A Calcium-Sensitive Magnetic Resonance Imaging Contrast Agent

Li, Wen Hong; Fraser, Scott E.; Meade, Thomas J.

doi:10.1021/ja983702l

Cited by 282 publications

(244 citation statements)

References 17 publications

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“…For the 3C:1M sensor, R2 was estimated to be 220 s Ϫ1 mM Ϫ1 Fe in the calcium-free condition and 45 s Ϫ1 mM Ϫ1 Fe in 1 mM CaCl 2 ; for 3C:1R, the R2s were 200 and 34 s Ϫ1 mM Ϫ1 Fe in calcium-free and calcium conditions, respectively. These roughly 5-fold relaxivity changes are significantly greater than the approximately 2-fold R1 changes reported (8) for T1-based MRI ion sensors.…”

Section: Mri Signal Changes In Response Tomentioning

confidence: 63%

“…Because it accumulates much faster than it is removed, Mn 2ϩ produces an ''integral'' of calcium signaling history that can be detected as brightening in T1-weighted images (7). A gadolinium complex synthesized by Meade and colleagues (8) acts as a T1 calcium sensor analogous to BAPTA-based probes and may be more compatible with time-resolved calcium imaging than are either Mn 2ϩ or 19 F-BAPTA.…”

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confidence: 99%

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Calcium-sensitive MRI contrast agents based on superparamagnetic iron oxide nanoparticles and calmodulin

Atanasijević¹,

Shusteff

Fam

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

227

169

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We describe a family of calcium indicators for magnetic resonance imaging (MRI), formed by combining a powerful iron oxide nanoparticle-based contrast mechanism with the versatile calciumsensing protein calmodulin and its targets. Calcium-dependent protein-protein interactions drive particle clustering and produce up to 5-fold changes in T2 relaxivity, an indication of the sensors' potency. A variant based on conjugates of wild-type calmodulin and the peptide M13 reports concentration changes near 1 M Ca 2؉ , suitable for detection of elevated intracellular calcium levels. The midpoint and cooperativity of the response can be tuned by mutating the protein domains that actuate the sensor. Robust MRI signal changes are achieved even at nanomolar particle concentrations (<1 M in calmodulin) that are unlikely to buffer calcium levels. When combined with technologies for cellular delivery of nanoparticulate agents, these sensors and their derivatives may be useful for functional molecular imaging of biological signaling networks in live, opaque specimens. magnetic resonance ͉ T2 relaxation ͉ signal transduction ͉ molecular imaging ͉ neuroimaging C alcium ions (Ca 2ϩ ) have been a favorite target in molecular imaging studies because of the important role of calcium as a second messenger in cellular signaling pathways. Fluorescent calcium sensors are used widely in optical imaging, both at the cellular level and at the cell population level. Calcium-sensitive dyes have recently been used in conjunction with laser scanning microscopy to follow neural network activity in small, threedimensional brain areas (1) and to characterize patterns of interaction among cells in developing vertebrate embryos (2). Because of the scattering properties of dense tissue, highresolution optical approaches like these are usually limited to superficial regions of specimens and to restricted fields of view (3). To probe calcium dynamics more globally in living systems, a different imaging modality must be used.Magnetic resonance imaging (MRI) is an increasingly accessible technique for imaging opaque subjects at fairly high spatial resolution, and MRI studies of calcium dynamics could, in principle, complement optical approaches by offering both greatly expanded coverage and depth penetration in vivo (4). Calcium isotopes are unsuitable for direct imaging by magnetic resonance, so attempts to sensitize MRI to calcium have focused around the use of molecular imaging agents. Fluorinated derivatives of the bivalent cation chelator 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid (BAPTA) have permitted calcium measurements in vivo by 19 F MRI but only at Ϸ10 Ϫ5 the sensitivity of standard MRI methods (5, 6). Two potentially more powerful proton T1 relaxation-promoting contrast agents were subsequently introduced. The paramagnetic ion manganese (Mn 2ϩ ) mimics calcium by entering cells through calcium channels. Because it accumulates much faster than it is removed, Mn 2ϩ produces an ''integral'' of calcium signaling history that can be d...

