Iterative Design of Near-Infrared Fluorescent Probes for Early Diagnosis of Alzheimer's Disease by Targeting Aβ Oligomers

被引：9

作者：

Liu, Bing ^{[1
]}

Li, Xiaofang ^{[1
]}

Liu, Zhengyang ^{[1
]}

He, Bing ^{[1
]}

Xu, Hanyue ^{[2
]}

Cao, Jianqin ^{[1
]}

Zeng, Fantian ^{[1
]}

Feng, Haiwei ^{[1
]}

Ren, Yanwei ^{[1
]}

Li, Haoyu ^{[1
]}

Wang, Tianyu ^{[1
]}

Li, Jia ^{[3
]}

Ye, Yuting ^{[3
]}

Zhao, Li ^{[4
]}

Ran, Chongzhao ^{[5
,6
]}

Li, Yuyan ^{[1
]}

机构：

[1] China Pharmaceut Univ, Dept Med Chem, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 211100, Jiangsu, Peoples R China

[2] Nanjing Foreign Language Sch, Nanjing 210008, Jiangsu, Peoples R China

[3] China Pharmaceut Univ, Pathol & PDX Efficacy Ctr, Nanjing 211100, Jiangsu, Peoples R China

[4] China Pharmaceut Univ, Sch Basic Med & Clin Pharmacol, Nanjing 211100, Jiangsu, Peoples R China

[5] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA

[6] Harvard Med Sch, Boston, MA 02129 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 11期

关键词：

ASSOCIATION WORKGROUPS; SECRETED OLIGOMERS; NATIONAL INSTITUTE; PROTEIN; BRAIN; RECOMMENDATIONS; HYPOTHESIS; GUIDELINES; MOLECULES;

D O I：

10.1021/acs.jmedchem.4c00252

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Amyloid-beta oligomers (A beta Os), crucial toxic proteins in early Alzheimer's disease (AD), precede the formation of A beta plaques and cognitive impairment. In this context, we present our iterative process for developing novel near-infrared fluorescent (NIRF) probes specifically targeting A beta Os, aimed at early AD diagnosis. An initial screening identified compound 18 as being highly selective for A beta Os. Subsequent analysis revealed that compound 20 improved serum stability while retaining affinity for A beta Os. The most promising iteration, compound 37, demonstrated exceptional qualities: a high affinity for A beta Os, emission in the near-infrared region, and good biocompatibility. Significantly, ex vivo double staining indicated that compound 37 detected A beta Os in AD mouse brain and in vivo imaging experiments showed that compound 37 could differentiate between 4-month-old AD mice and age-matched wild-type mice. Therefore, compound 37 has emerged as a valuable NIRF probe for early detection of AD and a useful tool in exploring AD's pathological mechanisms.

引用

页码：9104 / 9123

页数：20

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