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To determine the diagnostic value of the intravascular contrast agent gadocoletic acid (B-22956) in three-dimensional, free breathing coronary magnetic resonance angiography (MRA) for stenosis detection in patients with suspected or known coronary artery disease.Eighteen patients underwent three-dimensional, free breathing coronary MRA of the left and right coronary system before and after intravenous application of a single dose of gadocoletic acid (B-22956) using three different dose regimens (group A 0.050 mmol/kg; group B 0.075 mmol/kg; group C 0.100 mmol/kg). Precontrast scanning followed a coronary MRA standard non-contrast T2 preparation/turbo-gradient echo sequence (T2Prep); for postcontrast scanning an inversion-recovery gradient echo sequence was used (real-time navigator correction for both scans). In pre- and postcontrast scans quantitative analysis of coronary MRA data was performed to determine the number of visible side branches, vessel length and vessel sharpness of each of the three coronary arteries (LAD, LCX, RCA). The number of assessable coronary artery segments was determined to calculate sensitivity and specificity for detection of stenosisor = 50% on a segment-to-segment basis (16-segment-model) in pre- and postcontrast scans with x-ray coronary angiography as the standard of reference.Dose group B (0.075 mmol/kg) was preferable with regard to improvement of MR angiographic parameters: in postcontrast scans all MR angiographic parameters increased significantly except for the number of visible side branches of the left circumflex artery. In addition, assessability of coronary artery segments significantly improved postcontrast in this dose group (67 versus 88%, p0.01). Diagnostic performance (sensitivity, specificity, accuracy) was 83, 77 and 78% for precontrast and 86, 95 and 94% for postcontrast scans.The use of gadocoletic acid (B-22956) results in an improvement of MR angiographic parameters, asssessability of coronary segments and detection of coronary stenosesor = 50%.

Purpose To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy. Materials and Methods Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance™), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin™) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (KPS) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI. Results Tumors grew more slowly, although not significantly (P = 0.07), in the drug-treated group. The KPS determined for B22956/1 decreased significantly in the drug-treated group compared to baseline (P < 0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA). Conclusion With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting. J. Magn. Reson. Imaging 2004;20:865–873. © 2004 Wiley-Liss, Inc.

Purpose To evaluate gadocoletic acid (B-22956), a gadolinium-based paramagnetic blood pool agent, for contrast-enhanced coronary magnetic resonance angiography (MRA) in a Phase I clinical trial, and to compare the findings with those obtained using a standard noncontrast T2 preparation sequence. Materials and Methods The left coronary system was imaged in 12 healthy volunteers before B-22956 application and 5 (N = 11) and 45 (N = 7) minutes after application of 0.075 mmol/kg of body weight (BW) of B-22956. Additionally, imaging of the right coronary system was performed 23 minutes after B-22956 application (N = 6). A three-dimensional gradient echo sequence with T2 preparation (precontrast) or inversion recovery (IR) pulse (postcontrast) with real-time navigator correction was used. Assessment of the left and right coronary systems was performed qualitatively (a 4-point visual score for image quality) and quantitatively in terms of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel sharpness, visible vessel length, maximal luminal diameter, and the number of visible side branches. Results Significant (P < 0.01) increases in SNR (+42%) and CNR (+86%) were noted five minutes after B-22956 application, compared to precontrast T2 preparation values. A significant increase in CNR (+40%, P < 0.05) was also noted 45 minutes postcontrast. Vessels (left anterior descending artery (LAD), left coronary circumflex (LCx), and right coronary artery (RCA)) were also significantly (P < 0.05) sharper on postcontrast images. Significant increases in vessel length were noted for the LAD (P < 0.05) and LCx and RCA (both P < 0.01), while significantly more side branches were noted for the LAD and RCA (both P < 0.05) when compared to precontrast T2 preparation values. Conclusion The use of the intravascular contrast agent B-22956 substantially improves both objective and subjective parameters of image quality on high-resolution three-dimensional coronary MRA. The increase in SNR, CNR, and vessel sharpness minimizes current limitations of coronary artery visualization with high-resolution coronary MRA. J. Magn. Reson. Imaging 2004;20:288–293. © 2004 Wiley-Liss, Inc.

