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Engineering of donor-acceptor-donor curcumin analogues as near-infrared fluorescent probes for in vivo imaging of amyloid-β species. 2022

Daqing Fang, and Xidan Wen, and Yuqi Wang, and Yidan Sun, and Ruibing An, and Yu Zhou, and Deju Ye, and Hong Liu
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.

Near-infrared (NIR) fluorescent imaging of both soluble and insoluble Aβ species in the brain of Alzheimer's disease (AD) is crucial for the early diagnosis and intervention of AD. To date, a variety of NIR fluorescent probes have been reported for the detection of Aβ species. Among these probes, CRANAD-58 was reported to have the capability to detect both soluble and insoluble Aβ species, which is vital to monitor the changes of Aβ species during the pathological course of the disease. Though CRANAD-58 has shown promise to noninvasively detect Aβ species in transgenic AD mice, the emission wavelength (~670 nm) is still too short for further applications. Therefore, new probes with longer emission wavelength and improved physiological properties are in highly demand. Herein, we report the design and engineering of nine donor-acceptor-donor molecules as "off-on" near-infrared fluorescent probes for in vivo imaging of both soluble and insoluble Aβ species in living AD mice owing to its improved in vitro properties and in vivo performance. Methods: We report a two-round strategy to develop nine "off-on" NIR fluorescence probes via structural modification of a curcumin analogue-based donor-acceptor-donor architecture. In round one, probes 1 and 2 were synthesized, and probe 2 was identified to be an optimum probe as it showed distinct "off-on" NIR fluorescence at > 690 nm upon binding to Aβ monomers, oligomers and aggregates. To further improve the in vivo performance, further structural modification of probe 2 into probes 3-9 was then conducted. The fluorescence response with Aβ species and histological staining in vitro and in vivo imaging of Aβ species in APP/PS1 transgenic AD mice and age-matched wild-type mice were performed. Results: We demonstrate that, compared to probe 2, probe 9 with improved physiological properties hold the fastest kinetics (~10 min) to produce not only higher brain fluorescence intensity in 10-month-old APP/PS1 transgenic AD mice, but also afford a higher discrepancy in brain fluorescence to discriminate AD mice from wild-type (WT) mice. Probe 9 also hold the ability to detect soluble Aβ species in 6-month-old APP/PS1 transgenic mice. Probe 9 was further applied for dynamic visualization of Aβ plaques in a skull-thinning 14-month-old APP/PS1 mouse, which revealed its immediate penetration into brain parenchyma and selective labeling of both parenchymal and angiopathic Aβ plaques. In addition, probe 9 possessed significantly high attenuation effect on the aggregation of Aβ monomers. Conclusion: Our results demonstrate the good potential of probe 9 for longitudinal NIR fluorescence imaging of soluble and insoluble Aβ species in APP/PS1 transgenic AD mice, which may act as a useful tool for early diagnosis and intervention of AD.

UI MeSH Term Description Entries
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D003474 Curcumin A yellow-orange dye obtained from tumeric, the powdered root of CURCUMA longa. It is used in the preparation of curcuma paper and the detection of boron. Curcumin appears to possess a spectrum of pharmacological properties, due primarily to its inhibitory effects on metabolic enzymes. 1,6-Heptadiene-3,5-dione, 1,7-bis(4-hydroxy-3-methoxyphenyl)-, (E,E)-,Curcumin Phytosome,Diferuloylmethane,Mervia,Turmeric Yellow,Phytosome, Curcumin,Yellow, Turmeric
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D005456 Fluorescent Dyes Chemicals that emit light after excitation by light. The wave length of the emitted light is usually longer than that of the incident light. Fluorochromes are substances that cause fluorescence in other substances, i.e., dyes used to mark or label other compounds with fluorescent tags. Flourescent Agent,Fluorescent Dye,Fluorescent Probe,Fluorescent Probes,Fluorochrome,Fluorochromes,Fluorogenic Substrates,Fluorescence Agents,Fluorescent Agents,Fluorogenic Substrate,Agents, Fluorescence,Agents, Fluorescent,Dyes, Fluorescent,Probes, Fluorescent,Substrates, Fluorogenic
D000544 Alzheimer Disease A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57) Acute Confusional Senile Dementia,Alzheimer's Diseases,Dementia, Alzheimer Type,Dementia, Senile,Presenile Alzheimer Dementia,Senile Dementia, Alzheimer Type,Alzheimer Dementia,Alzheimer Disease, Early Onset,Alzheimer Disease, Late Onset,Alzheimer Sclerosis,Alzheimer Syndrome,Alzheimer Type Senile Dementia,Alzheimer's Disease,Alzheimer's Disease, Focal Onset,Alzheimer-Type Dementia (ATD),Dementia, Presenile,Dementia, Primary Senile Degenerative,Early Onset Alzheimer Disease,Familial Alzheimer Disease (FAD),Focal Onset Alzheimer's Disease,Late Onset Alzheimer Disease,Primary Senile Degenerative Dementia,Senile Dementia, Acute Confusional,Alzheimer Dementias,Alzheimer Disease, Familial (FAD),Alzheimer Diseases,Alzheimer Type Dementia,Alzheimer Type Dementia (ATD),Alzheimers Diseases,Dementia, Alzheimer,Dementia, Alzheimer-Type (ATD),Familial Alzheimer Diseases (FAD),Presenile Dementia,Sclerosis, Alzheimer,Senile Dementia
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016229 Amyloid beta-Peptides Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue. Alzheimer beta-Protein,Amyloid Protein A4,Amyloid beta-Peptide,Amyloid beta-Protein,beta Amyloid,beta-Amyloid Protein,Alzheimer's ABP,Alzheimer's Amyloid Fibril Protein,Amyloid AD-AP,Amyloid Fibril Protein, Alzheimer's,Amyloid beta-Proteins,ABP, Alzheimer's,AD-AP, Amyloid,Alzheimer ABP,Alzheimer beta Protein,Alzheimers ABP,Amyloid AD AP,Amyloid beta Peptide,Amyloid beta Peptides,Amyloid beta Protein,Amyloid beta Proteins,Amyloid, beta,Protein A4, Amyloid,Protein, beta-Amyloid,beta Amyloid Protein,beta-Peptide, Amyloid,beta-Peptides, Amyloid,beta-Protein, Alzheimer,beta-Protein, Amyloid,beta-Proteins, Amyloid
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D058225 Plaque, Amyloid Accumulations of extracellularly deposited AMYLOID FIBRILS within tissues. Amyloid Deposits,Plaques, Amyloid,Amyloid Plaques,Neuritic Plaques,Senile Plaques,Amyloid Deposit,Amyloid Plaque,Deposit, Amyloid,Deposits, Amyloid,Neuritic Plaque,Plaque, Neuritic,Plaque, Senile,Plaques, Neuritic,Plaques, Senile,Senile Plaque

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