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

通过对乙酰乙酸乙酯进行2位放射甲基化，再进行水解，合成了3-^<14>C-丙酸、2-甲基[^<14>C]-丙酸、2-甲基[^<14>C]-己酸和2-甲基[^<14>C]-己酸，产率为51 ~ 75%。用浓氢氧化钾溶液在70ºC的温度下在5 min内完成水解（59%）。因此，与丙二酸酯合成相比，该反应可以在更短的时间和更温和的条件下进行，而丙二酸酯的脱羧步骤需要相当激烈的条件或较长的时间。因此，乙酰乙酸酯合成被认为适合于^<11>C标记。用稀氢氧化钾溶液（5.3%）水解得到的主要是核心反应的1-甲基[^<14>C]-烷基甲基酮，产物中的酸酮比随碱浓度的增加而增加。用^<14>CO_2格氏反应制备的2-甲基[^<14>C]脂肪酸与1-^<14>C-2-甲基脂肪酸的放射性分布存在差异。一般来说，2-甲基[^<14>C]脂肪酸的组织放射性浓度高于羧基标记的2-甲基脂肪酸。特别是，大脑摄取的2-甲基[^<14>C -2]脂肪酸与相应的1-^<14>C-2-甲基脂肪酸有显著差异。以3-酮脂肪酸乙酯和^<14>CH_3-I为原料制备2-甲基[^<14>C]-3 -酮脂肪酸，如2-甲基-3-酮丁酸、2-甲基-3-酮戊酸和2-甲基-3-酮己酸。2-甲基[^<14>C]-3酮丁酸在小鼠体内的行为与2-甲基[^<14>C]-丁酸相似。但其他两种酮类化合物在小鼠放射分布中与相应的脂肪酸不同。

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.