第一部分：新穎多巴胺轉運體分子探針之設計與合成 第二部分：6-烷氧基四氫異喹啉衍生物之合成

Abstract

多巴胺轉運體主要之生理功能為回收突觸間的多巴胺，且與許多中樞神經疾病有關，例如：帕金森氏症、思覺失調症、注意力不足過動症、藥物濫用與抑鬱症。正子斷層掃描是一種非侵入性之技術，可協助這些疾病的早期診斷及追蹤，也可協助新藥開發。先前本實驗室發展出對多巴胺轉運體具有高度的結合力、選擇性和適當脂溶性的2-吡啶基取代之GBR12935衍生物。為合成以 [18F] 標定的化合物1應用於正子斷層掃描，必須設計出穩定且易於進行18F標定反應之前驅物，我們選擇具有缺電子和良好離去基團性質的不對稱雙芳香環碘鹽作為氟原子進行親核性芳香環取代反應的前驅物。本研究以前驅物2作為合成目標，探討關鍵中間體有機錫化合物3的合成，以建立一條合成路徑。先以格林納反應合成具溴取代的雙芳香環醇6，與化合物7經偶合反應與錫化反應後成功製備關鍵中間體化合物3，未來可以前驅物2進行18F標定反應，以探討其成為多巴胺轉運體分子探針之可能性。 血清素受體在人體中扮演重要的角色，且與多種中樞神經系統之生理功能有所關聯，例如：體溫調節、學習與記憶、焦慮以及精神分裂症等。這也意味著血清素受體為重要的藥物分子作用標靶。為發展一系列對於不同血清素受體亞型具有高親和力與選擇性之新穎化合物。延續本實驗室過去之研究成果，以8-苯基四氫異喹啉 (8-phenyl-1,2,3,4-tetrahydroisoquinoline) 作為核心結構，利用環烷氧基團與氟代烷氧基團取代C-6上酚基以合成新穎衍生物16a-b。未來可於C-8上進行不同芳香基團之修飾，以評估其作為新穎血清素受體配體之可能性。

Dopamine transporter (DAT) is responsible for reuptake of dopamine from the synaptic cleft and involved in many neurodegenerative and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, attention deficit hyperactivity disorder, substance abuse and depression. Position emission tomography (PET) is a non-invasive molecular imaging technique, which can be used for early diagnosis and disease monitoring, and also for new drug discovery and development. Previously, a potent and selective dopamine transporter ligand, compound 1, with suitable lipophilicity was discovered by using GBR12935 as the lead compound. To synthesize [18F]-1 as a positron emission tomography molecular probe for DAT, it is necessary to design and synthesize a suitable precursor for 18F-labeling reaction. Diaryliodonium salt with electron-deficient and good leaving group properties for proceeding nucleophilic aromatic substitution with fluoride was designed as precursor. In this study, diaryliodonium salt precursor 2 of [18F]-1 was chosen as target compound, and the synthesis of key intermediate aryl-stannane 3 was explored to establish a synthetic pathway. Bromo-substituted alcohol 6 was synthesized by Grignard reaction, through coupling reaction with compound 7 and stannylation for the preparation of key intermediate aryl-stannane 3. Precursor 2 will be used for 18F-labeling reaction for the discovery of novel PET molecular probe for DAT. Serotonin (5-HT) receptors play important roles in the human body and are related to various physiological functions of central nervous system, such as thermoregulation, learning and memory, anxiety, and schizophrenia. The 5-HT receptors are important drug targets to explore the etiology and pathophysiology of related diseases. As continuous efforts, to develop a series of novel compounds with high affinity and selectivity for the 5-HT receptor subtypes. 8-Phenyl-tetrahydroisoquinoline was chosen as the core structure, and the intermediates 16a-b with cyclopropylmethoxy and fluoroalkoxy-substituted on C-6 were prepared as target compounds. Further modification of aromatic groups on C-8 could provide novel derivatives as potential ligands for 5-HT receptors.