Bifunctional Chelates Optimized for Molecular MRI – ScienceOpen
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      Bifunctional Chelates Optimized for Molecular MRI

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          Abstract

          Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α 1 R4 R7 R10 R)-α 14710-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, 17O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin–avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent.

          Abstract

          Multigram preparation of enantiopure bifunctional derivatives of DOTMA for Gd-based contrast agents will enable coupling to targeting systems via click or amide-bond chemistry. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Using biotin−avidin complexation to compare constrained systems, the Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C compared to the DOTA analogue, which could increase its sensitivity as an efficient MRI agent.

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          Neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation. Magnetic resonance imaging (MRI) techniques sensitive to changes in cerebral blood flow and blood oxygenation were developed by high-speed echo planar imaging. These techniques were used to obtain completely noninvasive tomographic maps of human brain activity, by using visual and motor stimulus paradigms. Changes in blood oxygenation were detected by using a gradient echo (GE) imaging sequence sensitive to the paramagnetic state of deoxygenated hemoglobin. Blood flow changes were evaluated by a spin-echo inversion recovery (IR), tissue relaxation parameter T1-sensitive pulse sequence. A series of images were acquired continuously with the same imaging pulse sequence (either GE or IR) during task activation. Cine display of subtraction images (activated minus baseline) directly demonstrates activity-induced changes in brain MR signal observed at a temporal resolution of seconds. During 8-Hz patterned-flash photic stimulation, a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.8% (GE) and 1.8% +/- 0.9% (IR) was observed in the primary visual cortex (V1) of seven normal volunteers. The mean rise-time constant of the signal change was 4.4 +/- 2.2 s for the GE images and 8.9 +/- 2.8 s for the IR images. The stimulation frequency dependence of visual activation agrees with previous positron emission tomography observations, with the largest MR signal response occurring at 8 Hz. Similar signal changes were observed within the human primary motor cortex (M1) during a hand squeezing task and in animal models of increased blood flow by hypercapnia. By using intrinsic blood-tissue contrast, functional MRI opens a spatial-temporal window onto individual brain physiology.
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            Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells.

            Magnetic resonance (MR) tracking of magnetically labeled stem and progenitor cells is an emerging technology, leading to an urgent need for magnetic probes that can make cells highly magnetic during their normal expansion in culture. We have developed magnetodendrimers as a versatile class of magnetic tags that can efficiently label mammalian cells, including human neural stem cells (NSCs) and mesenchymal stem cells (MSCs), through a nonspecific membrane adsorption process with subsequent intracellular (non-nuclear) localization in endosomes. The superparamagnetic iron oxide nanocomposites have been optimized to exhibit superior magnetic properties and to induce sufficient MR cell contrast at incubated doses as low as 1 microg iron/ml culture medium. When containing between 9 and 14 pg iron/cell, labeled cells exhibit an ex vivo nuclear magnetic resonance (NMR) relaxation rate (1/T2) as high as 24-39 s-1/mM iron. Labeled cells are unaffected in their viability and proliferating capacity, and labeled human NSCs differentiate normally into neurons. Furthermore, we show here that NSC-derived (and LacZ-transfected), magnetically labeled oligodendroglial progenitors can be readily detected in vivo at least as long as six weeks after transplantation, with an excellent correlation between the obtained MR contrast and staining for beta-galactosidase expression. The availability of magnetodendrimers opens up the possibility of MR tracking of a wide variety of (stem) cell transplants.
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              We investigated the potential of magnetic resonance imaging (MRI) to track magnetically labeled mesenchymal stem cells (MR-MSCs) in a swine myocardial infarction (MI) model. Adult farm pigs (n=5) were subjected to closed-chest experimental MI. MR-MSCs (2.8 to 16x107 cells) were injected intramyocardially under x-ray fluoroscopy. MRIs were obtained on a 1.5T MR scanner to demonstrate the location of the MR-MSCs and were correlated with histology. Contrast-enhanced MRI demonstrated successful injection in the infarct and serial MSC tracking was demonstrated in two animals. MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of MSCs in MI.
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                Author and article information

                Journal
                Inorg Chem
                Inorg Chem
                ic
                inocaj
                Inorganic Chemistry
                American Chemical Society
                0020-1669
                1520-510X
                16 June 2015
                16 June 2014
                07 July 2014
                : 53
                : 13
                : 6554-6568
                Affiliations
                []Hillman Cancer Center, University of Pittsburgh Medical Center , 5117 Centre Avenue, Pittsburgh, Pennsylvania 15213, United States
                []Department of Chemistry and Biochemistry, San Diego State University , 5500 Campanile Drive, San Diego, California 92182-1030, United States
                [§ ]Department of General, Organic and Biomedical Chemistry, University of Mons , 7000 Mons, Hainaut, Belgium
                []Department of Chemistry and Biochemistry, University of California , San Diego, La Jolla, California 92093-0385, United States
                Author notes
                Article
                10.1021/ic500085g
                4095910
                24933389
                cffb0e5e-a1e2-4b04-b99c-ece0986af6b3
                Copyright © 2014 American Chemical Society

                Terms of Use

                History
                : 14 January 2014
                Funding
                National Institutes of Health, United States
                Categories
                Article
                Custom metadata
                ic500085g
                ic-2014-00085g

                Inorganic & Bioinorganic chemistry
                Inorganic & Bioinorganic chemistry

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