On-bead combinatorial synthesis and imaging of chemical exchange saturation transfer magnetic resonance imaging agents to identify factors that influence water exchange

The sensitivity of magnetic resonance imaging (MRI) contrast agents is highly dependent on the rate of water exchange between the inner sphere of a paramagnetic ion and bulk water. Normally, identifying a paramagnetic complex that has optimal water exchange kinetics is done by synthesizing and testing one compound at a time. We report here a rapid, economical on-bead combinatorial synthesis of a library of imaging agents. Eighty different 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetraacetic acid (DOTA)-tetraamide peptoid derivatives were prepared on beads using a variety of charged, uncharged but polar, hydrophobic, and variably sized primary amines. A single chemical exchange saturation transfer image of the on-bead library easily distinguished those compounds having the most favorable water exchange kinetics. This combinatorial approach will allow rapid screening of libraries of imaging agents to identify the chemical characteristics of a ligand that yield the most sensitive imaging agents. This technique could be automated and readily adapted to other types of MRI or magnetic resonance/positron emission tomography agents as well.     

A myelin-specific contrast agent for magnetic resonance imaging of myelination

Myelination is one of the most fundamental biological processes in the development of vertebrate nervous systems. Abnormal or disrupted myelination occurs in many acquired or inherited neurodegenerative diseases, including multiple sclerosis (MS) and various leukodystrophies. To date, magnetic resonance imaging (MRI) has been the primary tool for diagnosing and monitoring the progression of MS and related diseases; however, any change in signal intensity of conventional MRI reflects a change only in tissue water content, which is a nonspecific measure of the overall changes in macroscopic tissue injury. Thus, the use of MRI as a primary measure of disease activity was shown to be disassociated from the clinical outcome due to the lack of specificity for myelination. In order to increase the MRI specificity for myelin pathologies, we designed and synthesized the first Gd-based T(1) MR contrast agent (MIC) that binds to myelin with high specificity. In this Communication, we demonstrate that MIC localizes in brain regions in proportion to the extent of myelination. In addition, MIC possesses promising MR contrast properties, which allow for direct detection of myelin distribution through T(1) mapping in the mouse brain.     

Size-induced enhancement of chemical exchange saturation transfer (CEST) contrast in liposomes

Liposome-based chemical exchange saturation transfer (lipoCEST) agents have shown great sensitivity and potential for molecular magnetic resonance imaging (MRI). Here we demonstrate that the size of liposomes can be exploited to enhance the lipoCEST contrast. A concise analytical model is developed to describe the contrast dependence on size for an ensemble of liposomes. The model attributes the increased lipoCEST contrast in smaller liposomes to their larger surface-to-volume ratio, causing an increased membrane water exchange rate. Experimentally measured rates correlate with size, in agreement with the model. The water permeability of liposomal membrane is found to be 1.11 +/- 0.14 microm/s for the specific lipid composition at 22 degrees C. Availability of the model allows rational design of the size of liposomes and quantification of their properties. These new theoretical and experimental tools are expected to benefit applications of liposomes to sensing the cellular environment, targeting and imaging biological processes, and optimizing drug delivery properties.     

A magnetic resonance imaging contrast agent capable of detecting hydrogen peroxide

The redox-active ligand N-(2-hydroxy-5-methylbenzyl)-N,N',N'-tris(2-pyridinylmethyl)-1,2-ethanediamine (Hptp1) was prepared and complexed to manganese(II). The isolated [Mn(Hptp1)(MeCN)](2+) serves as a magnetic resonance imaging contrast agent, with an r(1) value comparable to those of other mononuclear gadolinium(III) and manganese(II) complexes. The metal and ligand are stable in aerated aqueous solutions, but the addition of H(2)O(2) causes the complex to oxidatively couple to itself through a bimolecular reaction involving the phenol groups of two Hptp1 ligands. The binuclear product is less paramagnetic per manganese(II) than its mononuclear precursor, lowering the measured r(1) per manganese(II). The manganese(II) complex with Hptp1 can thereby serve as a sensor for oxidative stress.     

An esterase-activated magnetic resonance contrast agent

A Gd(III) complex bearing pendant acetoxymethyl esters is activated on exposure to porcine liver esterase; the 84% increase in relaxivity is a result of suppression of HCO(3)(-)/CO(3)(2-) binding by the resulting negative charge.     

