The synthesis of carbon 11 labeled pharmaceuticals for PET by malonic ester synthesis and related methods

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By radiomethylation of ethyl acetoacetates at the 2-position followed by hydrolysis, sereral 2-methyl [^<14>C]-fatty acid as 3-^<14>C-propionic acid, 2-methyl [^<14>C]-propionic acid, 2-methy [^<14>C]-hexanoic acid and 2-methy [^<14>C]-hexadecanoic acid, were synthesized with 51-75% yields. The hydrolysis with concentrated potassium hydroxide solution (59%) were completed in 5 min. at 70ﾟC.This reaction hence can be carried out inmuch shorter times and under milder conditions than the malonic ester synthesis, in which the decarboxylation step needs rather drastic condition or long times. The acetoacetate synthesis is thus thought to be suitable for ^<11>C labeling. The hydrolysis with a dilute potassium hydroxide solution (5.3%) gave predominantly the coreesponding 1-methyl [^<14>C]-alkyl methyl ketones, with the acid/ketone ratio in the product increasing with the alkali concentrations.The difference of the radiodistributions beween 2-methyl [^<14>C]-fatty acids and 1-^<14>C-2-methyl fatty acids which were prepared by Grignard reaction with ^<14>CO_2 were found. In generally, the radioconcentrations of tissues for 2-methyl [^<14>C]-fatty acids were higher than the these for carboxyl-labeled 2-methyl fatty acids. Especially, the brain uptakes of 2-methyl [^<14>C]-fatty acids were remarkably different from the corresponding 1-^<14>C-2-methyl-fatty acid.2-methyl [^<14>C]-3 -keto-fatty acid, such as 2-methyl-3-ketobutanoic acid, 2-methyl-3-ketopentanoic acid and 2-methyl-3-ketohexanoic acid, were easily prepared from 3-keto-fatty acid ethyl ester and ^<14>CH_3-I.The behavior of 2-methyl [^<14>C]-3 ketobutanoic acid in mouse was similar to the one of 2-methyl [^<14>C]-butanoic acid. But other two keto-compounds were unlike the corresponding fatty acids in mouse radiodistribution.