Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging

Ekanger, Levi A.; Allen, Matthew J.

doi:10.1039/c4mt00289j

Cited by 43 publications

(41 citation statements)

References 114 publications

(200 reference statements)

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“…52). Thus, their potential clinical application is likely limited because, for example, of a combination of lack of U.S. Food and Drug Administration approval for the contrast agent, difficulty of the contrast agent crossing blood-brain/retina barriers, concerns about how disease may alter contrast agent pharmacokinetics, and possible modifications to endogenous neuronal redox signaling due to binding of free radicals (55,57,(75)(76)(77)(78)(79)(80). However, Quest MRI does not require injection of a contrast agent or require specialized equipment, and Food and Drug Administration-approved antioxidants can be used for the confirmatory quench.…”

Section: Discussionmentioning

confidence: 99%

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

et al. 2017

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Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured as a greater-than-normal 1/ that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

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Section: Discussionmentioning

confidence: 99%

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

et al. 2017

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“…Magnetic resonance imaging (MRI) offers a noninvasive platform to image opaque objects, but often requires responsive contrast agents to relay chemical information regarding the local redox environment. The Gd III ion has dominated the clinical landscape and preclinical research in MRI because it provides excellent T 1 -shortening (positive) contrast enhancement (14)(15)(16), but Gd III is restricted to the +3 oxidation state under physiological conditions preventing metal-based redox responses (17). The Eu II ion is isoelectronic with Gd III (4f 7 ), and both ions provide positive contrast enhancement in MRI (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Eu^II‐based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections

Ekanger

Polin

Shen

et al. 2016

Contrast Media & Molecular

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EuII-based contrast agents offer physiologically relevant, metal-based redox sensing that is unachievable with GdIII-based contrast agents. To evaluate the in vivo contrast enhancement of EuII as a function of injection type, we performed intravenous, intraperitoneal, and subcutaneous injections in mice. Our data reveal a correlation between reported oxygen content and expected rates of diffusion with the persistence of EuII-based contrast enhancement. Biodistribution studies revealed europium clearance through the liver and kidneys for intravenous and intraperitoneal injections, but no contrast enhancement was observed in organs associated with clearance. These data represent a step toward understanding the behavior of EuII-based complexes in vivo.

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“…For PARACEST agents, the indirect nature of the detection continues to be a challenge when determining the absolute concentration for many cases of molecule. Although a number of agents have been synthesized and evaluated for sensitivity to physiological parameters in vitro (reviewed in ), relatively few have been successfully demonstrated in vivo , and in some cases have used direct injection into tissue of interest and/or high injected doses to obtain high local tissue concentrations. Recently, PARACEST agents have been used in mouse models to measure extracellular pH and enzyme activity .…”

Section: Discussionmentioning

confidence: 99%

A new paramagnetically shifted imaging probe for MRI

Senanayake

Rogers

Finney

et al. 2016

Magnetic Resonance in Med

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PurposeTo develop and characterize a new paramagnetic contrast agent for molecular imaging by MRI.MethodsA contrast agent was developed for direct MRI detection through the paramagnetically shifted proton magnetic resonances of two chemically equivalent tert‐butyl reporter groups within a dysprosium(III) complex. The complex was characterized in phantoms and imaged in physiologically intact mice at 7 Tesla (T) using three‐dimensional (3D) gradient echo and spectroscopic imaging (MRSI) sequences to measure spatial distribution and signal frequency.ResultsThe reporter protons reside ∼6.5 Å from the paramagnetic center, resulting in fast T 1 relaxation (T 1 = 8 ms) and a large paramagnetic frequency shift exceeding 60 ppm. Fast relaxation allowed short scan repetition times with high excitation flip angle, resulting in high sensitivity. The large dipolar shift allowed direct frequency selective excitation and acquisition of the dysprosium(III) complex, independent of the tissue water signal. The biokinetics of the complex were followed in vivo with a temporal resolution of 62 s following a single, low‐dose intravenous injection. The lower concentration limit for detection was ∼23 μM. Through MRSI, the temperature dependence of the paramagnetic shift (0.28 ppm.K−1) was exploited to examine tissue temperature variation.ConclusionsThese data demonstrate a new MRI agent with the potential for physiological monitoring by MRI. Magn Reson Med 77:1307–1317, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging

Cited by 43 publications

References 114 publications

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Evaluation of Eu^II‐based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections

A new paramagnetically shifted imaging probe for MRI

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Overcoming the concentration-dependence of responsive probes for magnetic resonance imaging

Cited by 43 publications

References 114 publications

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Evaluation of EuII‐based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections

A new paramagnetically shifted imaging probe for MRI

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Product

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Evaluation of Eu^II‐based positive contrast enhancement after intravenous, intraperitoneal, and subcutaneous injections