In three-dimensional (3D) coronary magnetic resonance angiography (MRA), the in-flow contrast between the coronary blood and the surrounding myocardium is attenuated as compared to thin-slab two-dimensional (2D) techniques. The application of a gadolinium (Gd)-based intravascular contrast agent may provide an additional source of signal and contrast by reducing T(1blood) and supporting the visualization of more distal or branching segments of the coronary arterial tree. In six healthy adults, the left coronary artery (LCA) system was imaged pre- and postcontrast with a 0.075-mmol/kg bodyweight dose of the intravascular contrast agent B-22956. For imaging, an optimized free-breathing, navigator-gated and -corrected 3D inversion recovery (IR) sequence was used. For comparison, state-of-the-art baseline 3D coronary MRA with T(2) preparation for non-exogenous contrast enhancement was acquired. The combination of IR 3D coronary MRA, sophisticated navigator technology, and B-22956 allowed for an extensive visualization of the LCA system. Postcontrast, a significant increase in both the signal-to-noise ratio (SNR; 46%, P < 0.05) and contrast-to-noise ratio (CNR; 160%, P < 0.01) was observed, while vessel sharpness of the left anterior descending (LAD) artery and the left coronary circumflex (LCX) were improved by 20% (P < 0.05) and 18% (P < 0.05), respectively.

Contrast-enhanced coronary angiography has become an important technique for magnetic resonance (MR) coronary artery imaging. However, the relationship between the quality of the coronary artery images and blood T1 has not yet been fully explored. In this paper, we assessed this relationship in an animal model by using a prototypical blood pool agent. With accumulated injections of this agent, the blood T1 would be maintained at different levels. The measured blood T1 values in vivo were 147 6 3, 82 6 6, 48 6 4, 40 6 3, and 30 6 8 msec (N 5 7). Fixed and variable flip angle schemes were used in coronary artery imaging. The signal to noise ratios (SNR) of coronary arteries were measured and the image quality was assessed. It was found that blood T1 less than 80 msec might be desired. No statistically significant difference was observed between two flip angle schemes. There was better vessel definition using variable flip angle at blood T1 lower than 50 msec. Understanding this relationship may be beneficial to optimizing image protocol and/or design of blood pool contrast agents for contrast-enhanced coronary angiography. J. Magn. Reson. Imaging 2001;14: 348‐354. © 2001 Wiley-Liss, Inc.

Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6-hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato-thalamo-cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. 11C-PET studies of ligands which bind to the dopamine transporter (2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane 1,5-naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding. Synapse 36:57–65, 2000. © 2000 Wiley-Liss, Inc.

The purpose of this work was to optimize a technique to measure blood T1 dynamically after contrast agent administration with a high temporal resolution. This technique uses a 90° prepared gradient-echo sequence and has a temporal resolution of one T1 measurement per cardiac cycle. The non-ideal excitation slice profiles on the estimation of T1 were evaluated by theoretical simulations and used to obtain corrected blood T1 values. The technique was validated on phantom and in vivo pig studies, which demonstrated significant improvement on the accuracy of the dynamic T1 measurement method after slice profile correction. This technique may find important applications in studying the dynamic blood T1 after injection of various contrast agents. J. Magn. Reson. Imaging 1999;10:576–581. © 1999 Wiley-Liss, Inc.

The effect of off-resonance irradiation on the water proton NMR signal intensity has been investigated as follows: (a) in the presence of a paramagnetic probe like manganese(II); (b) in the presence of bovine serum albumin (BSA) and two gadolinium(III) complexes, Gd-DTPA and Gd-BOPTA; (c) in the presence of cross-linked BSA and the two above-mentioned gadolinium(III) complexes. The experimental data have been rationalized on the basis of the available theoretical models. The effectiveness of the two complexes as contrast agents for MRI has been predicted. It is shown that contrast agents providing comparable longitudinal and transverse relaxation rate enhancements are those of general interest for off-resonance magnetization transfer-MRI.

