synthesis of [11C]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 [11C]PLC in high radioactivities ready for intravenous administration within 25 min from radionuclide production. The [11C]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.
authors.affiliation: MRC Cyclotroh Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, U.K.
authors.forename: R J
authors.initials: RJ
authors.lastname: Davenport
authors.forename: V W
authors.initials: VW
authors.lastname: Pike
authors.forename: K
authors.initials: K
authors.lastname: Dowsett
authors.forename: D R
authors.initials: DR
authors.lastname: Turton
authors.forename: K
authors.initials: K
authors.lastname: Poole
mesh_terms: D000084:Acetate Kinase; D001331:Automation; D002245:Carbon Dioxide; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002331:Carnitine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002332:Carnitine O-Acetyltransferase; D017357:Cyclotrons; D006801:Humans; D007202:Indicators and Reagents; D007553:Isotope Labeling / Q000379:methods / Q000592:standards; D010709:Phosphate Acetyltransferase; D011835:Radiation Protection; D014055:Tomography, Emission-Computed / Q000379:methods
chemical_list: D002250:Carbon Radioisotopes; D007202:Indicators and Reagents; D002245:Carbon Dioxide; C003223:propionylcarnitine; D002332:Carnitine O-Acetyltransferase; D010709:Phosphate Acetyltransferase; D000084:Acetate Kinase; D002331:Carnitine