Detection of in vivo enzyme activity with CatalyCEST MRI

Yoo, Byunghee; Sheth, Vipul; Howison, Christine M.; Douglas, Molly; Pineda, Carlos T.; Maine, Erin A.; Baker, Amanda F.; Pagel, Mark

doi:10.1002/mrm.24763

Cited by 52 publications

(77 citation statements)

References 40 publications

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“…Chemical exchange saturation transfer (CEST) MRI is a new type of molecular imaging method that can detect enzyme activity within in vivo tumour tissues (1). CEST MRI is initiated by selectively saturating a proton of the agent, which eliminates the net coherent magnetization of the proton.…”

Section: Introductionmentioning

confidence: 99%

“…1B). To date, CEST agents for catalyCEST MRI have been developed that detect the activity of caspase-3 (2), urokinase Plasminogen Activator (1,3), cathepsin D (4), transglutaminase (5), β-galactosidase (6), esterase (7), protein kinase A (8), and cytosine deaminase enzymes (9). …”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the larger chemical shift range facilitates the selective detection of two CEST agents during the same catalyCEST MRI study. The comparison of an enzyme-responsive CEST agent with an unresponsive CEST agent at the same concentration can provide a concentration-independent assessment of enzyme activity, which greatly improves the specificity for detecting enzyme activity (1). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Hingorani

Montano

Randtke

et al. 2015

Contrast Media & Molecular

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CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non-responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non-Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Hingorani

Montano

Randtke

et al. 2015

Contrast Media & Molecular

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“…Three recent dedicated CEST workshops (3rd, 4th, and 5th international CEST workshops in Annapolis, 2012, Torino, 2014, and Philadelphia 2016) drew about 90-200 registrants. The last decade has shown major developments for paraCEST agents, 14,15,20,89,90,119,[135][136][137][138][139][140][141][142][143][144][145][146][147][148] diaCEST agents, 12,13,17,42,43,68,72,88,102,116,125,128,[149][150][151][152][153][154][155][156][157][158][159][160] and even hyperpolarized (hyperCEST) agents. 161,162 This is not surprising in view of the number of potential applications including pH imaging, metabolite detection, ion detection, cellular protein and peptide imaging, cell labeling, temperature i...…”

Section: Potential and Clinical Translation Of Cest Methodsmentioning

confidence: 99%

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

Zijl

Sehgal

2016

eMagRes

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Proton magnetic resonance spectroscopy ( 1 H MRS) of biological systems has higher specificity than MRI because resonances of multiple metabolites can be distinguished, reflecting chemistry and physiology in situ. Unfortunately, this approach has very low sensitivity as the metabolites are typically at millimolar concentrations compared to the molar signal strength of water-based MRI. As a consequence, even though 1 H MRS is a powerful and common research tool, its inroad into daily clinical practice has been limited. Until very recently, 1 H MRS applications have focused on the resonances upfield (i.e., at lower frequency) of the water resonance. This article deals with protons that are generally not observed in a typical water-suppressed spectrum, namely, the exchangeable protons found predominantly downfield from water. These can usually be detected by MRS only if the transfer of water proton saturation (established during water suppression) is not a confounding factor, or by using water exchange (WEX) spectroscopy, in which RF labeling of the water protons is transferred to the exchangeable protons and subsequently detected. More importantly, it has recently become clear that the presence of such exchangeable protons on low concentration solute molecules can be detected via the water signal by RF labeling of these protons and subsequent transfer of this label to water protons. This process, leading to saturation of the water signal and enhancement of the effect through repeated exchange, can be used for the imaging of metabolite signals or exchangeable-proton-based contrast agents with enhanced sensitivity. This has given rise to the field of chemical exchange saturation transfer (CEST) MRI, which has greatly increased the potential for translating spectroscopic methods to the clinic. Examples include the measurement of pH, temperature, and enzyme activity as well as detection of cellular metabolites, ions, and proteins and peptides. In addition, bio-organic compounds can now be used for contrast agents, cell and nanoparticle labeling, and reporter genes.

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“…[8] The field of “catalyCEST MRI” has been used to detect enzyme-mediated catalysis of caspase-3, [7] urokinase Plasminogen Activator, [8,9] cathepsin B, [10] cathepsin D, [11] transglutaminase, [12] β-galactosidase, [13] esterase, [14] protein kinase A, [15] and cytosine deaminase [16] enzymes. In some cases, we and others have developed diamagnetic catalyCEST agents that do not require a potentially toxic metal ion, which facilitates clinical translation.…”

mentioning

confidence: 99%

A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities

2016

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The simultaneous detection of multiple enzyme activities can improve the specificity of disease diagnoses. We have synthesized and characterized a diamagnetic CEST MRI contrast agent that can simultaneously detect two enzyme activities. Sulfatase and esterase enzymes cleaved the ligands of the CEST agent, to release salicylic acid that was detected with CEST MRI. Importantly, both enzymes were required to activate the agent to produce a CEST MRI contrast, and the CEST agent was stable without enzyme treatment. These results have established that this diamagnetic CEST MRI contrast agent is a platform technology with a modular design that can be potentially exploited to detect other combinations of enzyme activities, which can expand the armamentarium of contrast agents for molecular imaging.

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Detection of in vivo enzyme activity with CatalyCEST MRI

Cited by 52 publications

References 40 publications

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Proton Chemical Exchange Saturation Transfer (CEST) MRS and MRI

A CatalyCEST MRI Contrast Agent that Can Simultaneously Detect Two Enzyme Activities

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