Magnetic resonance angiography at 0.3 T using MS-325.

Preliminary results on MS-325 versus ProHance enhanced magnetic resonance angiography (MRA) at low field strength in a rabbit model are reported. MS-325-enhanced images were acquired in vivo and compared with pre-contrast as well as conventional contrast-enhanced images. Visual image quality observations correlated with measurements of signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). While published in vitro data show 7-fold greater relaxivity for MS-325 compared with conventional contrast agents, we observed an even greater effect here due, presumably, to better matching of the longer vascular lifetime with longer scan time in this study. In addition, overall vessel clarity improved significantly throughout all the phases of the experiment in MS-325-enhanced images when compared with conventional contrast-enhanced images.

Blood pool agent strongly improves 3D magnetic resonance coronary angiography using an inversion pre-pulse.

The ability of a blood pool contrast agent to enhance MR coronary angiography was defined. The proximal coronary vessels of pigs were imaged before and after administration of Gd-DTPA bound covalently to bovine serum albumin (0.2 mmol/ kg). The contrast agent resulted in a reduction of the blood T1 value to 33+/-5 msec, as determined in vivo with a Look-Locker technique. Both 2D and 3D imaging techniques were performed. An inversion pulse suppressed the signal of nonblood tissue postcontrast. After contrast agent administration, in the 3D data set the signal-to-noise ratio (SNR) of blood and contrast-to-noise ratio (CNR) of blood to myocardium were improved by factors of 2.0+/-0.2 and 15+/-8, respectively (P < 0.05). Postcontrast, the 3D acquisition was superior to the 2D technique in terms of spatial resolution, SNR of blood, and CNR of blood to myocardium. The high contrast of the 3D data set allowed for direct and rapid display of coronary arteries using a "closest vessel projection."

Three-dimensional MRI of coronary arteries using an intravascular contrast agent.

To assess the effectiveness of an intravascular contrast agent, MS-325, for enhancing the vascular signal in coronary MR angiograms, six minipigs were studied using a three-dimensional, gradient-echo sequence with retrospective respiratory gating. To suppress the myocardial signal, preparatory RF pulses were applied before data acquisition. With the administration of MS-325, the blood signal-to-noise ratio increased by 97-276%, depending on the region of interest in which the blood signal was measured and the precontrast imaging sequence structures. The blood/myocardium contrast-to-noise ratio also significantly increased. High-resolution images (0.58 x 0.58 x 1 mm3) obtained from postmortem pig hearts demonstrated the potential delineation of coronary arteries with MS-325. In conclusion, this study supports further evaluation of the utility of MS-325 in improving coronary MR angiography in humans.

MS-325: albumin-targeted contrast agent for MR angiography.

PURPOSE: To evaluate the protein-binding and signal enhancement characteristics of MS-325, a gadolinium-based magnetic resonance (MR) imaging blood pool agent that binds to albumin, and compare results with those obtained with existing gadolinium- and iron oxide-based agents. MATERIALS AND METHODS: Protein binding in human plasma was measured by means of ultrafiltration. T1 relaxation times (20 MHz) were measured in human plasma or ex vivo samples from rabbits and monkeys injected with 0.1 mmol of MS-325 per kilogram of body weight. Imaging (three-dimensional fast imaging with steady-state precession, or FISP) was performed at 1.0 T in phantoms, which contained varying concentrations of different agents, or rabbits after injection of 0.015-0.100 mmol/kg MS-325. RESULTS: MS-325 is 80%-96% bound in human plasma and exhibits a relaxivity approximately six to 10 times that of gadolinium diethylenetriaminepentaacetic acid (DTPA). Images of phantoms containing MS-325 were significantly brighter than those containing existing gadolinium chelates or iron particles (monocrystalline iron oxide nanoparticle, or MION) at equivalent concentrations. Findings of in vivo studies indicated strong, persistent plasma T1 reduction with MS-325 for 1 hour (T1 of MS-325, 50-100 msec; T1 of Gd-DTPA, 200-400 msec) and strong vascular enhancement on MR images. CONCLUSION: MS-325 is highly protein bound after injection and provides vascular signal enhancement superior to that provided with other agents. As the first gadolinium-based blood pool agent in human trials, MS-325 has the potential to enhance both dynamic and steady-state MR angiograms.

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.

