新型α突触核蛋白PET探针的合成及初步生物学评价  

Synthesis and preliminary biological evaluation of a novel PET tracer forα-synuclein PET imaging

作　　者：王策 潘栋辉[2] 谭思怡 王立振[2] 王辛宇 严骏杰 陈重阳 徐宇平[2] 邹亮华 WANG Ce;PAN Donghui;TAN Siyi;WANG Lizhen;WANG Xinyu;YAN Junjie;CHEN Chongyang;XU Yuping;ZOU Lianghua(School of Life Science and Health Engineering,Jiangnan University,Wuxi 214122,China;Jiangsu Key Laboratory of Molecular Nuclear Medicine,Jiangsu Institute of Nuclear Medicine,Wuxi 214063,China)

机构地区：[1]江南大学生命科学与健康工程学院,无锡214122 [2]江苏省原子医学研究所分子影像中心,无锡214063

出　　处：《核技术》2024年第10期56-65,共10页Nuclear Techniques

基　　金：江苏省卫健委重点项目(No.ZD2021005);江苏省自然基金(No.BK20231141);无锡市"太湖之光"科技攻关(医疗卫生技术攻关)项目(No.Y20212050)资助。

摘　　要：异常聚集的α-突触核蛋白(α-synuclein)是帕金森病的主要病理特征,研发α-synuclein PET显像剂有助于帕金森病的早期诊断和治疗。本文设计并合成了一种新型α-synuclein探针^(18)F-YM(2-((3-氟[^(18)F]苄基)硫基)-6-(3-氟丙氧基)苯并噻唑),采用铜介导的放射性氟化标记策略,结合A53T小鼠和正常小鼠PET成像,评估此新型探针的体内性能。研究表明,^(18)F-YM的合成时间约60min,未校正收率大于10%,比活度为8.5 GBq·μmol^(-1),放射化学纯度大于95%。小动物PET显像结果显示,苯并噻唑类化合物^(18)F-YM在表达α-synuclein的A53T小鼠脑中浓聚且摄取值显著高于正常小鼠脑中对应值。定量分析结果显示,注射后30 min,A53T小鼠与正常小鼠脑摄取值分别为(2.35±0.06)%ID/g和(1.38±0.15)%ID/g。体内外自显影和病理分析证实^(18)F-YM能够识别A53T小鼠中丘脑、黑质和纹状体等脑区聚集的α-synuclein。而体内生物分布观测显示^(18)FYM在正常小鼠脑中被快速清除。这表明^(18)F-YM在大脑中的非特异性结合较低,有利于获得对比度良好的图像。临床前研究初步表明,苯并噻唑类化合物,^(18)F-YM,具有较好的成像性能,可能是潜在的α-synuclein PET探针。[Background]Accumulation ofα-synuclein is a major hallmark of Parkinson's disease(PD).The development of PET tracers to visualize aggregatedα-synuclein is useful for early diagnosis and treatment of PD.[Purpose]This study aims to design and synthetize a novel PET tracer,i.e.,^(18)F-YM,for for alpha-synuclein PET imaging,and conduct preliminary biological evaluation.[Methods]Firstly,based on benzothiazole scaffolds,2-((3-fluorobenzyl)thio)-6-(3-[fluorine-18]propoxy)benzo[d]thiazole,a small molecule compound,denoted as ^(18)F-YM,was prepared as PET tracer and labeled using Cu(II)mediated radiofluorination methods.The imaging properties of the tracer were primarily evaluated through PET imaging at A53T mice and normal mice.Additionally,the imaging properties of the tracer were also investigated through biodistribution experiments as well as ex vivo autoradiography and pathological analysis.Then,through chemical synthesis,compounds Sn-YM and ^(19)F-YM were obtained,and the Sn-YM was labeled with ^(18)F using organic tin fluoride method whilst the resulting product ^(18)F-YM was verified by high performance liquid chromatography.The in vitro stability and octanol-water partition coefficient of ^(18)F-YM were determined.Finally,small animal Micro PET imaging was employed to assess the affinity of ^(18)F-YM forα-synuclein,and autoradiography,pathological analysis,and biodistribution were used to validate the results of small animal Micro PET imaging.[Results]Observed results show that ^(18)F labeled small molecule compound is prepared in nearly 1 h with an undecayed yield greater than 10%and a radiochemical purity greater than 95%.In vivo PET imaging of ^(18)F-YM reveals that more radioactivity is significantly detected in the brains of A53T mice than those of normal mice after administration of ^(18)F-YM.Quantitative analysis shows that the uptake values in the brain of A53T mice and normal mice are(2.35±0.06)%ID/g and(1.38±0.15)%ID/g,respectively while ex vivo autoradiography and histological examination confirm

关 键 词：Α-突触核蛋白 帕金森病 PET探针 

分 类 号：TL99[核科学技术—核技术及应用]