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Section: Mri Signal Changes In Response Tomentioning

confidence: 63%

mentioning

confidence: 99%

Calcium-sensitive MRI contrast agents based on superparamagnetic iron oxide nanoparticles and calmodulin

Atanasijević¹,

Shusteff

Fam

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

227

169

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“…A contrast agent sensor designed for real-time calcium imaging was developed by Li et al [19]. The agent was formed by attaching the calcium chelator 1,2-bis-(O-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA) to two copies of the highly paramagnetic gadolinium complex Gd 3+ -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA); the agent undergoes a change in T 1 relaxivity (a measure of efficacy) near 1 μM Ca 2+ .…”

Section: Indicators For Ca 2+ and Other Metal Ionsmentioning

confidence: 99%

“…Sensors may be based on modulation of the exchange rate or resonance frequency of labile protons on a CEST agent. (D) Contrast agents incorporating 13 C, 19 F, or a variety of other nuclei may be imaged directly using modified MRI hardware. Images of 13 C agent distribution may be formed, analogous to standard proton images, but typically with much lower resolution and signal-to-noise ratio.…”

Section: Boldmentioning

confidence: 99%

“…Most MRI contrast agents are paramagnetic chemicals that increase parameters called the T 1 and T 2 relaxation rates of water, as observed in tissue and solution; T 1 or T 2 relaxation enhancements produce image brightening or darkening, respectively. Additional classes of contrast agents work by a chemical exchangebased mechanism called CEST [5], or involve imaging nonstandard nuclei like 19 F and 13 C. The characteristics and physical mechanisms of different types of contrast agent are discussed at length in a number of book chapters and reviews [6][7][8][9][10][11], and are summarized in Figure 1. In general, for any agent to be used in functional imaging, either its ability to influence MRI contrast or its spatial distribution must be sensitized to neural activity in some way.…”

Section: Introductionmentioning

confidence: 99%

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MRI contrast agents for functional molecular imaging of brain activity

Jasanoff

2007

Current Opinion in Neurobiology

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SummaryFunctional imaging with MRI contrast agents is an emerging experimental approach that can combine the specificity of cellular neural recording techniques with noninvasive whole-brain coverage. A variety of contrast agents sensitive to aspects of brain activity have recently been introduced. These include new probes for calcium and other metal ions that offer high sensitivity and membrane permeability, as well as imaging agents for high resolution pH and metabolic mapping in living animals. Genetically-encoded MRI contrast agents have also been described. Several of the new probes have been validated in the brain; in vivo use of other agents remains a challenge. This review outlines advantages and disadvantages of specific molecular imaging approaches and discusses current or potential applications in neurobiology.

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Imaging

Mazziotta¹

2000

Arch Neurol

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Given the rapid advances in neuroimaging and brain mapping, it is no surprise that a whole host of new and burgeoning techniques are on the horizon as we enter the 21st century. This brief review focuses on methods that are just entering the clinical experience or are now being explored in a research setting but have the imminent potential for clinical use. A number of brain mapping techniques now allow the clinician to monitor disease progression and therapeutic effects in either the routine clinical setting or experimental clinical trials. A battery of methods are now available for the preoperative and intraoperative evaluation of patients with lesions in or near critical cortical areas or for targeting purposes when deep nuclei of the brain are potential sites of therapeutic ablation or electrophysiologic stimulation. The development of probabilistic atlases will soon provide a means of understanding normal variants of human brain structure and function and studying brain disorders and their treatment in an objective and quantifiable fashion. Techniques that are now on the horizon for imaging gene expression, neuronal excitivity, and connectivity are presented in their current stage of development. It is clear that brain mapping and neuroimaging will continue to be ever more important parts of clinical neuroscience and may ultimately serve as the bridge between the molecular and clinical domains of this field. Arch Neurol. 2000;57:1413-1421

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A Calcium-Sensitive Magnetic Resonance Imaging Contrast Agent

Cited by 282 publications

References 17 publications

Calcium-sensitive MRI contrast agents based on superparamagnetic iron oxide nanoparticles and calmodulin

Calcium-sensitive MRI contrast agents based on superparamagnetic iron oxide nanoparticles and calmodulin

MRI contrast agents for functional molecular imaging of brain activity

Imaging

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