二-取代-八-芳香基異喹林衍生物作為血清素第七型 受體正子斷層掃描藥物之研究

Abstract

血清素第七型受體為一種連結G蛋白受體分佈于哺乳類動物的周邊組織器官以及中樞神經系統中。在中樞神經系統，血清素第七型受體無論在體溫調節、晝夜節律、學習、記憶以及許多神經疾病的病理機制中上都扮演著重要的角色。正子斷層掃描為一種非侵入性的核子醫學影像技術，目前已被廣泛應用于癌症、結核病、心血管以及神經退化性疾病之診斷。為發展專一結合於血清素第七型受體的正子斷層掃描探針，以對血清素第七型受體俱有高度親和性的CYY054作為先導化合物，透過二號及八號碳位置的結構修飾，設計及合成出多樣化的八-苯基異喹林衍生物。結果發現其中的化合物1, 2以及23皆對血清素第七型受體展現高度的親和力（Ki值分別為1.52, 0.98 以及2.74 nM）以及專一性。另外，經由探討各個化合物之物理化學性質以及藥理活性，化合物42（Log D = 3.62, tPSA = 43.3, Ki = 7.34 nM）被評估為最有潛力成為血清素第七型受體的氟十八標記正子斷層掃描分子探針。氯取代衍生物43亦被成功合成作為日後放射化學合成[18F]-42所需之前驅物。

The serotonin 5-HT7 receptor (5-HT7R) is a G-protein coupled receptors expressed in both peripheral tissues and central nervous system (CNS). In the CNS, 5-HT7R plays crucial roles in the control of thermoregulation, circadian rhythm, learning, memory and many disorders. Positron Emission Tomography (PET) is a non-invasive imaging technique which is widely used for the diagnosis of cancer, tuberculosis, cardiac disease and neurodegenerative disorders. To develop PET imaging agents for 5-HT7R, a potent 5HT7R ligand of CYY054 was selected as the lead compound for the design and synthesis of various 8-phenyl-1,2,3,4-tetrahydroisoquinolines. Structural modifications on both C-2 and C-8 positions resulted in several potent and selective 5-HT7R ligands. In the series, compound 1, 2 and 23 possessed the highest 5-HT7R binding affinity (Ki = 1.52, 0.98 and 2.74 nM, respestively). Compound 42 can be consider as a potential 18F-labeled PET imaging agent for 5HT7R in CNS based on its desirable physiochemical and pharmacological profiles (Log D = 3.62, tPSA = 43.3, Ki = 7.34 nM). The chloro- substituted derivative 43 has been synthesized successfully as a precursor for the radiosynthesis of [18F]-42 as a novel PET imaging agent.