Identification of the Protein Target of Myelin-Binding Ligands by Immunohistochemistry and Biochemical Analyses

Bajaj, Anshika; LaPlante, Nicole; Cotero, Victoria; Fish, Kenneth; Bjerke, Roger M.; Siclovan, Tiberiu M.; Hehir, Cristina A. Tan

doi:10.1369/0022155412467353

Cited by 26 publications

(32 citation statements)

References 26 publications

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“…[7][8][9][10] These tracers, all previously known as amyloid markers, were hypothesized to bind to proteins characterized by a similar conformation contained in amyloid plaques and myelin. 11,12 On this basis, Pittsburgh compound B (PiB), a thioflavin compound binding to amyloid plaques, was also identified as a promising myelin tracer suitable for human PET studies. 13 In rodent demyelinating lesions, microPET with [ 11 C]PiB showed great sensitivity in capturing remyelination after demyelination.…”

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confidence: 99%

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Bodini

Veronese

García-Lorenzo

et al. 2016

Annals of Neurology

197

110

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BackgroundQuantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.MethodsPatients with active relapsing‐remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel‐wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination.ResultsAt baseline, there was a progressive reduction in [11C]PiB binding from the normal‐appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow‐up, high between‐patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta‐coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta‐coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index.Interpretation[11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738

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confidence: 99%

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Bodini

Veronese

García-Lorenzo

et al. 2016

Annals of Neurology

197

110

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“…Note the thin layer of fascia obscuring the nerve under white light imaging, but not under fluorescence visualization. More detailed in vivo dosing and kinetics results for these three dyes were described elsewhere ( d7 17,19,28 ; d9 18 ; manuscript submitted for d10 ;).…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, we were presented with the challenge of having to determine what molecular characteristics were necessary to retain in order to maintain the binding affinity to our target of interest - myelin basic protein. 17 In order to obtain reasonable solubility in the three ring system and attenuate lipophilicity we incorporated a methoxy- group in the middle aryl ring. 29 …”

Section: Resultsmentioning

confidence: 99%

“…17 A buffer only control (no dye) was performed using exactly the same procedure to determine autofluorescence under identical imaging settings.…”

Section: Methodsmentioning

confidence: 99%

“…We have since reported on bis-styryl dyes ( d1, d7 and d9 ) for selectively targeting myelin basic protein (MBP), a major component of nerves, 17-19 along with compact optical imaging instruments for open and minimal access surgeries. 20,21 Following intravenous injection, these dyes visualized central and peripheral nerves in vivo with high contrast relative to the surrounding muscle tissue, despite absorbing and emitting in the visible region.…”

Section: Introductionmentioning

confidence: 99%

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Fluorescence phenomena in nerve-labeling styryl-type dyes

Siclovan

Zhang

Cotero

et al. 2016

Journal of Photochemistry and Photobiology A: Chemistry

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Several classes of diversely substituted styryl type dyes have been synthesized with the goal of extending their expected fluorescent properties as much towards red as possible given the constraint that they maintain drug-like properties and retain high affinity binding to their biological target. We report on the synthesis, optical properties of a series of styryl dyes (d1-d14), and the anomalous photophysical behavior of several of these Donor-Acceptor pairs separated by long conjugated π-systems (d7-d10). We further describe an unusual dual emission behavior with two distinct ground state conformers which could be individually excited to locally excited (LE) and twisted intramolecular charge transfer (TICT) excited state in push-pull dye systems (d7, d9 and d10). Additionally, unexpected emission behavior in dye systems d7 and d8 wherein the amino- derivative d7 displayed a dual emission in polar medium while the N,N-dimethyl derivative d8 and other methylated derivatives d12-d14 showed only LE emission but did not show any TICT emission. Based on photophysical and nerve binding studies, we down selected compounds that exhibited the most robust fluorescent staining of nerve tissue sections. These dyes (d7, d9, and d10) were subsequently selected for in-vivo fluorescence imaging studies in rodents using the small animal multispectral imaging instrument and the dual-mode laparoscopic instrument developed in-house.

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Clinically Translatable Formulation Strategies for Systemic Administration of Nerve‐Specific Probes

Barth

Shah

Wang

et al. 2021

Advanced Therapeutics

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Nerves are extremely difficult to identify and are often accidently damaged during surgery, leaving patients with lasting pain and numbness. Herein, a novel near-infrared (NIR) nerve-specific fluorophore, LGW01-08, is utilized for enhanced nerve identification using fluorescence guided surgery (FGS), formulated using clinical translatable strategies. Formulated LGW01-08 is examined for toxicology, pharmacokinetics, and pharmacodynamics parameters in preparation for future clinical translation. Optimal LGW01-08 imaging doses are identified in each formulation resulting in a 10x difference between the toxicity and imaging dose window. Laparoscopic swine surgery completed using the da Vinci surgical robot (Intuitive Surgical) demonstrates the efficacy of formulated LGW01-08 for enhanced nerve identification. NIR fluorescence imaging enables clear identification of nerves buried beneath ≈3 mm of tissue that are unidentifiable by white light imaging. These studies provide a strong basis for future clinical translation of NIR nerve-specific fluorophores for utility during FGS to improve patient outcomes.

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Identification of the Protein Target of Myelin-Binding Ligands by Immunohistochemistry and Biochemical Analyses

Cited by 26 publications

References 26 publications

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

Fluorescence phenomena in nerve-labeling styryl-type dyes

Clinically Translatable Formulation Strategies for Systemic Administration of Nerve‐Specific Probes

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