Enzyme-Activated Gd3+ Magnetic Resonance Imaging Contrast Agents with a Prominent Receptor-Induced Magnetization Enhancement

Nivorozhkin, A. L.; Kolodziej, Andrew F.; Caravan, Peter; Greenfield, Matthew T.; Lauffer, Randall B.; McMurry, Thomas J.

doi:10.1002/1521-3773(20010803)40:15<2903::aid-anie2903>3.0.co;2-n

Cited by 137 publications

(72 citation statements)

References 18 publications

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“…Conjugation of Gd-DOTA to larger molecules is known to increase relaxivity by reducing rotational correlation time. (38) This has been observed for lipophilic Gd-DOTP and Gd-DOTA complexes that bind to albumin (39,40), as well as for other Gd-DOTA conjugates (41,42).…”

Section: Resultsmentioning

confidence: 78%

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

2006

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Atherosclerosis is a leading cause of death in the U.S. Because there is a potential to prevent coronary and arterial diseases through early diagnosis, there is a need for methods to image arteries in the subclinical stage as well as clinical stage using various non-invasive techniques, including Magnetic Resonance Imaging (MRI). We describe a development of a novel MRI contrast agent targeted to plaques that will allow imaging of lesion formation. The contrast agent is directed to macrophages, one of the earliest components of developing plaques. Macrophages are labeled through the macrophage scavenger receptor A, a macrophage specific cell surface protein, using an MRI contrast agent derived from scavenger receptor ligands. We have synthesized and characterized these contrast agents with a range of relaxivities. In vitro studies show that the targeted contrast agent accumulates in macrophages and solution studies indicate that micromolar concentrations are sufficient to produce contrast in an MR image. Cell toxicity and initial biodistribution studies indicate low toxicity, no detectable retention in normal blood vessels, and rapid clearance from blood. The promising performance of this contrast agent targeted towards vascular inflammation opens doors to tracking of other inflammatory diseases such as tumor immunotherapy and transplant acceptance using MRI.

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Section: Resultsmentioning

confidence: 78%

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

2006

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“…T1-shortening MR contrast agents can, for example, be synthesized through conjugation of small ligands (e. g. small molecules, peptides, antibodies or glucose) with gadolinium chelate. The specific bond of such a probe to static or slowly-moving target structures leads to increased relaxivity, due to the so-called RIME effect (receptor-induced magnetization enhancement) [33]. An example of a contrast agent with this operating principle is gadofosveset trisodium.…”

Section: T1-shortening Contrast Agents and Molecular Probesmentioning

confidence: 99%

Molecular Imaging in Cardiovascular Diseases

Botnar

Ebersberger

Noerenberg

et al. 2015

Fortschr Röntgenstr

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Cardiovascular diseases remain the leading cause of morbidity and mortality in industrialized and developing countries. In clinical practice, the in-vivo identification of atherosclerotic lesions, which can lead to complications such as heart attack or stroke, remains difficult. Imaging techniques provide the reference standard for the detection of clinically significant atherosclerotic changes in the coronary and carotid arteries. The assessment of the luminal narrowing is feasible, while the differentiation of stable and potentially unstable or vulnerable atherosclerotic plaques is currently not possible using non-invasive imaging. With high spatial resolution and high soft tissue contrast, magnetic resonance imaging (MRI) is a suitable method for the evaluation of the thin arterial wall. In clinical practice, native MRI of the vessel wall already allows the differentiation and characterization of components of atherosclerotic plaques in the carotid arteries and the aorta. Additional diagnostic information can be gained by the use of non-specific MRI contrast agents. With the development of targeted molecular probes, that highlight specific molecules or cells, pathological processes can be visualized at a molecular level with high spatial resolution. In this review article, the development of pathophysiological changes leading to the development of the arterial wall are introduced and discussed. Additionally, principles of contrast enhanced imaging with non-specific contrast agents and molecular probes will be discussed and latest developments in the field of molecular imaging of the vascular wall will be introduced. Key Points: ??Molecular magnetic resonance imaging has great potential to improve the in vivo characterization of atherosclerotic plaques. ??Based on the molecular information is feasible to enable a better differentiation of stable and unstable (vulnerable) atherosclerotic plaques. Citation Format: ??Botnar RM, Ebersberger H, Noerenberg D et?al. Molecular imaging in cardiovascular diseases. Fortschr R?ntgenstr 2015; 187: 92???101