To monitor with fast gradient-echo magnetic resonance (MR) imaging the dynamics of gadolinium benzyloxypropionictetraacetate (gadobenate) dimeglumine on myocardial signal intensity in dogs with critical left circumflex coronary artery stenosis.Fast gradient-echo MR images were acquired in a short axis of the left ventricle. Two bolus injections of 0.05 mmol/kg gadobenate dimeglumine were administered in the basal state after stenosis and after infusion of 0.5 mg/kg dipyridamole.In the basal state, there was an equivalent increase in signal intensity of normal and hypoperfused myocardium during the first pass. Dipyridamole increased left anterior descending flow (287% +/- 36; P.05) and decreased left circumflex flow (65% +/- 14; P.05). The magnitude of signal intensity increase during the second bolus in the hypoperfused region was less than that of normal myocardium (P.05). Contrast-enhanced images showed the hypoperfused region as smaller than the postmortem measurement (43.8% +/- 3.3; P.05).Contrast-enhanced fast MR imaging in the vasodilated state allows detection of hypoperfused myocardium in the presence of critical coronary stenosis.

The use of contrast agents has the potential to improve several technical shortcomings of present-day coronary MR angiography (MRCA), notably the limited spatial resolution and field of view, and the poor contrast between the signal of the vessel lumen and the surrounding tissue(s). However, MR coronary angiography using the existing “extracellular” contrast agents is still unsatisfactory due to the insufficient time window that is available for MR scanning: therefore, suitable contrast can be achieved only at the cost of substantial restrictions in either the spatial resolution or the field of view. An intravascular contrast agent would extend the available time for imaging the coronary vessels by shortening the longitudinal relaxation time (T1) value of blood over a longer time period. The need for strong blood relaxation enhancement—depending primarily on the very early plasma kinetics of the contrast agent and on its relaxivity—is essential if MRCA uses a breath-hold approach for circumventing the problem of respiratory motion. On the other hand, a persistent blood relaxation enhancement is essential if so-called “navigator echo” techniques or any other data reduction for correcting the artefacts of respiratory motion are exploited. Based on the expected performance of advanced MRI scanners, an effective “blood pool” agent should therefore show high relaxivity combined with high intravascular containment allowing for longer scan times and good vessel contrast, which are essential for a diagnostic imaging of coronary arteries. B22956/1 is a stable acyclic chelate of Gd linked by means of a flexible spacer to a deoxycholic acid derivative. B22956/1 greatly enhances in vivo relaxivity owing to a strong interaction with serum proteins; in turn, such interaction is the key for a persistent containment of B22956/1 in the vascular space, thus ensuring high vessel delineation and allowing for successful imaging of cardiac vessels. B22956/1 0.5 mM has been shown in vitro to have a specific binding to human serum albumin of 94%, compared to a binding of about 80% exhibited in similar experimental conditions by MS-325, an intravascular contrast agent under development for magnetic resonance coronary artery imaging (MRCA) (1). The preliminary results of safety, pharmacokinetic and contrast efficacy of the first administration to humans of B22956/1 are reported in this abstract.

The novel tissue-specific contrast agent, Gd-BOPTA/Dirmeg, was tested in MR imaging of experimental focal liver disease and of acute myocardial ischemia in rats. Directly implanted liver tumors and blood-borne metastases were used as models for focal liver disease and occlusion of the lower anterior descending coronary artery as model for acute ischemia. The studies with implanted tumors, at a dose level of 250 μmol/kg, showed a very high (370%) and persistent (>2h) increase in the tumor-liver contrast-to-noise ratio (CNR), owing to selective enhancement of normal liver parenchyma signal intensity. While all blood-borne metastases showed a similar late CNR enhancement, some of them experienced early contrast loss due to transient signal intensity enhancement. In myocardial imaging. Gd-BOPTA/Dimeg produced a signal intensity enhancement in normal myocardium and an injured area-normal area CNR enhancement which were both much stronger and more presistent than those produced by Gd-DTPA/Dimeg. © 1991 Academic Press, Inc.