Preclinical evaluation of the pharmacokinetics, biodistribution, and elimination of MS-325, a blood pool agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors evaluate MS-325, a new albumin-targeted magnetic resonance imaging (MRI) contrast agent, for its pharmacokinetics, biodistribution, and elimination characteristics in multiple animal species. METHODS: Studies were performed in rats, rabbits, and nonhuman primates at intravenous doses ranging from 0.025 to 0.20 mmol/kg. Concentrations of MS-325 in blood, urine, feces, and organs were determined using gadolinium-153-labeled MS-325 and gamma counting or by using non-labeled MS-325 and inductively coupled plasma atomic emission spectrometry. RESULTS: In rabbits and nonhuman primates, MS-325 is approximately 85% to 95% bound to serum proteins and, as a result, exhibits low volume of distribution (Vd) values, 0.11 to 0.14 L/kg, and a long elimination half-life (Te1/2), 2 to 3 hours. Some dose-dependence in the parameters is apparent in rabbits. MS-325 is eliminated primarily through the renal system in non-human primates. In contrast, the behavior of MS-325 in rats is different, exhibiting increased biliary excretion, a larger Vd value, and a shorter Te1/2. CONCLUSIONS: The pharmacokinetics and elimination profile of MS-325, including vascular retention and renal excretion, are favorable for use in humans as an intravascular contrast agent for MRI.

Detection and characterization of primary liver cancer in rats by MS-264-enhanced MRI.

A new MR contrast agent, MS-264 (Gd(1RS)-1-(p-butylbenzyl)-DTPA), was developed to achieve hepatobiliary specificity and its potential evaluated for detecting and characterizing liver tumors in rats with chemically induced hepatocellular carcinoma (HCC). In seven rats with 66 HCC lesions, enhancements of different abdominal organs and tumors were compared on T1-weighted images after intravenous administration of Gd-DTPA (0.3 mmol/kg) and MS-264 (0.05 mmol/kg). MR images were correlated with postmortem microangiographic and histological findings. An overall enhancement of different organs, which normalized within 24 h, was observed after Gd-DTPA and MS-264 injection. MS-264 caused a higher relative enhancement (RE) in liver (60%), compared with that of Gd-DTPA (40%), which resulted in a prompt negative contrast enhancement in 59 of 66 HCCs. All were moderately to poorly differentiated (Grades II-IV) tumors. Six of these 59 negative contrast-enhancing lesions showed a positively enhanced peritumoral rim, which corresponded histologically to malignant infiltration (n = 2) or compression (n = 4). On the other hand, six well differentiated HCCs showed prolonged positive enhancement. However, one well differentiated HCC was not positively enhanced by MS-264, probably due to poor access of the agent to the lesion. In comparison to that of the precontrast images, enhancement with Gd-DTPA and MS-264 increased the number of detected lesions by 22 and 42%, respectively. In this animal study, MS-264 proved to be useful in detection and characterization of primary liver cancers.

Targeted relaxation enhancement agents for MRI.

The design, relative merits, and initial applications of targeted relaxation enhancement agents, a new form of MRI contrast media, are briefly discussed. These agents are designed to bind reversibly to target macromolecules in a tissue of interest, thus enhancing water proton relaxation efficiency and MRI contrast. Initial applications for targeted agents include blood pool and hepatobiliary imaging.

Exercise as prevention: do the health benefits derive in part from lower iron levels?

The mechanism by which exercise, a key component of modern preventative medicine, protects man from strikingly different diseases such as heart disease and cancer, is largely a mystery. It is proposed that exercise-induced reductions in iron levels, either through iron loss or enhanced iron storage, could be responsible for some of the beneficial effects. Possible roles for iron in coronary artery disease and cancer have recently emerged, particularly as a catalyst for oxygen free radical-induced tissue damage. The iron hypothesis is consistent with the graded reductions in mortality observed as a function of fitness level, and it is the first unified mechanism which can explain the reductions in both heart disease and cancer. If confirmed, preventative medicine in the future will need to include close monitoring of iron levels and, possibly, occasional blood donation for those with moderately high iron stores.

Iron stores and the international variation in mortality from coronary artery disease.

Possible roles for iron in coronary artery disease (CAD) have emerged, including contributions to atherogenesis and/or the vulnerability of the myocardium to ischemia/reperfusion events. The value of hepatic storage iron as a potential risk factor for CAD was evaluated independently and in combination with various lipoprotein indices using CAD mortality data from 11 countries along with available data on liver iron stores. CAD mortality rates were found to be best correlated with the liver iron-serum cholesterol product in both men (r = 0.72) and, more importantly, in both genders combined (r = 0.74). It was also found that estimated CAD incidence could be related in a non-linear fashion to iron-cholesterol values in a simple normal distribution model where all subjects above a threshold value of iron-cholesterol were assumed to have CAD. Hepatic iron values thus appear to be useful in describing the differences in CAD due to both diet (and/or culture) and sex.

MR imaging of blood-borne liver metastases in mice: contrast enhancement with Fe-EHPG.

