一种PD多靶点正电子探针的制备与表征

Preparation and Characterization of A Positron Probe for PD Multi-target Imaging

帕金森病(PD)是一种常发于老年人的神经系统退行性疾病,病理上与脑内多巴胺转运体(DAT)、5-羟色胺转运体(SERT)和去甲肾上腺素转运体(NET)等功能密切相关,同时靶向这3个靶点的多靶点PET探针有可能为PD研究提供有用的显像工具。以特索芬辛(Tesofensine)为先导化合物,合成了一种新型多靶点探针[^(18)F]11。合成步骤为:化合物3经脱水、酯化、格氏反应和异构化得到化合物7,再用氢化铝锂直接还原化合物7得到化合物8,化合物8与溴乙烷反应得到Tesofensine(9),化合物9经1-氯乙基氯甲酸酯去甲基化,得到化合物10。化合物10与1-氟-3-溴丙烷反应得到化合物11。采用“两步一锅法”进行放射性合成得到正电子探针[^(18)F]11。[^(18)F]11的脂水分配系数为2.36±0.31(pH=7.4),且在磷酸盐缓冲液(PBS)和胎牛血清(FBS)中的360 min内保持稳定。microPET/MR显像结果显示:[^(18)F]11在SD大鼠脑内有一定的放射性摄取,该结果为进行下一步体内生物学评价提供了基础。

Parkinson’s disease(PD)is a neurodegenerative disease which is closely related to dopamine transporter(DAT),serotonin transporter(SERT),and norepinephrine transporter(NET).Positron Emission Tomography(PET)probes targeting these three targets simultaneously may provide good imaging tools for PD research.In this study,Tesofensine was used as the lead compound to synthesize a novel multi-target probe[18 F]11.The synthesis steps are as follows:compound 3 was dehydrated,esterified,grignard reacted and isomerized to obtain compound 7.Direct reduction of compound 7 with lithium aluminum hydride to give compound 8.Then,compound 8 was reacted with bromoethane to obtain tesfensine(9).Demethylation with 1-Chloroethyl chloroformate to give compound 10.Finally,compound 10 is reacted with 1-fluoro-3-bromopropane to give compound 11.Radioactive synthesis of the probe[18 F]11 was obtained by the"two-step,one-pot method"with compound 10 and[18 F]fluoroethyl methylbenzenesulfonate.The lipid-water partition coefficient of[18 F]11 was 2.36±0.31(pH=7.4)which falls in the range of good blood-brain barrier permeability.[18 F]11 was stable within 360 min in phosphate buffer solution(PBS)and fetal bovine serum(FBS).MicroPET/MR imaging demonstrated rapid brain uptake in normal rats.These results provided a basis for further in vivo biological evaluation.