International audience; PURPOSE: To test whether B-22956/1, a novel intravascular contrast agent with a high affinity to serum albumin (Bracco Imaging SpA.), allowed quantifying neovessel and macrophage density in atherosclerotic plaques of rabbits using MRI. MATERIALS AND METHODS: A T1-weighted MRI of the aorta was acquired in 10 rabbits (7 atherosclerotic and 3 control rabbits) before and up to 2 h after intravenous injection of 100 mumol/kg of Gd-DTPA or 75 mumol/kg of B-22956/1. Plaque enhancement was measured at different time points. Immunohistochemistry was performed using anti-CD 31 antibodies and anti-RAM 11 antibodies to correlate to neovessel and macrophage density, respectively. RESULTS: MRI showed a significant plaque enhancement 2 h after B-22956/1 versus Gd-DTPA in the atherosclerotic group (39.75% versus 9.5%; P < 0.0001. Early atherosclerotic plaques (n = 146) enhancement positively correlates with neovessel density on corresponding histological sections (r = 0.42; P < 0.01). Enhancement of atherosclerotic plaques 2 h after injection of B-22956/1 correlated with macrophage density (r = 0.71; P < 0.01). CONCLUSION: Enhancement of atherosclerotic plaques with MRI correlated with neovessel density at early time points after the injection of B-22956/1 and with macrophage density, at later time points. Hence, B-22956/1-enhanced MRI represents a promising imaging technique for the identification of "high-risk" plaques.

The feasibility of three-dimensional (3D) whole-heart imaging of the coronary venous (CV) system was investigated. The hypothesis that coronary magnetic resonance venography (CMRV) can be improved by using an intravascular contrast agent (CA) was tested. A simplified model of the contrast in T(2)-prepared steady-state free precession (SSFP) imaging was applied to calculate optimal T(2)-preparation durations for the various deoxygenation levels expected in venous blood. Non-contrast-agent (nCA)- and CA-enhanced images were compared for the delineation of the coronary sinus (CS) and its main tributaries. A quantitative analysis of the resulting contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) in both approaches was performed. Precontrast visualization of the CV system was limited by the poor CNR between large portions of the venous blood and the surrounding tissue. Postcontrast, a significant increase in CNR between the venous blood and the myocardium (Myo) resulted in a clear delineation of the target vessels. The CNR improvement was 347% (P < 0.05) for the CS, 260% (P < 0.01) for the mid cardiac vein (MCV), and 430% (P < 0.05) for the great cardiac vein (GCV). The improvement in SNR was on average 155%, but was not statistically significant for the CS and the MCV. The signal of the Myo could be significantly reduced to about 25% (P < 0.001).

Inversion recovery, three-dimensional, gradient-recalled echo magnetic resonance coronary angiography (IR-3D-GRE-MRCA), performed after administration of an intravascular T1-relaxing agent with prolonged permanence in the blood, is one of the most promising approaches to noninvasive magnetic resonance imaging (MRI) of the coronaries. The aim of the present study was the evaluation of the physicochemical properties in solution, pharmacokinetics, elimination from the body, protein binding, and signal enhancement characteristics of gadocoletic acid trisodium salt (B22956/1), a candidate gadolinium-based MRI contrast agent for coronary angiography.The pharmacokinetics and elimination from the body of gadocoletate ion, the contrastographically active component of gadocoletic acid trisodium salt, was evaluated after intravenous administration in rats and monkeys, using for assays high-performance liquid chromatography, x-ray fluorescence, and inductively coupled plasma atomic emission spectrometry. The binding of the gadocoletate ion to animal and human serum albumin was studied by means of ultrafiltration. The imaging properties of blood outside coronary arteries after contrast agent administration were evaluated in cynomolgus monkeys (Macaca fascicularis) by measuring aortic signal-to-noise and contrast-to-noise ratios in lower body angiograms. The suitability of gadocoletic acid trisodium salt for achieving contrast-enhanced magnetic resonance coronary angiography (ceMRCA) was tested in Yucatan micropigs with an IR-3D-GRE sequence. All in vivo relaxation rate measurement and images were obtained using a 1.5 T Siemens Symphony scanner.The fractional binding of gadocoletate ion at a concentration of 0.5 mM to serum albumin at the physiological concentration was 95%, 92%, 88%, and 86% for human, monkey, pig, and rat, respectively. In rats and monkeys, gadocoletate ion was excreted unmetabolized through the biliary and urinary routes. It was recovered with feces depending on the injected dose in percentages from 18% to 97%, providing evidence for a saturable biliary pathway. Plasma pharmacokinetics showed the complete elimination of gadocoletate ion within 24 hours after administration. In the monkey, the gadocoletate ion showed the pharmacokinetic behavior of a compound with partial vascular confinement and long plasma half-life, which may be ascribed to elevated binding to serum albumin. These properties manifested themselves in lower body angiograms with excellent image contrast between vessels and muscle. The slowly decaying aortic blood signal-to-noise and contrast-to-noise ratios over a 15-minute period is expected to allow 3-dimensional coronary angiography. The potential of gadocoletic acid trisodium salt for ceMRCA was also demonstrated in Yucatan micropigs. Elevated blood signal intensity and almost total myocardial signal suppression was maintained for almost 1 hour after administration, ie, for much longer than expected to be necessary for coronary angiography. During the whole period high resolution images of the right coronary artery could be obtained.On the basis of the pharmacokinetic profile and imaging characteristics, gadocoletic acid trisodium salt shows promise as a MR contrast agent for coronary angiography.

