"第一部分：微波輔助Mannich反應之研究 第二部分：氮取代8-苯基-1,2,3,4-四氫異喹啉衍生物之合成及生物活性評估"

Abstract

第一部分： 為了開發用於多巴胺轉運體 (dopamine transporter) 正子斷層造影 (positron emission tomography, PET) 之影像劑 (imaging agent)，LTC1000被設計且合成，在經過生物活性的測試，發現LTC1000具有高度選擇性 (SERT/DAT = 311) 及適當的脂溶性 (logP = 3.41)，LTC1000被認為是具有潛力能開發為多巴胺轉運體正子斷層造影的影像劑，目前大部分正子藥物的應用皆受限於放射性同位素的半衰期過短影響而造成合成及分析上的困難。在本研究中以微波輔助加熱的方式進行Mannich反應快速製備化合物3-{4-[2-(benzhydryloxy)ethyl]piperazin-1-yl}-1- phenylpropan- 1-one (2)，並利用高效能液相層析儀 (high performance liquid chromatography, HPLC) 和液相層析質譜儀 (liquid chromatography-mass spectrometry, LC-MS) 監測反應。相較原文獻合成方法，此方法的建立大幅提高了合成的效率，最佳化後的反應條件是具有潛力應用於開發正子斷層造影影像劑的方法。 第二部份： 一系列氮取代以8-phenyl-1,2,3,4-tetrahydroisoquinoline為架構的衍生物已經被設計與合成；經過5-HT2A與5-HT7受體親合力的評估，此類化合物對於5-HT2A受體不具顯著的親和力 (no significant response)，但對5-HT7受體顯示了高度的選擇性 (selectivity)。消旋化合物20對於5-HT7受體顯示高度的親和力 (Ki = 7.41 nM)，為了探討化合物20與5-HT7受體的結合模式，單一鏡像異構物已經被合成且生物活性已在評估中。在側鏈具有羰基修飾的衍生物中，側鏈2號碳上的酯類官能基若為極性較小的甲基酯和乙基酯取代衍生物23與27則具有較佳的5-HT7受體親和力 (23, Ki = 6.53 nM; 27, Ki = 8.64 nM)。一系列具有氟取代長碳鏈的衍生物32-34以及胺基取代衍生物24-25已經被合成，且生物活性已在評估中。

Part 1: To develop novel positron emission tomography (PET) imaging agents for dopamine transporter (DAT). LTC1000 was designed and synthesized with high selectivity (SERT/DAT = 192) and suitable lipophilicity (logP = 3.41). The utilities of most traditional organic synthetic method for the preparation of 18F-labeled PET imaging agents are limited due to the very short half-life of 18F. In this study, 3-{4-[2-(benzhydryloxy)ethyl]piperazin-1-yl}-1-phenylpropan-1-one (2) was rapidly prepared by microwave-assisted Mannich reaction. The progress of reaction was monitored by HPLC and LC-MS and this method is more efficient than previous methods. The optimized reaction condition has potential to be used for the preparation of 18F-labeled PET imaging agents.

Part 2: A series of N-substituted 8-phenyl-1,2,3,4-tetrahydroisoquinoline derivatives was synthesized and evaluated for their 5-HT2A and 5-HT7 receptor binding affinity. All of these compounds had no significant binding to 5-HT2A receptor and moderate to high binding affinity for 5-HT7 receptor. In the series, the racemic 2-(3-hydroxy-3- phenylpropyl)-6-methoxy-8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-7-ol (20), displayed the highest binding affinity (Ki = 7.41 nM) for 5-HT7 receptor. To investigate the enantioselectivity of 5-HT7 receptor binding, R and S enantiomers of 20 were synthesized and their binding affinity is currently under evaluation. Hydrophobic group-substituted esters 23 and 27 showed high affinity (23, Ki = 6.53 nM, 27, Ki = 8.64 nM) for 5-HT7 receptor than corresponding hydrophilic group-substituted ester. The fluoro-substituted derivatives 32-34 and enantiomeric amino-substituted derivatives 24-25 were synthesized and their binding affinity is currently under evaluation.