脑淀粉样血管病显像剂 Al18F-PEG-芳基苯并噻唑衍生物的合成及评价

Synthesis and evaluation of AlF-PEG-arylbenzothiazole as imaging agents for cerebral amyloid angiopathy

目的设计合成聚乙二醇(PEG)链修饰的Al18F标记的芳基苯并噻唑衍生物,作为靶向β-淀粉样蛋白(Aβ)的脑淀粉样血管病(CAA)显像剂,并对其活性及生物性质进行初步评价。方法以2-(4-(二甲氨基)苯基)苯并噻唑-5-酚为起始原料,经过Williamson反应、溴代反应、偶联反应、螯合反应制得Al19F-PEG-9和Al19F-PEG-10;在水溶液中,通过"一锅两步"的螯合反应制得放射性产物Al18F-PEG-9和Al18F-PEG-10;放射配基体外竞争结合试验测试目标化合物对Aβ1-42聚集体的亲和力;动物分布实验测试目标化合物的体内药代动力学性质。结果成功制备了PEG链修饰的Al18/19F标记的芳基苯并噻唑衍生物Al18/19F-PEG-9和Al18/19F-PEG-10,稳定氟化合物的结构经1H-NMR和MS谱确证,放射性氟化合物的结构经HPLC确证;体外活性测试结果表明,目标化合物对Aβ1-42聚集体具有中等亲和活性[Ki值分别为(75.3±31.5)nmol·L-1和(82.4±19.8)nmol·L-1];初步体内动力学分布结果显示,该类显像剂具有合适的初始脑摄取值(brain2 min=0.17、0.24%ID/g)和快速的血浆清除率(plasma clearance,CL)(blood2 min/60 min=36、61),而且与同类显像剂相比,肝脏摄取有一定降低,清除速率加快。结论PEG链的修饰有效改善了显像剂的体内性质,Al18F-PEG-9和Al18F-PEG-10具有成为用于CAA诊断的Aβ显像剂的潜力。

Cerebral amyloid angiopathy(CAA)is a common disorder in the elderly,which is related toβ-amyloid(Aβ)deposition in blood vessel walls of the brain.In order to selectively visualize the Aβdeposition,new probes for positron emission tomography(PET)imaging were synthesized and evaluated.Oligoethyleneoxy linkers were introduced for conjugation between Al18F-1,4,7-triazacyclononane-1,4-diacetic acid(NODA)and 2-arylbenzothiazole,an Aβbinding scaffold.Two Al19F-PEG-arylbenzothiazole complexes exhibited moderate binding affinity to Aβ1-42 aggregates with Ki values of(75.3±31.5)nmol·L-1 and(82.4±19.8)nmol·L-1 in vitro competitive binding assay.After radiolabeling,the Al18F-labeled probes,Al18F-PEG-9 and Al18F-PEG-10,revealed favorable initial brain uptake(brain2 min=0.17 and 0.24%ID/g)and fast plasma clearance(blood2 min/60 min=36 and 61)in normal mice.Besides,compared with their analogues,these compounds showed lower liver uptake and faster clearance,which implied the strategy of introducing PEG linker in the probes improved their pharmacokinetics.These preliminary results suggested that Al18F-PEG-9 and Al18F-PEG-10 would be candidates as Aβimaging agents for detection of CAA ■.