Objectives: Intravascular contrast agents may offer longer imaging times and better vessel visualization over conventional extravascular agents for magnetic resonance coronary angiography. The purpose of this study was to evaluate the effect of intravascular contrast (B-22956/1) on coronary visualization. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were compared in inversion-recovery (IR)-prepared FLASH (fast low-angle shot) and IR-trueFISP (true fast imaging with steady-state precession) sequences before and after contrast. Materials and Methods: Numeric simulations were performed to compare blood signals in IR-trueFISP and IR-FLASH sequences. Coronary imaging was performed in 15 swine. Results: Postcontrast CNR was improved 23% with breathhold IR-FLASH and 55% with breathhold IR-trueFISP as compared with precontrast trueFISP. With free-breathing, long TR IR-FLASH provided 131% and 55.8% higher SNR and 132% and 58.7% increased CNR compared with IR-FLASH with shorter TR and IR-trueFISP, respectively. Conclusion: Intravascular contrast agents improve CNR and vessel visualization in coronary magnetic resonance angiography with IR-FLASH and IR-trueFISP.

The currently prevailing trends in industrial contrast agent research for MRI are discussed. Specific mention is made of contrast agents for liver imaging using both static and delayed procedures, of the potential for blood pool agents and the form such agents may take, and of the ultimate challenge for contrast agent R&D: tissue-targeting in a wider sense to both normal and pathologic tissues.

The objective of this study was to evaluate a new blood pool contrast agent, B-22956, for detecting myocardial perfusion abnormality and coronary artery stenosis by magnetic resonance imaging (MRI) in 1 setting.Coronary artery atherosclerotic stenoses were created in 6 miniswine. Myocardial first-pass perfusion imaging was performed with a bolus injection of 0.015 mmol/kg B-22956 during pharmacologic stress followed by postcontrast coronary artery imaging after another injection of B-22956/1. The total doses for the 6 pigs were 0.1 mmol/kg (n=3) and 0.15 mmol/kg (n=3). Perfusion upslope maps were analyzed and MR coronary artery images were reviewed by 2 readers.For all 6 pigs, the normalized upslopes of the perfusion curves were 0.83+/-0.12, 0.74+/-0.15, and 0.52+/-0.05 (P0.01 vs. normal) with normal or mild (50% area stenosis), moderate (50% and75%), and severe stenosis (75%), respectively. Mean signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in right coronary artery images improved 90% and 200%, respectively, with a total dose of 0.1 mmol/kg of B-22956. Excellent agreements (kappa=0.82) were achieved for evaluating the grade of stenosis between MR postcontrast coronary artery images and histopathology by 2 reviewers.The MR blood pool contrast agent B-22956 demonstrated the ability for detecting myocardial perfusion abnormalities and coronary artery stenosis in 1 setting.