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“…The agent reacts with carbonic an- hydrase, and thus targets enzyme-rich tissues. Nivorozhkin et al 66 reported the enzymatic transformation of a prodrug Gd 3ϩ complex with poor affinity to HSA and low relaxivity to a species with improved HSA affinity and enhanced relaxivity. In this approach, the origin of the relaxivity increase was the slower rotation for protein-bound chelates with respect to the small-molecular-weight prodrug.…”

Section: Ph-sensitive Probesmentioning

confidence: 99%

Smart MR Imaging Agents Relevant to Potential Neurologic Applications

Bonnet¹,

Tóth²

2009

AJNR Am J Neuroradiol

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SUMMARY: Molecular imaging is aimed at the noninvasive visualization of the expression and function of bioactive molecules that often represent specific molecular signatures in disease processes. Any molecular imaging procedure requires an imaging probe that is specific to a given molecular event, which puts an important emphasis on chemistry development. In MR imaging, the past years have witnessed significant advances in the design of molecular agents, though most of these efforts have not yet progressed to in vivo studies. In this review, we present some examples relevant to potential neurobiologic applications. Our aim was to show what chemistry can bring to the area of molecular MR imaging with a focus on the 2 main classes of imaging probes: Gd 3ϩ -based and PARACEST agents. We will discuss responsive probes for the detection of metal ions such as Ca, Zn, Fe, and Cu, pH, enzymatic activity, and oxygenation state.ABBREVIATIONS: BBB ϭ blood-brain barrier; BOLD ϭ blood oxygen levelϪdependent; bpy ϭ bipyridine; C, carbon; Ca ϭ calcium; CEST ϭ chemical exchange saturation transfer; CO 3 ϭ carbonate; Cu ϭ copper; DTPA ϭ diethylene-triamine pentaacetic acid; DOTA ϭ 1,4,7,10-tetraaza-1,4,7,10-tetrakis(carboxymethyl)cyclododecane; Eu ϭ europium; Fe ϭ iron; Gd ϭ gadolinium; H ϭ hydrogen; HSA ϭ human serum albumin; k ex ϭ exchange rate; M ϭ metal ion; Mn ϭ manganese; N ϭ nitrogen; O ϭ oxygen; OH ϭ hydroxide; PARACEST ϭ paramagnetic CEST; PO 4 ϭ phosphate; q ϭ number of water molecules coordinated to Gd 3ϩ ; T 1,2e ϭ electron spin relaxation times; TPEN ϭ N,N,NЈ,NЈ-tetrakis(2-pyridylmethyl)ethylene-diamine; tpps ϭ 5,10,15,20-tetrakis-(p-sulfonatophenyl porphinate; tpy ϭ terpyridine; Yb ϭ ytterbium; Zn ϭ zinc; tau R ϭ reorientational correlation time of the molecule M olecular imaging is an emerging science area aimed at noninvasive visualization of the expression and function of bioactive molecules that often represent specific molecular signatures in disease processes. It seeks the biochemical or physiologic abnormalities underlying the disease, rather than the structural consequences of these abnormalities. Potential clinical applications of molecular imaging have been widely recognized, though the limited sensitivity and specificity of current molecular imaging approaches are often a major roadblock for clinical applications. Besides clinical settings, drug development can also largely benefit from the integration of molecular imaging. Molecular imaging not only allows rationalization of the parameters related to disease processes but it can also replace the common invasive research techniques (such as histology, which requires sacrificing animals for each time point in the experiment) by time-effective repeatable real-time visualization of biologically relevant processes. Currently, progress in the molecular imaging area is simultaneously moving at 3 levels: 1) improving the imaging hardware for use in preclinical and clinical settings, 2) identifying and validating new biologically relevant imaging targets, and 3...

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Enzyme-Activated Gd3+ Magnetic Resonance Imaging Contrast Agents with a Prominent Receptor-Induced Magnetization Enhancement

Cited by 137 publications

References 18 publications

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

Development of Contrast Agents Targeted to Macrophage Scavenger Receptors for MRI of Vascular Inflammation

Molecular Imaging in Cardiovascular Diseases

Smart MR Imaging Agents Relevant to Potential Neurologic Applications

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