To determine whether iron(III)ethylenebis-(2-hydrophenylglycine) (Fe-EHPG), a prototype hepatobiliary magnetic resonance imaging agent, can enhance the liver-to-tumor contrast-to-noise ratio (C/N) in models of liver tumors in mice, two types of cell inoculation were used: intrahepatic implantation of M5076 sarcoma and intrasplenic injection of colon tumor (C-26) or M5076 sarcoma. Significant enhancement of the liver-to-tumor C/N and/or improved visualization of small lesions was consistently observed on T1-weighted images obtained after injection of the contrast material. For intrahepatic implants, the C/N on postinjection T1-weighted images was superior to that on T1- and T2-weighted preinjection images. For the C-26 metastatic liver lesions of larger diameter (greater than 5 mm), the C/N on postinjection T1-weighted studies was superior to that on preinjection T1-weighted images but was comparable to that on preinjection T2-weighted images. However, higher C/N after administration of Fe-EHPG improved visualization of medium-sized (3-5 mm) and small (1-3-mm) metastatic lesions in both M5076 and C-26 models. These results demonstrate that MR imaging with appropriate hepatobiliary agents appears promising for early detection of liver metastases.

Site-specific water proton relaxation enhancement of iron(III) chelates noncovalently bound to human serum albumin.

Binding of potential blood pool and hepatobiliary paramagnetic iron(III) contrast agents, rac- and meso-Fe(5-Br-EHPG)- (iron(III) N,N'-ethylenebis [(5-bromo-2-hydroxyphenyl)glycinate]) and Fe(5-Br-HBED)- (iron(III) N,N'-bis-(5-bromo-2-hydroxybenzyl)ethylenediaminediacetic acid) to human serum albumin (HSA) has been studied using the proton relaxation enhancement (PRE) effect on solvent protons. These chelates bind avidly to multiple sites on HSA with binding constants on the order of 10(4) to 10(5) M-1. Interestingly, binding results in a decrease in the diamagnetic component of the water relaxivity due to HSA, while the expected enhancement of the paramagnetic component of water proton relaxation rates occurs due to the increase in the rotational correlation times of the protein-bound agents. These relaxation enhancements are variable, depending upon the site on the protein to which these chelates are bound, and can be as high as approximately 7 mM-1 s-1 at 5 degrees C and approximately 5 mM-1 s-1 at 37 degrees C at 20 MHz (enhancements of approximately 2-5). Change of temperature from 5 to 37 degrees C also appears to switch the relative affinities of these chelates for their primary and secondary binding sites. It is found that the important HSA binding site for the heme breakdown product, bilirubin-IX alpha, is a target for these agents and is the site of highest relaxivity for all the agents.

Magnetic resonance contrast media: principles and progress.

The principles and current state of the art for magnetic resonance (MR) imaging contrast media are reviewed. All forms of paramagnetic and superparamagnetic MR contrast agents are covered, including discussions of their effect on MR relaxation and image intensity as well as their chemical and physiological properties.

Detection of site-specific binding and co-binding of ligands to human serum albumin using 19F NMR.

Binding and co-binding of various 19F-labeled ligands to human serum albumin (HSA) has been studied using 19F NMR. Specifically shifted resonances in slow exchange with the free resonances are detected for many of the ligands. These specifically shifted resonances can be studied to yield accurate estimates of site-specific binding constants and stoichiometries. In addition, the use of two different 19F-labeled ligands can directly reveal competition for a given site or independent binding at different sites. For instance, it is easily shown that both 5-F-L-tryptophan and 5-F-salicylic acid are capable of binding independently to two sites on HSA at the same time, without the need for any curve-fitting or assumptions. These results demonstrate that the concept of "sites" on HSA is not only useful but is necessary. The technique also reveals allosteric interactions between 5-F-L-Trp and warfarin co-bound to HSA. This technique proves to be a powerful methodology for studying ligand and drug binding to HSA that is free from some of the pitfalls associated with more traditional techniques such as equilibrium dialysis.

Dynamic imaging with lanthanide chelates in normal brain: contrast due to magnetic susceptibility effects.

Using a one-dimensional rapid imaging technique, we have found that injection of lanthanide chelates such as Gd(DTPA)2- leads to a significant decrease (50%) in rat brain signal intensity at 1.45 T using T2-weighted pulse sequences; however, no effect of comparable size is observed with T1-weighted pulse sequences. The transient effect and its kinetics were followed with a temporal resolution of between 1 and 8 s. Experiments with different lanthanide chelates show that the observed decrease in signal intensity correlates with the magnetic moment of each agent but not with their longitudinal relaxivity. Three-dimensional chemical-shift resolved experiments demonstrate significant line broadening in brain during infusion with Dy(DTPA)2-. Our results show that the cause of this effect is the difference in susceptibility between the capillaries, containing the contrast agent, and the surrounding tissue. As a result of these susceptibility differences, field gradients are produced in the tissue and diffusion of water through these gradients leads to a loss of spin phase coherence and thus a decrease in signal intensity. We propose this as a new type of contrast agent mechanism in NMR. The effect and its kinetics are likely to be related to important physiological parameters such as cerebral blood volume and cerebral blood flow, and do not depend on a breakdown of the blood-brain barrier as do conventional contrast agent techniques.