Nanoshell magnetic resonance imaging contrast agents

Nanocontrast agents have great potential in magnetic resonance (MR) molecular imaging applications for clinical diagnosis. We synthesized Au(3)Cu(1) (gold and copper) nanoshells that showed a promising MR contrast effect. For in vitro MR images, the large proton r1 relaxivities brightened T(1)-weighted images. As for the proton-dephasing effect in T(2), Au(3)Cu(1) lightened MR images at the low concentration of 0.125 mg mL(-1) (3.84 x 10(-7) mM), and then the signal continuously decreased as the concentration increased. For in vivo MR imaging, Au(3)Cu(1) nanocontrast agents enhanced the contrast of blood vessels and suggested their potential use in MR angiography as blood-pool agents. We propose that (1) the cooperativity originating from the form of the nanoparticles and (2) the large surface area coordinated to water from their porous hollow morphology are important for efficient relaxivity. In a cytotoxicity and animal survival assay, Au(3)Cu(1) nanocontrast agents showed a dose-dependent toxic effect: the viability rate of experimental mice reached 83% at a dose of 20 mg kg(-1) and as much as 100% at 2 mg kg(-1).     

靶向淋巴系统造影剂的制备及其动物实验

采用两种方法,一种方法是以右旋糖酐（Dextran）和DTPA的二酐为原料,DMAP为催化剂,另一种是以右旋糖酐和DTPA为原料,采用DMAP及EDC.HCl为联合催化剂,合成造影剂Dextran-DTPA-Gd.通过比较产物的水溶性及Gd含量确定了最佳制备条件,得到了钆含量为16.1%、水溶性好的高分子造影剂;通过FTIR、粒度分析表征了Dextran-DTPA-Gd的结构及其分子粒径大小（分布范围为100～150nm,平均值为130nm）;动物实验中,以钆喷酸葡胺注射液（Magnevist）为阳性对照,通过对比家兔腿部磁共振成像图,绘制腿部淋巴系统信号增强率-时间曲线,证明Dextran-DTPA-Gd具有更高的信号增强效果（最高值为314%）及淋巴系统选择性的特点,为其进一步应用奠定了基础.     

A smart magnetic resonance imaging contrast agent responsive to adenosine based on a DNA aptamer-conjugated gadolinium complex

We report a general strategy for developing a smart MRI contrast agent for the sensing of small molecules such as adenosine based on a DNA aptamer that is conjugated to a Gd compound and a protein streptavidin. The binding of adenosine to its aptamer results in the dissociation of the Gd compound from the large protein, leading to decreases in the rotational correlation time and thus change of MRI contrast.     

Design and synthesis of a novel magnetic resonance imaging contrast agent for selective sensing of zinc ion

A series of new diethylenetriaminepentaacetic acid (DTPA)-bisamide chelators has been prepared and characterized for application as zinc sensors. We have designed and synthesized (GdL(a))(2-), which contains a DTPA-bisamide moiety. The R(1) relaxivity of (GdL(a))(2-) solution decreased monotonically on the addition of Zn(2+). Moreover, (GdL(a))(2-) showed high selectivity for Zn(2+) against Ca(2+) and Mg(2+). We also measured the UV-visible spectra and the coldspray ionization (CSI) MS spectra and concluded that the 1-to-1 Zn(2+) complex of (GdL(a))(2-) is stable at higher concentrations of Zn(2+). These complexes should provide the basis for creating a superior Zn(2+)-sensitive MRI contrast agent and are excellent candidates for incorporation into sensors designed for selective detection of Zn(2+) in biological applications.     

The detection of tetrahydrofuran hydrate formation and saturation using magnetic resonance imaging technique

Tetrahydrofuran (THF) hydrate was formed in bulk as well as in glass beads pack with a mean diameter of 3.0 mm by controlling the temperature under ambient pressure. Images of THF hydrate formation procedure were obtained using the magnetic resonance imaging (MRI) technique. The experiment results showed that MRI is an effective method for the detection of hydrate formation. Saturation of hydrate formed both in bulk and glass beads can be confirmed by intensity integration of MRI images.     

Mannan-coated liposome delivery of gadolinium-diethylenetriaminepentaacetic acid, a contrast agent for use in magnetic resonance imaging.

Gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), a paramagnetic contrast agent for use in magnetic resonance imaging (MRI) was bound to stearylamine and incorporated into the liposomal membranes (Gd-DTPA liposomes). In addition, the Gd-DTPA liposomes were coated with mannan (cholesterol-aminoethylcarbamylmethyl mannan), a polysaccharide, to obtain the mannan-coated liposomes. An in vitro MRI study showed that the Gd-DTPA liposomes produced a greater intensity of contrast than did the Gd-DTPA solution with a reduced T1 relaxation time. Intravenous injection of the Gd-DTPA liposomes containing 153Gd or liposomes containing 153Gd or 14C-DTPA to mice showed an accumulation of Gd-DTPA primarily in the liver and lung. When the mannan-coated liposomes were administered, an increased uptake of Gd-DTPA by these tissues was demonstrated. The mannan-coated liposomes may enhance contrast of the liver in MRI at a lower dose of Gd-DTPA.     

Synthesis of NanoQ, a copper-based contrast agent for high-resolution magnetic resonance imaging characterization of human thrombus

A new site-targeted molecular imaging contrast agent based on a nanocolloidal suspension of lipid-encapsulated, organically soluble divalent copper has been developed. Concentrating a high payload of divalent copper ions per nanoparticle, this agent provides a high per-particle r1 relaxivity, allowing sensitive detection in T1-weighted magnetic resonance imaging when targeted to fibrin clots in vitro. The particle also exhibits a defined clearance and safety profile in vivo.     

A Gd3+-based magnetic resonance imaging contrast agent sensitive to beta-galactosidase activity utilizing a receptor-induced magnetization enhancement (RIME) phenomenon

Magnetic resonance imaging (MRI) permits noninvasive three-dimensional imaging of opaque organisms. Gadolinium (Gd(3+)) complexes have become important imaging tools as MRI contrast agents for MRI studies, though most of them are nonspecific and report solely on anatomy. Recently, MRI contrast agents have been reported whose ability to relax water protons is triggered or greatly enhanced by recognition of a particular biomolecule. This new class of MRI contrast agents could open up the possibility of reporting on the physiological state or metabolic activity deep within living specimens. One possible strategy for this purpose is to utilize the increase in the longitudinal water proton r(1) relaxivity that occurs upon slowing the molecular rotation of a small paramagnetic complex, a phenomenon which is known as receptor-induced magnetization enhancement (RIME), by either binding to a macromolecule or polymerization of the agent itself. Here we describe the design and synthesis of a novel beta-galactosidase-activated MRI contrast agent, the Gd(3+) complex [Gd-5], by using the RIME approach. beta-Galactosidase is commonly used as a marker gene to monitor gene expression. This newly synthesized compound exhibited a 57% increase in the r(1) relaxivity in phosphate-buffered saline (PBS) with 4.5% w/v human serum albumin (HSA) in the presence of beta-galactosidase. Detailed investigations revealed that RIME is the dominant factor in this increase of the observed r(1) relaxivity, based on analysis of Gd(3+) complexes [Gd-5] and [Gd-8], which is generated from [Gd-5] by the activity of beta-galactosidase, and spectroscopic analysis of their corresponding Tb(3+) complexes, [Tb-5] and [Tb-8].     

Inulin as a carrier for contrast agents in magnetic resonance imaging

Magnetic resonance angiography (MRA) has put forth an impetus for the development of macromolecular GdIII complexes that have a prolonged lifetime in the vascular system. Herein, we report the synthesis and GdIII complexation of a new sugar conjugate based on inulin and the DO3A ligand (DO3A = 1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid). Two API-DO3ASQ conjugates (API = O-(aminopropyl)inulin, SQ = squaric acid = 3,4-dihydroxy-3-cyclobutene-1,2-dione) with different degrees of substitution (ds = 0.7 and ds = 1.5) were prepared from API by using the diethyl ester of squaric acid as a linking agent for the DO3A chelate. The efficacies of the resulting GdIII compounds were evaluated by investigation of their water 1H longitudinal-relaxation-rate enhancements at variable field (NMRD). A dramatic increase in relaxivity was observed in the more highly substituted conjugate (ds = 1.5); this prompted us to do a variable-temperature (17)O study in order to further characterize the relaxation parameters involved in this system. [Gd(API-DO3ASQ)] shows promising properties for application as a contrast agent for MRI.