Characterization of a Brain Permeant Fluorescent Molecule and Visualization of Aβ Parenchymal Plaques, Using Real-Time Multiphoton Imaging in Transgenic Mice

Sundaram, G. S. M.; Garai, Kanchan; Rath, Nigam P.; Yan, Ping; Cirrito, John R.; Cairns, Nigel J.; J, Lee; Sharma, Vijay

doi:10.1021/ol501264q

Cited by 13 publications

(21 citation statements)

References 39 publications

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“…While nearly 1:1 correlation was apparent for Aβ extracellular plaques (Fig. 3; right panel; arrows), 5 also demonstrated substantially higher sensitivity for labeling CAA compared with anti Aβ antibody thus consistent with slight variations in staining patterns observed between a small organic molecule and a large antibody25.…”

Section: Resultsmentioning

confidence: 52%

“…Additionally, two intermolecular hydrogen bonds involve the N atoms N2 from the ring and the solvent N, N1s [C3-H3….N2 (1.5-x, y-0.5, z-0.5) = 2.61 Å and the bond angle around H3 = 164.5°; C15-H15a…N1s (1+x, y, z) = 2.68 Å and the angle around H15a = 170.5°]. While search of the Cambridge Crystallographic database does not show organic scaffolds sharing a similar arrangement of atoms around Se in the molecule, the closest chemical structure for comparative analysis remains the first generation Aβ targeted molecule reported earlier25. Importantly, the chemical structures of 5 and its first generation benzothiazole derivative counterpart (C 18 H 18 FN 3 OS) are identical except that Se is swapped with S (while the six membered aromatic ring of 5 possesses 2Ns, the aromatic ring of the benzothiazole derivative contains only one N atom).…”

Section: Resultsmentioning

confidence: 83%

“…Furthermore, the bond angle around the Se atom of 5 is also significantly narrower than that of benzothiazole derivative (84.6° vs 89.1°). Overall, comparative analysis indicate both 5 and its first generation counterpart25 share planar geometry with the F atoms displaying out of plane deviation. Finally, NMR spectral data of 5 was also consistent with the crystal structure thus indicating the presence of identical structures both in solid and solution state ( J H-H = 7.4 Hz; alkene protons indicating the presence of Z isomer) and the results are in accord with the first generation Aβ agent25.…”

Section: Resultsmentioning

confidence: 95%

“…Our strategic design for obtaining a second generation Aβ-targeted agent involved five functional components described earlier25. Incorporating those characteristic features into a template scaffold, the Aβ targeted probe 5 was synthesized as shown (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent investigations examining [ 3 H]-PiB and [ 18 F]-AV-4523 binding to AD homogenates also indicate multiple binding sites on Aβ24 thus mandating development of new tracers to study Aβ pathophysiology. To further supplement the existing armamentarium of FDA approved Aβ imaging agents, earlier we have shown that a heterocyclic fluorescent molecule is capable of traversing the BBB to label Aβ plaques in brains of APP +/− /PS1 +/− mice and also indicates sensitivity for detecting diffuse plaques in autopsy confirmed AD human tissues2526. Although the PET counterpart showed high first pass extraction into the brains of normal mice and Aβ labeling in brain frontal cortex of APP +/− /PS1 +/− mice, its binding affinity to AD homogenates was 5–10 fold inferior compared with two FDA approved agents27.…”

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confidence: 99%

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Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer’s Disease

Sundaram

Dhavale

Prior

et al. 2016

Sci Rep

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Fluselenamyl (5), a novel planar benzoselenazole shows traits desirable of enabling noninvasive imaging of Aβ pathophysiology in vivo; labeling of both diffuse (an earlier manifestation of neuritic plaques) and fibrillar plaques in Alzheimer’s disease (AD) brain sections, and remarkable specificity for mapping Aβ compared with biomarker proteins of other neurodegenerative diseases. Employing AD homogenates, [18F]-9, a PET tracer demonstrates superior (2–10 fold higher) binding affinity than approved FDA tracers, while also indicating binding to high affinity site on Aβ plaques. Pharmacokinetic studies indicate high initial influx of [18F]-9 in normal mice brains accompanied by rapid clearance in the absence of targeted plaques. Following incubation in human serum, [18F]-9 indicates presence of parental compound up to 3h thus indicating its stability. Furthermore, in vitro autoradiography studies of [18F]-9 with AD brain tissue sections and ex vivo autoradiography studies in transgenic mouse brain sections show cortical Aβ binding, and a fair correlation with Aβ immunostaining. Finally, multiphoton- and microPET/CT imaging indicate its ability to penetrate brain and label parenchymal plaques in transgenic mice. Following further validation of its performance in other AD rodent models and nonhuman primates, Fluselenamyl could offer a platform technology for monitoring earliest stages of Aβ pathophysiology in vivo.

