Hualong Fu

Highly Sensitive Near-Infrared Fluorophores for in Vivo Detection of Amyloid-β Plaques in Alzheimer’s Disease

Alzheimers disease (AD) is pathologically characterized by the accumulation of β-amyloid (Aβ) deposits in the parenchymal and cortical brain. In this work, we designed, synthesized, and evaluated a series of near-infrared (NIR) probes with electron donor-acceptor end groups interacting through a π-conjugated system for the detection of Aβ deposits in the brain. Among these probes, 3b and 3c had excellent fluorescent properties (emission maxima > 650 nm and high quantum yields) and displayed high sensitivity and high affinities to Aβ aggregates (3b, Kd = 8.8 nM; 3c, Kd = 1.9 nM). Both 3b and 3c could readily penetrate the blood-brain barrier with high initial brain uptake and fast to moderate washout from the brain. In vivo NIR imaging revealed that 3b and 3c could efficiently differentiate transgenic and wild-type mice. In summary, our research provides new hints for developing smarter and more activatable NIR probes targeting Aβ.

Novel Cyclopentadienyl Tricarbonyl Complexes of 99mTc Mimicking Chalcone as Potential Single-Photon Emission Computed Tomography Imaging Probes for β-Amyloid Plaques in Brain

Rhenium and technetium-99m cyclopentadienyl tricarbonyl complexes mimicking the chalcone structure were prepared. These complexes were proved to have affinity to β-amyloid (Aβ) in fluorescent staining on brain sections of Alzheimers Disease (AD) patient and binding assay using Aβ(1-42) aggregates, with K(i) values ranging from 899 to 108 nM as the extension of conjugated π system. In vitro autoradiograpy on sections of transgenic mouse brain confirmed the affinity of [(99m)Tc]5 (K(i) = 108 nM). In biodistribution, all compounds showed good initial uptakes into the brain and fast blood clearance, while the decreasing of initial brain uptakes correspond to increasing of conjugation length, from 4.10 ± 0.38% ID/g ([(99m)Tc]3) to 1.11 ± 0.34% ID/g ([(99m)Tc]5). These small technetium-99m complexes (<500 Da) designed by an integrated approach provide encouraging evidence that development of a promising (99m)Tc-labeled agent for imaging Aβ plaques in the brain may be feasible.

99mTc-labeled dibenzylideneacetone derivatives as potential SPECT probes for in vivo imaging of β-amyloid plaque

Four (99m)Tc-labeled dibenzylideneacetone derivatives and corresponding rhenium complexes were successfully synthesized and biologically evaluated as potential imaging probes for Aβ plaques using SPECT. All rhenium complexes (5a-d) showed affinity for Aβ(1-42) aggregates (Ki = 13.6-120.9 nM), and selectively stained the Aβ plaques on brain sections of transgenic mice. Biodistribution in normal mice revealed that [(99m)Tc]5a-d exhibited moderate initial uptake (0.31%-0.49% ID/g at 2 min) and reasonable brain washout at 60 min post-injection. Although additional optimizations are still needed to facilitate its penetration through BBB, the present results indicate that [(99m)Tc]5a may be a potential SPECT probe for imaging Aβ plaques in Alzheimers brains.

Amyloid-β Deposits Target Efficient Near-Infrared Fluorescent Probes: Synthesis, in Vitro Evaluation and in Vivo Imaging

The formation of extracellular amyloid-β (Aβ) plaques is a common molecular change that underlies several debilitating human conditions, including Alzheimers disease (AD); however, the existing near-infrared (NIR) fluorescent probes for the in vivo detection of Aβ plaques are limited by undesirable fluorescent properties and poor brain kinetics. In this work, we designed, synthesized, and evaluated a new family of efficient NIR probes that target Aβ plaques by incorporating hydroxyethyl groups into the ligand structure. Among these probes, DANIR 8c showed excellent fluorescent properties with an emission maximum above 670 nm upon binding to Aβ aggregates and also displayed a high sensitivity (a 629-fold increase in fluorescence intensity) and affinity (Kd = 14.5 nM). Because of the improved hydrophilicity that was induced by hydroxyls, 8c displayed increased initial brain uptake and a fast washout from the brain, as well as an acceptable biostability in the brain. In vivo NIR fluorescent imaging revealed that 8c could efficiently distinguish between AD transgenic model mice and normal controls. Overall, 8c is an efficient and veritable NIR fluorescent probe for the in vivo detection of Aβ plaques in the brain.

Compounds for imaging amyloid-β deposits in an Alzheimer’s brain: a patent review

Introduction: β-amyloid (Aβ) plaques in the brain are regarded as a hallmark of Alzheimer’s disease (AD), and the imaging of Aβ is a critical step for early diagnosis. Extensive research has been done to develop probes for targeting Aβ with available imaging modalities. Areas covered: In this review, the authors give an overview of published patents and papers about the discovery and development of compounds possessing potential utilization in imaging Aβ for the diagnosis of AD. SciFinder is the main electronic database for patent study in this review. Expert opinion: Despite achievements in Aβ imaging, there is still a need to develop innovative compounds with selectivity and high affinity to Aβ. Positron emission tomography imaging agents will still be the trend in the field in the short term. Due to the low costs for single-photon emission computed tomography (SPECT) and the excellent nuclear properties of 99mTc, substantial research should be conducted on the development of the probes for SPECT. Refining the current imaging techniques and in the meantime developing new efficient imaging multimodality and compounds would be a promising approach to imaging Aβ.

Synthesis and biological evaluation of 18F-labled 2-phenylindole derivatives as PET imaging probes for β-amyloid plaques

A novel series of fluorinated 2-phenylindole derivatives were synthesized and evaluated as β-amyloid imaging probes for PET. The in vitro inhibition assay demonstrated that their binding affinities for Aβ(1-42) aggregates ranged from 28.4 to 1097.8 nM. One ligand was labeled with (18)F ([(18)F]1a) for its high affinity (K(i)=28.4 nM), which was also confirmed by in vitro autoradiography experiments on brain sections of transgenic mouse (C57BL6, APPswe/PSEN1, 11 months old, male). In vivo biodistribution experiments in normal mice showed that this radiotracer displayed high initial uptake (5.82±0.51% ID/g at 2 min) into and moderate washout (2.77±0.31% ID/g at 60 min) from the brain. [(18)F]1a could be developed as a promising new PET imaging probe for Aβ plaques although necessary modifications are still needed.

In vivo near-infrared and Cerenkov luminescence imaging of amyloid-β deposits in the brain: a fluorinated small molecule used for dual-modality imaging

Three fluorinated (19F or 18F) small molecules were evaluated as fluorescent or radiolabeled probes for Aβ deposits in the brain. In vivo near-infrared imaging suggested that probe 4c could efficiently distinguish between transgenic mice and wild-type controls. Furthermore, the in vivo Cerenkov luminescence imaging with [18F]4c showed modest differences between the two groups.