Albumin binding of paramagnetic hepatobiliary contrast agents: enhancement of outer sphere relaxivity.
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Biliary Tract↗
Biomedical subjects
R B Lauffer
Publications and source records attributed to R B Lauffer.
Iron-EHPG as an hepatobiliary MR contrast agent: initial imaging and biodistribution studies.
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Animals↗
Hepatobiliary MR contrast agents: 5-substituted iron-EHPG derivatives.
A series of iron(III) ethylenebis(2-hydroxyphenyl)glycine [Fe(EHPG)]- derivatives have been examined for their role as paramagnetic hepatobiliary contrast agents for magnetic resonance (MR) imaging. The 5-substituted complexes, Fe(5-Me-EHPG)-, Fe(5-Cl-EHPG)-, and Fe(5-Br-EHPG)-, have been compared to the parent compound in rat biodistribution and MR imaging studies; correlative in vitro parameters for the complexes, including octanol-buffer partition coefficients and albumin binding affinity, have also been obtained. The three new derivatives exhibited higher degrees of lipophilicity and albumin binding affinity and varying degrees of improvement in liver-to-blood and bile-to-liver concentration ratios measured at 30 min postinjection. The 5-Cl complex had the best overall performance in terms of these tissue ratios as well as in terms of total biliary excretion. Sequential MR images of rats after administration of the complexes revealed subtle pharmacokinetic differences among the derivatives and, in general, correlated well with and complemented the biodistribution results. This study points to the sensitivity of hepatocellular uptake and excretion to simple chemical modifications and, moreover, demonstrates the importance of screening multiple derivatives to select optimal hepatobiliary MR imaging agents.
Animals↗
Use of gadolinium-DTPA as a myocardial perfusion agent: potential applications and limitations for magnetic resonance imaging.
To establish the effect of the paramagnetic contrast agent gadolinium diethylenetriaminepentaacetic acid ([Gd]DTPA) on myocardial magnetic resonance relaxation parameters T1 and T2, and its relationship to myocardial perfusion, we administered [Gd] DTPA 0.2 mM/kg to two groups of dogs. Group I had severe, resting myocardial ischemia induced by coronary occlusion, followed in 2 min by [Gd]DTPA infusion and heart excision 1 min later. Group II had a variable reduction in blood flow. In Group II the coronary vasodilator dipyridamole was infused to enhance blood flow to the normal myocardium before [Gd]DTPA was given. In Group I [Gd]DTPA caused a significant difference in T1 between the normal and severely ischemic zones; changes in T1 correlated with the severity of myocardial ischemia. Although vasodilatation delivered more Gd-DTPA to the normal myocardium in Group II, the lack of further decrease in T1 suggested that it was cleared more rapidly. Thus, [Gd]DTPA permits the detection and characterization of severe, resting myocardial ischemia by magnetic resonance techniques. Using the experimental techniques described in this study, less severe flow differences caused by vasodilatation and resultant hyperemia are not detected.
Animals↗
1/T1 NMRD profiles of solutions of Mn2+ and Gd3+ protein-chelate conjugates.
Bovine immunoglobulins (IgG) and bovine serum albumin (BSA) were multiply labeled with multidentate ligands, either ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA), and metal ions were inserted to form the ternary protein-ligand-ion conjugates. The NMRD profiles (the magnetic field dependence of 1/T1) of solutions of the ternary conjugates differ greatly from those of the corresponding binary ligand-metal-ion complexes, both in magnitude and functional form, exhibiting 5- to 10-fold greater relaxivities and prominent peaks near 20 MHz. The inference is that the protein-bound chelates are relatively rigidly attached to the macromolecules. The structure and metal ion affinities of these novel conjugates, as well as the relevance to contrast enhancement in NMR imaging, is discussed.
Binding Sites↗
Preparation and water relaxation properties of proteins labeled with paramagnetic metal chelates.
The proteins bovine serum albumin (BSA) and bovine immunoglobulin (IgG) have been labeled with paramagnetic gadolinium (III) and manganese (II) complexes using the bifunctional chelate approach. Diethylenetriaminepentaacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) were attached to several free amino groups on the proteins using cyclic anhydride forms of these ligands. The incorporation of the metal ions Gd+3 and Mn+2 into the chelating groups yielded highly paramagnetic proteins. The water relaxation ability (or relaxivity) of the protein-bound chelates at 20 MHz was found to be superior to that of the free metal complexes. Differences in relaxivity between the DTPA and EDTA conjugates could largely be accounted for by differences in the metal ion exposure to water. This labeling technique can be used in the preparation of intravascular NMR contrast agents (like paramagnetically-labeled human serum albumin) or target-specific agents (labeled monoclonal antibodies or fibrinogen).
Contrast Media↗
Pulse sequence optimization for MR imaging using a paramagnetic hepatobiliary contrast agent.
Paramagnetic agents enhance contrast between tissues in magnetic resonance (MR) imaging by altering tissue relaxation times. The effect of these changes on MR image intensity depends in part on the choice of operator-controlled pulse sequence parameters. With the newly described paramagnetic hepatobiliary contrast agent, iron(III) ethylenebis-(2-hydroxyphenylglycine), Fe(EHPG)-, an in vivo experimental analysis of pulse sequence optimization was performed on the rat. We compared the enhancement of the liver divided by background noise, EL/N, of standard inversion-recovery (IR) and spin-echo (SE) T1-weighted pulse sequences and several pulse sequences theoretically predicted to have improved EL/N. Optimization of the echo time (TE = TEmin) gave a substantial (greater than 60%) increase in EL/N over the standard IR and SE pulse sequences. Images obtained with optimized repetition rate and inversion time gave only a slight additional improvement. Within the uncertainties of our relaxation measurements, the measured changes in EL/N with pulse sequence optimization corresponded well with theoretical predictions. With the experimental and theoretical data, the importance of using a short echo time to obtain maximal T1 contrast in contrast-enhanced MR imaging and the relative merits of optimized SE versus IR pulse sequences for contrast-enhanced MR imaging are discussed.