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Section: Resultsmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer’s Disease

Sundaram

Dhavale

Prior

et al. 2016

Sci Rep

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Fluorescent Diagnostic Probes in Neurodegenerative Diseases

et al. 2020

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Both chronic and acute neurodegenerative diseases have been associated with high morbidity and mortality, along with the death of neurons in different areas of the brain, and there are few or no effective curative therapy options for treatment of patients. [3,4] These disorders are a major cause of concern for the health and quality of life in the aging society, since age is the greatest risk factor for neurodegenerative disease. [5] The World Health Organization has predicted that in next 20 years neurodegenerative disease will become the second most common cause of mortality after cardiovascular disease. [6] Neurodegenerative processes begin long before their clinical symptoms are evident, and evolve for years slowly and irreversibly. Hence, there is an urgent need to diagnose neurodegenerative disease as early as possible and to distinguish between different neurodegenerative disorders with shared and unique symptoms to facilitate decision making regarding choice of treatment. Timely diagnosis is important for the adoption of therapeutic modalities in clinical trials prior to moderate dementia exhibition, to appraise and apply antidotes to maximally preserve the cognitive functions or to slow down the course of these disorders. The ability to analyze and identify risk factors for cognitive deficit would represent an extraordinary advancement in the field of dementia. [5] The main modern diagnostic technologies for the early examination of neurodegenerative disease pathology, neuroimaging techniques, include radioligandsbased positron emission tomography (PET), 3D single-photon emission-computed tomography (SPECT), and structural magnetic resonance imaging (MRI). Although PET and SPECT are the most used imaging techniques for neurodegenerative diseases, their application is limited by high cost, involvement of hazardous radiolabeled compounds, need for sophisticated instruments, and application of complex data acquisition and analysis protocols. The MRI technique has relatively low spatial resolution as well as intrinsically poor sensitivity to distinguish morphological differences between disease biomarkers and the surrounding tissue. Recently, fluorescence diagnosis technology has become an attractive and potential alternative to diagnose and probe the progression of neurodegenerative diseases, because of being rapid, noninvasive, sensitive, simple, real-time, low-cost, and high-resolution in nature. [7] There are several uses for Neurodegenerative diseases are debilitating disorders that feature progressive and selective loss of function or structure of anatomically or physiologically associated neuronal systems. Both chronic and acute neurodegenerative diseases are associated with high morbidity and mortality along with the death of neurons in different areas of the brain; moreover, there are few or no effective curative therapy options for treating these disorders. There is an urgent need to diagnose neurodegenerative disease as early as possible, and to distinguish between different disorders with overlap...

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Harnessing Intramolecular Rotation To Enhance Two‐photon Imaging of Aβ Plaques through Minimizing Background Fluorescence

et al. 2019

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The aggregation of amyloid beta (Aβ) proteins in senile plaques is a critical event during the development of Alzheimer's disease, and the postmortem detection of Aβ‐rich proteinaceous deposits through fluorescent staining remains one of the most robust diagnostic tools. In animal models, fluorescence imaging can be employed to follow the progression of the disease, and among the different imaging methods, two‐photon microscopy (TPM) has emerged as one of the most powerful. To date, several near‐infrared‐emissive two‐photon dyes with a high affinity for Aβ fibrils have been developed, but there has often been a tradeoff between excellent two‐photon cross‐sections and large fluorescence signal‐to‐background ratios. In the current work, we introduced a twisted intramolecular charge state (TICT)‐based de‐excitation pathway, which results in a remarkable fluorescence increase of around 167‐fold in the presence of Aβ fibrils, while maintaining an excellent two‐photon cross section, thereby enabling high‐contrast ex vivo and in vivo TPM imaging. Overall, the results suggest that adopting TICT de‐excitation in two‐photon fluorophores may represent a general method to overcome the tradeoff between probe brightness and signal‐to‐background ratio.

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Characterization of a Brain Permeant Fluorescent Molecule and Visualization of Aβ Parenchymal Plaques, Using Real-Time Multiphoton Imaging in Transgenic Mice

Cited by 13 publications

References 39 publications

Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer’s Disease

Fluselenamyl: A Novel Benzoselenazole Derivative for PET Detection of Amyloid Plaques (Aβ) in Alzheimer’s Disease

Fluorescent Diagnostic Probes in Neurodegenerative Diseases

Harnessing Intramolecular Rotation To Enhance Two‐photon Imaging of Aβ Plaques through Minimizing Background Fluorescence

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