Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-β plaques in Alzheimer's disease

Nan Yue; Hualong Fu; Yimin Chen; Xi Gao; Jiapei Dai; Mengchao Cui

doi:10.1016/j.ejmech.2022.114715

Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid-β plaques in Alzheimer's disease

Eur J Med Chem. 2022 Dec 5:243:114715. doi: 10.1016/j.ejmech.2022.114715. Epub 2022 Aug 30.

Authors

Nan Yue¹, Hualong Fu², Yimin Chen¹, Xi Gao¹, Jiapei Dai³, Mengchao Cui⁴

Affiliations

¹ Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
² Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China. Electronic address: fuhualong@bnu.edu.cn.
³ Wuhan Institute for Neuroscience and Neuroengineering, South-Central University for Nationalities, Wuhan, 430074, China.
⁴ Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China. Electronic address: cmc@bnu.edu.cn.

PMID: 36070630
DOI: 10.1016/j.ejmech.2022.114715

Abstract

The presence of Aβ plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity. Among them, probe 4b (K_d = 8.5 nM) with a phenyl-pyridine ring showed a 98-fold increase in fluorescence intensity upon binding with Aβ aggregates. In addition, 4b could identify Aβ plaques in brain sections of both a transgenic (Tg) mouse and AD patients. Furthermore, 4b could readily penetrate the mouse blood-brain barrier (brain_2min = 10.11% ID/g) and washed out rapidly. Finally, the NIR imaging with Tg mice confirmed the practical application of 4b in detecting Aβ plaques in vivo. Altogether, our work widens the landscape of Aβ NIR probes and offers a new tool for Aβ detection.

Keywords: Alzheimer's disease; Aβ plaques; In vivo imaging; Near-infrared probe.

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Brain / diagnostic imaging
Brain / metabolism
Fluorescent Dyes / chemistry
Mice
Mice, Transgenic
Molecular Probes / metabolism
Plaque, Amyloid / diagnostic imaging
Plaque, Amyloid / metabolism

Substances

Fluorescent Dyes
Molecular Probes
Amyloid beta-Peptides