To evaluate the diagnostic and prognostic potential of a new protein-binding contrast medium, B22956/1, for quantitatively characterizing tumor microvessels by MRI and monitoring response to antiangiogenic therapy.Dynamic contrast-enhanced MRI (DCE-MRI) was performed in an experimental cancer model with the use of the novel protein-binding agent B22956/1, a low molecular contrast agent (ProHance), and a macromolecular contrast medium, albumin-(Gd-DTPA). MDA-MB-435, a human cancer cell line, was implanted in 22 athymic rats. Animals were assigned randomly to a control (saline) or drug-treated (Avastin) group. MRI was performed at baseline and after nine days of treatment. The transendothelial permeability (KPS) and the fractional blood volume (fBV) were estimated from the kinetic analysis of dynamic MR data using a two-compartment model. Tumor growth was also measured from volumetric MRI.Tumors grew more slowly, although not significantly (P=0.07), in the drug-treated group. The KPS determined for B22956/1 decreased significantly in the drug-treated group compared to baseline (P0.05), and progressed significantly in the control group. However, no significant changes were resolved with the use of ProHance or albumin-(Gd-DTPA).With the use of appropriate contrast media, the therapeutic effects of an anti-VEGF antibody on tumor microvessels can be monitored by dynamic MRI. The dynamic range of permeability to B22956/1, and the sensitivity to change of this parameter suggest a potential application in the clinical setting.

Initial evaluation of a new blood pool agent, B-22956/1, for pulmonary imaging was performed in five domestic pigs with artificial embolism. Pre-embolism 3D pulmonary perfusion images were first acquired by injecting an extravascular agent, gadoteridol. The pulmonary arteries of the pigs were then occluded by the artificial emboli. Post-embolism perfusion scans were subsequently performed by injecting B-22956/1. Additional post-embolism high-spatial-resolution angiograms were also acquired. Parenchyma perfusion deficits were well depicted in the post-embolism perfusion maps. The post-embolism angiography clearly revealed the location and extent of the filling defects in the pulmonary vessels. Signal intensities of perfusion maps on the normal parenchyma were significantly improved (30%) by using B-22956/1, in comparison with perfusion images using gadoteridol (P < 0.01). Many pulmonary angiograms with approximately equal contrast could be obtained even at 22 minutes after the injection of B-22956/1. Our initial results indicate that blood pool agent B-22956/1 may provide opportunities for whole-lung-coverage perfusion mapping and additional high-resolution target angiograms after a single injection. J. Magn. Reson. Imaging 2001;14:425–432. © 2001 Wiley-Liss, Inc.

The authors assess the effect of weak protein binding on the efficacy of gadolinium chelates as contrast agents for magnetic resonance imaging (MRI).Chelates with no (gadopentetate dimeglumine), weak (gadobenate dimeglumine), and strong (B-21326/7) protein binding were compared by in vitro MRI at 2T (spin echo [SE]: repetition time [TR]/echo time [TE] 350/8 mseconds) on solutions in 0.5 mM bovine serum albumin and in rat whole blood, and by in vivo MRI at 2T on rat models of brain tumors (SE TR/TE 350/10 mseconds) and of focal blood-brain barrier disruption (SE TR/TE 400/15 mseconds) after injection of MPP+. Relaxation rate enhancement in the blood of normal rabbits was measured in vivo after administration of contrast agents using IR-Snapshot FLASH.Signal intensity enhancement measured in vitro for whole rat blood 0.1 mM in gadobenate was 142% relative to the same concentration of gadopentetate. Peak signal intensity enhancement in brain tumors was 87% +/- 8% and 64% +/- 5% after 0.1 mmol/kg intravenous administration of gadobenate and gadopentetate, respectively; in MPP+ lesions, the peak signal intensity enhancement was 22% +/- 9%, 32% +/- 7%, and 64% +/- 14% after 0.2 mmol/kg intravenous of gadopentetate, gadobenate, and B-21326/7, respectively. In rabbits, the relaxation enhancement of blood 5 minutes after B-21326/7 and gadobenate administration was 323% and 182%, respectively, relative to the same dose (0.1 mmol/kg intravenous) of gadopentetate.Weak protein binding can substantially increase the efficacy of gadolinium chelates as general purpose contrast agents for MRI.

