新穎多巴胺轉運體探針之合成與評估

Abstract

多巴胺轉運體與注意力不足過動症、帕金森氏症等中樞神經疾病息息相關，正子造影示蹤劑可幫助這些疾病的早期診斷及追蹤，也可協助新藥開發。為發展具潛力的多巴胺轉運體正子造影示蹤劑，一系列2-吡啶基取代之GBR12935衍生物被設計及合成，並評估這些衍生物對血腦屏障的穿透力及脂溶性。在此系列衍生物中，所有的衍生物皆顯示適當的脂溶性 (Log P從4.09降至2.55) 及血腦屏障穿透能力 (Pe% = 57%-66%)，未來可望用於發展多巴胺轉運體正子造影示蹤劑。 為合成出易於進行放射標記氟化反應的前驅物，必須解決在電子密度大的芳香環上不易進行放射標記氟化反應的問題。具有缺電子及易作離去基等特點的不對稱雙芳香環碘鹽是利於氟原子進行親核性取代反應的前驅物，而硼酸化合物則常被設計為合成不對稱雙芳香環碘鹽前驅物的中間體。本研究以2-吡啶基取代之GBR12935衍生物22作為氟化反應的目標產物，探討關鍵中間體硼酸化合物21的合成。先以turbo Grignard reagent 合成具硼酸酯取代的雙芳香環醇15，經偶合反應及水解反應後成功製備關鍵中間體硼酸化合物21，未來可用於合成放射標記氟化反應的前驅物。

英文摘要 Dopamine transporters are related to central nervous system diseases such as attention deficit hyperactivity disorder and Parkinson's disease. Positron emission tomography (PET) tracers help early diagnosis and monitoring of these diseases, and also assist new drug discovery and development. To develop potential PET radiotracer for dopamine transporter (DAT), a series of 2-pyridyl-substituted 1- (2- (diphenyl-methoxy) ethyl) -4- (3-phenylpropyl) piperazine (GBR12935) derivatives was designed and synthesized. In this series, all the compounds show desirable lipophilicity (from LogPof 4.09 to 2.55) and blood-brain barrier (BBB) penetration ability, and maybe used to develop DAT PET radiotracers. To synthesis a precursor that can be easy to label 18F, the problem of 18F labeling on electron-rich aromatic ring need to be solved. Diaryliodonium salts possess electron-deficient and good leaving group properties, in favor of nucleophilic substitution with fluoride proceeding, and boronic acid compounds are used as intermediate for preparation of diaryliodonium salts. In this study, the 2-pyridyl substituted GBR12935 derivative 22 was designed as target product and the synthesis of the key intermediate boronic acid compound 21 was explored. By using turbo Grignard reagent to synthesis pinacol substituted diaryl alcohol 15, through coupling reaction and hydrolysis reaction to produce key intermediate boronic acid compound 21, which may use for the preparation of diaryliodonium salt precursor in future.