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

丙二酸酯合成法合成PET用碳11标记药物及相关方法

• 批准号: 05671903
• 负责人: OGAWA Koji
• 金额: $ 1.15万
• 依托单位: School of Allied Health Sciences, Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05671903/
• 关键词: malonic ester synthesis; ethyl acetoacetate; carbon-11; brain; 2-methyl-fatty acid; propionic acid; 2-methyl-3-keto-fatty acid.; 炭素-11; 標識化合物; 2-メチル脂肪酸; サイクロトロン; α-メチル〔^<11>CH_3〕-脂肪酸; β-ケト酸; alpha-メチル[^<11>CH_3]-脂肪酸

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.

通过乙酰乙酸乙酯在2-位的放射性甲基化，再经水解，合成了3-甲基[14&gt；C]-脂肪酸，2-甲基[^&lt；14&gt；C]-丙酸，2-甲基[^&lt；14&gt；C]-己酸和2-甲基[^&lt；14&gt；C]-十六酸，产率为51-75%。用59%浓度的氢氧化钾溶液在5min内即可完成水解率。因此，在70ﾟC下，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，在丙二酸酯合成中，脱羧步骤需要相当剧烈的条件或较长的时间。因此，乙酰乙酸酯的合成被认为适合于^&lt；11&gt；C的标记。用5.3%的稀氢氧化钾溶液进行水解，主要生成1-甲基[14&gt；C]-烷基甲基酮，产物中的酸/酮比随碱浓度的增加而增大。2-甲基[14&gt；C]-脂肪酸和1-甲基[14&lt；14&gt；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&gt；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2-甲基[14&gt；C]-脂肪酸与相应的1-甲基[14&gt；C]-脂肪酸的脑摄取明显不同。2-甲基[14&lt；14&gt；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-酮已酸，很容易由3-酮基脂肪酸乙酯和2-甲基-3-酮己酸合成。CH3-I.2-甲基[14&gt；C]-3酮丁酸在小鼠体内的行为与2-甲基[14&gt；C]-丁酸相似。但另外两种酮基化合物与相应的脂肪酸在小鼠体内的辐射分布不同。

项目成果

Noguchi J.: "Mesurement of chemical change in vivo by the use of a double labelled compound" J.Label.Compd.Radiopharm.37. 248-250 (1995)

Noguchi J.：“使用双标记化合物测量体内化学变化”J.Label.Compd.Radiopharm.37。

Ogawa,K: "Comparison of Biodistribution in 2-Methyl-fatty Acids Labeled at Different Positions." J.Labelled compds.and Radiopharm.35. 343-344 (1994)

Okawa,K：“不同位置标记的 2-甲基脂肪酸的生物分布比较。”

Kiichi Ishiwata: "Synthesis and preliminary evaluation of[1-^<11>C]hexanoate as a PET tracer of fatty acid metabolism." Annal of Nuclear Medicine. 9. 51-57 (1995)

Kiichi Ishiwata：“[1-^11C]己酸作为脂肪酸代谢PET示踪剂的合成和初步评价。”