合成新穎5-HT7受體配體作為有潛力之正子斷層掃描影像劑

Abstract

本研究目的為發展有潛力具選擇性之 5-HT7 受體配體，並且應用於正子掃描影像劑。根據過去本實驗室設計合成的幾個系列化合物藥理活性之結果， 6-Methoxy-8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinolin-7-ol 被選定為核心結構。在這項研究中，一套有效的硝化方法被發展出來，且合成了了一系列的硝基和硝基-氟取代丙基苯的合成子；並且藉 GC 分析硝化反應的位向選擇性。此外，優化的還原法也被建立，製備了不同的溴-取代丙基苯合成子。這些合成子被用於合成一系列新穎的衍生物；其中，硝基-取代之化合物 11 (Ki = 2.78 nM)，14 (Ki = 3.60 nM)，16 (Ki = 6.04 nM)，展現了顯著的 5-HT7 受體的結合親合力，極有潛力作為5-HT7 受體之 18F 標定的正子斷層影像劑前驅物。最後，以氟離子芳香環親核性取代反應之模型研究，為未來使用 18F 製備正子斷層掃描影像劑，提供了有價值的參考資訊。

Based on the preliminary pharmacological data of several series of compounds synthesized in our laboratory, 6-methoxy-8-(2-methoxyphenyl)-1,2,3,4- tetrahydroisoquinolin-7-ol was chosen as the core structure for the development of selective 5-HT7 receptor ligands as potential positron emission tomography (PET) imaging agents for 5-HT7 receptor. In this study, an efficient nitration method was developed for the preparation of a series of nitro and nitro-fluoro-substituted propylbenzene synthons, and the regioselectivities of nitration reactions were determined by GC. In addition, optimization of the reduction reaction conditions was conducted to prepare various bromo-substituted propylbenzene synthons. The nitro-substituted compounds 11 (Ki = 2.78 nM), 14 (Ki = 3.60 nM), 16 (Ki = 6.04 nM) with profound 5-HT7 receptor binding affinity are promising to be potential precursors for the development of 18F-labeled PET imaging agents. Model study of aromatic nucleophilic substitution using fluoride was conducted, which provided valuable information for preparation of PET imaging agents using [18F]-fluoride in the future.