Evaluation of N, O-Benzamide difluoroboron derivatives as near-infrared fluorescent probes to detect β-amyloid and tau tangles

Yimin Chen; Qingwen Ouyang; Yuying Li; Qi Zeng; Bin Dai; Yi Liang; Baian Chen; Hongwei Tan; Mengchao Cui

doi:10.1016/j.ejmech.2021.113968

Evaluation of N, O-Benzamide difluoroboron derivatives as near-infrared fluorescent probes to detect β-amyloid and tau tangles

Eur J Med Chem. 2022 Jan 5:227:113968. doi: 10.1016/j.ejmech.2021.113968. Epub 2021 Oct 31.

Authors

Yimin Chen¹, Qingwen Ouyang¹, Yuying Li¹, Qi Zeng¹, Bin Dai², Yi Liang², Baian Chen³, Hongwei Tan¹, Mengchao Cui⁴

Affiliations

¹ Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
² Hubei Key Laboratory of Cell Homeostasis, State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
³ School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing, 100069, China; Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China. Electronic address: baianchen@ccmu.edu.cn.
⁴ Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China; Center for Advanced Materials Research, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai 519087, China. Electronic address: cmc@bnu.edu.cn.

PMID: 34752954
DOI: 10.1016/j.ejmech.2021.113968

Abstract

β-Amyloid (Aβ) plaques and Tau tangles are cognitive impairment markers vital for diagnosing and preventing Alzheimer's disease (AD). To systematically explore the relationship between the number or position of nitrogen atoms and their optical properties and biological properties, five series of new N, O-coordinated organo-difluoroboron probes were introduced as binding scaffolds for Aβ plaques and Tau tangles. These probes exhibited suitable optical properties for near-infrared (NIR) imaging. Probe 4PmNO-2 (4-((1E,3E)-4-(1,1-difluoro-1H-1λ⁴,9λ⁴-pyrimido[1,6-c][1,3,5,2]oxadiazaborinin-3-yl)buta-1,3-dien-1-yl)-N,N-dimethylaniline) displayed the excellent emission maximum (716 nm in PBS), a high quantum yield (61.4% in CH₂Cl₂), and a high affinity for synthetic Aβ_1-42 (K_d = 23.64 ± 1.08 nM) and Tau (K18) aggregates (K_d = 26.38 ± 1.29 nM), as well as for native Aβ plaques and NFTs in the brain tissue from AD patients. 4PmNO-2, with significantly enhanced fluorescence (Aβ_1-42, 136 fold; Tau (K18), 96 fold) and the highest initial brain uptake (11.57% ID/g at 2 min) in normal ICR mice, was evaluated further. In vivo NIR fluorescent imaging studies in living Aβ and Tau transgenic mice revealed that it could differentiate healthy and diseased animals. Further ex vivo fluorescent staining studies showed that 4PmNO-2 specifically bound to Aβ plaques and Tau tangles in transgenic mice. In summary, the probe 4PmNO-2 may be a useful near-infrared fluorescence (NIRF) probe for AD biomarkers.

Keywords: Alzheimer's disease; Aβ plaques; Difluoroboron; Near-infrared imaging; Tau tangles.

MeSH terms

Alzheimer Disease / diagnostic imaging
Alzheimer Disease / metabolism
Amyloid beta-Peptides / analysis*
Amyloid beta-Peptides / metabolism
Animals
Benzamides / chemical synthesis
Benzamides / chemistry*
Fluorescent Dyes / chemical synthesis
Fluorescent Dyes / chemistry*
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Structure
tau Proteins / analysis*
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Benzamides
Fluorescent Dyes
tau Proteins
benzamide