Animals↗
Contrast agents and spectroscopic probes in NMR.
The demand for higher diagnostic specificity has led to the increased use of "foreign" agents to increase tissue contrast and/or spectroscopic sensitivity in NMR studies. The primary agents used to enhance tissue contrast in NMR imaging are paramagnetic. They cause a decrease in the proton T1 of H2O leading to enhanced signal intensity. This effect depends on the large gyromagnetic ratio of the electron, the number of unpaired electrons, the concentration of paramagnetic ions, the number of coordinated water molecules, and the rate of exchange of water. Spectroscopic enhancement has relied primarily on attempt at isotopic enrichment (usually C-13), which causes a direct increase in signal.
Carbon Isotopes↗
1H NMR studies of porcine uteroferrin. Magnetic interactions and active site structure.
Pink (reduced) uteroferrin exhibits well resolved paramagnetic NMR spectra with resonances ranging from 90 ppm downfield to 70 ppm upfield. The intensities of these signals depend on the degree of reduction and correlate well with the intensity of the EPR signals with gave = 1.74. Analyses of chemical shifts and the temperature dependence of the paramagnetically shifted resonances indicate that the Fe(III)-Fe(II) cluster in the reduced protein exhibits weak antiferromagnetic exchange coupling (-J approximately equal to 10 cm-1), in agreement with the estimate derived from the temperature dependence of the EPR signal intensity. Purple (oxidized) uteroferrin, on the other hand, exhibits no discernible paramagnetically shifted resonances, reflecting either strong antiferromagnetic coupling or an unfavorable electron spin-lattice relaxation time. Evans susceptibility comparisons between pink and purple uteroferrin show that the Fe(III)-Fe(III) cluster in the oxidized protein is more strongly coupled (-J greater than 40 cm-1). This value concurs with low temperature magnetic susceptibility measurements on both the porcine and splenic purple acid phosphatases. The isotropically shifted protons of tyrosine coordinated to the cluster are assigned by comparison with synthetic complexes. Tyrosine, earlier implicated as a ligand by resonance Raman spectroscopy, appears to coordinate only to the ferric site in pink uteroferrin. This is consistent with the relatively invariant extinction coefficients of uteroferrin in its oxidized and reduced forms and the ease of reduction of the nonchromophoric iron compared to its chromophoric partner. Other possible ligands to the cluster include histidine, suggested by the presence of downfield-shifted solvent-exchangeable resonances with appropriate isotropic shifts.
Acid Phosphatase↗
Intravascular contrast agent improves magnetic resonance angiography of carotid arteries in minipigs.
This study was designed to optimize three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) sequences and to determine whether contrast-enhanced MRA could improve the accuracy of lumen definition in stenosed carotid arteries of minipigs. 3D TOF MRA was acquired with use of either an intravascular (n = 13) and/or an extravascular contrast agent (n = 5) administrated at 2 to 4 weeks after balloon-induced injury to a carotid artery in 16 minipigs. Vascular contrast, defined as signal intensity differences between blood vessels and muscle normalized to the signal intensity of muscle, was compared before and after the injection of each contrast agent and between the two agents. Different vascular patencies were observed among the animals, including completely occluded vessels (n = 5), stenotic vessels (n = 3), and vessels with no visible stenosis (n = 8). Superior vascular contrast improvement was observed for small arteries and veins and for large veins with the intravascular contrast agent when compared with the extravascular contrast agent. In addition, preliminary studies in two of the animals showed a good correlation for the extent of luminal stenosis defined by digital subtraction angiography compared with MRA obtained after administration of the intravascular contrast agent (R2 = .71, with a slope of .96 +/- .04 by a linear regression analysis). We concluded that use of an intravascular contrast agent optimizes 3D TOF MRA and may improve its accuracy compared with digital subtraction angiography.
Animals↗
Iron-EHPG as an hepatobiliary MR contrast agent: initial imaging and biodistribution studies.
The paramagnetic metal complex iron(III) ethylenebis-(2-hydroxyphenylglycine) [Fe(EHPG)-] is an effective hepatobiliary contrast agent for liver enhancement in magnetic resonance (MR) imaging. The intravenous administration of 0.2 mmol/kg of Fe(EHPG)- to rats yields a 200% increase in the signal intensity of the liver when using a T1-weighted inversion recovery pulse sequence on a 1.4 T imaging system. Biodistribution studies in rats and a rabbit, along with imaging studies in a dog at 0.6 T, confirm that the complex has significant hepatocellular uptake and appears to be excreted unaltered into the bile. Control experiments with a different iron complex, iron(III) diethylenetriaminepentaacetic acid, reveal little hepatic affinity and poor enhancement capability due to its extracellular distribution. This initial evaluation of Fe(EHPG)- demonstrates that paramagnetic metal complexes with hepatobiliary specificity are well suited for enhancement of normal liver parenchyma and may increase the sensitivity of MR in the detection of liver disease.
Animals↗