靶向脑淀粉样血管病Aβ的Al^18/19 F-NODA-芳基苯并噁唑衍生物的合成及生物活性

Synthesis and affinity evaluation of Al^18/19 F-NODA-arylbenzoxazole derivatives targeting to Aβ in cerebral amyloid angiopathy

设计并制备靶向脑淀粉样血管病(CAA)中β-淀粉样蛋白(Aβ)的Al^18/19 F-NODA-芳基苯并噁唑衍生物生物,并对其生物活性作初步评价。以2-(4-(二甲氨基)苯基)苯并噁唑-5-酚为原料,经Williamson、溴代、偶联、脱保护、络合反应制得非标记目标化合物Al^19 F-9和Al^19 F-10,所有新合成化合物的结构经1H-NMR确证;通过“一锅两步”的水相络合反应制得放射性标记目标产物Al^18 F-9和Al^18 F-10,采用高效液相色谱法(HPLC)对Al^18 F-9和Al^18 F-10进行分离纯化及鉴定;采用“摇瓶法”测试Al^18 F-9和Al^18 F-10的脂溶性;采用[125 I]IMPY作为放射性竞争配基,通过体外竞争结合实验测试非标记目标化合物Al^19 F-9和Al^19 F-10对Aβ1-42聚集体的亲和力。成功制备了Al^18/19 F-NODA-芳基苯并噁唑衍生物,放射性标记产率约为35%,放射性化学纯度均高于98%,两对化合物在HPLC上的保留时间分别是5.058 min与5.383min和5.891 min与6.058 min;Al^18 F-9和Al^18 F-10的log D值分别为1.05±0.01和0.90±0.03;目标化合物Al^19 F-9和Al^19 F-10的K i值分别是1068.6±86.3 nM和736.5±195.3 nM。结论Al^18/19 F-NODA-芳基苯并噁唑衍生物生物对Aβ的亲和力较低,需要通过进一步结构优化可能成为用于CAA诊断的Aβ显像剂。

Al^18/19 F-NODA-arylbenzooxazole derivatives targetingβ-amyloid(Aβ)deposition in cerebral amyloid angiopathy(CAA)was designed,prepared and evaluated.By reaction of Williamson,bromide,coupling,deprotection and complexation,unlabeled targeting compounds Al^19 F-9 and Al^19 F-10 were prepared from 2-(4-(dimethylaminophenyl)benzooxazole-5-phenol as starting material.The structures of all the newly synthesized compounds were confirmed by 1H-NMR.The targeting products Al^18 F-9 and Al^18 F-10 were prepared by"one-pot and two-steps"complexation reaction in aqueous phase.The purification and identification of Al^18 F-9 and Al^18 F-10 were performed by high performance liquid chromatography(HPLC).The lipophilicity of Al^18 F-9 and Al^18 F-10 was tested by“flask-shaking method”.Using[125 I]IMPY as the radio-competitive ligand,the affinity of Al^19 F-9 and Al^19 F-10 binding to Aβ1-42 aggregates was tested by in vitro competitive binding experiments.Al^18 F-NODA-arylbenzooxazole derivatives,Al^18 F-9 and Al^18 F-10,were successfully prepared.The radiochemical yield was approximate 35%and the radiochemical purity was higher than 98%.The retention time of the two pairs of compounds in HPLC was 5.058 min v.s.5.383 min and 5.891 min v.s.6.058 min,respectively.The log D of Al^18 F-9 and Al^18 F-10 were 1.05±0.01 and 0.90±0.03,respectively.The K i values of Al^19 F-9 and Al^19 F-10 were 1068.6±86.3 nM and 736.5±195.3 nM,respectively.Al^18/19 F-NODA-arylbenzooxazole derivative showed poor affinities for Aβ1-42 aggregates,which might be used as Aβprobes for CAA imaging through further structural optimization.