This study tested whether Gd-BOPTA/Dimeg or Gd-DTPA exerts greater relaxation enhancement for blood and reperfused infarcted myocardium. Relaxivity of Gd-BOPTA is increased by weak binding to serum albumin. Thirty-six rats were subjected to reperfused infarction before contrast (doses = 0.05, 0.1, and 0.2 mmol/kg). delta R1 was repeatedly measured over 30 min. Gd-BOPTA caused greater delta R1 for blood and myocardium than did Gd-DTPA; clearance of both agents from normal- and infarcted myocardium was similar to blood clearance; plots of delta R1 myocardium/delta R1 blood showed equilibrium phase contrast distribution. Fractional contrast agent distribution volumes were approximately 0.24 for both agents in normal myocardium, 0.98 and 1.6 for Gd-DTPA and Gd-BOPTA, respectively, in reperfused infarction. The high value for Gd-BOPTPA was ascribed to greater relaxivity in infarction versus blood. It was concluded that Gd-BOPTA/Dimeg causes a greater delta R1 than Gd-DTPA in regions which contain serum albumin.

This work was conducted to test the hypothesis that contrast-enhanced MRI with hepatocyte-specific contrast agents facilitates quantitation and mapping of diffuse liver diseases such as hepatitis and cirrhosis. Gadobenate dimeglumine (Gd-BOPTA/Dimeg, Bracco SpA, Millano, Italy) is a new paramagnetic hepatocyte-specific contrast agent currently undergoing clinical trials. We have assessed the usefulness of gadobenate dimeglumine for the diagnosis of diffuse liver diseases in a rat model of chemically induced hepatitis. The study was based on the measurements of in vivo liver relaxation times as well as on the acquisition of standard SE images. Acute hepatitis considerably reduced the degree of T1 shortening of liver parenchyma caused by intravenous injection of .25 mmol/kg of gadobenate dimeglumine. Analogously, the enhancement of the MRI signal intensity of the liver of rats with hepatitis observed in T1-weighted spin-echo (SE) images was inferior, in terms of both strength and duration, to that recorded in control rats at doses of .25 mmol/kg and .075 mmol/kg of gadobenate dimeglumine. Our results show that gadobenate dimeglumine-enhanced MR imaging has the potential for visualization of hepatitis and for assessment of liver function. Our conclusions differ from those previously published on this subject by other authors. The reasons that led to differing conclusions are discussed.

We monitored the differences in the first passage of gadobenate dimeglumine through normal and ischemic myocardium with left anterior descending (LAD) coronary artery occlusion in dogs.Dynamic multislice images of the heart were taken on a 1.5-T magnetic resonance (MR) imager. In six normal dogs, inversion recovery (IR)-prepared fast gradient-recalled echo (GRE) images were acquired at five doses of gadobenate dimeglumine (0.005-0.1 mmol/kg). First passage of the contrast medium through normal and acutely ischemic myocardium were monitored in seven dogs subjected to LAD coronary artery occlusion.IR-prepared GRE images showed a dose-dependent increase in the signal intensity (SI) of the myocardium. In dogs with LAD coronary artery occlusion, there was a significant increase in the SI of normal myocardium (p.01) than in ischemic myocardium after injection of 0.025 mmol/kg gadobenate dimeglumine.The first-pass dynamics of gadobenate dimeglumine through normal and ischemic myocardium can be monitored with a multislice acquisition using a clinical MR imager and differentiated between normal and ischemic myocardium in dogs.

RATIONALE AND OBJECTIVES The purposes of this study are to evaluate the first-pass profile of gadolinium-BOPTA/Dimeg (Gd-BOPTA/Dimeg) during its transit through hearts subjected to acute myocardial infarction, and to delineate these infarcted regions by the use of ultrafast magnetic resonance imaging (MRI). METHODS Regional ischemia was induced in anesthetized rats by occluding the left coronary artery. Imaging parameters for single shot EPI included TE, 10 mseconds; AT, 33 mseconds; and 64 x 64-pixel matrix. Consecutive images were obtained every 1 to 2 seconds over a 30-second period. After approximately two images, Gd-BOPTA/Dimeg was injected intravenously (0.05 and 0.25 mmol/kg). RESULTS Gd-BOPTA/Dimeg (0.05 mmol/kg), with inversion recovery EPI, produced a substantial increase in signal intensity of right and then left ventricular blood. Normally perfused myocardium also was enhanced, but not the acutely infarcted region. Clear delineation of the infarcted region as negatively enhanced "cold spots" persisted for at least 20 seconds. Gd-BOPTA/Dimeg (0.25 mmol/kg) with standard gradient-recalled EPI produced a different profile of signal intensity changes. Signal intensities of ventricular blood and normal myocardium were greatly reduced, leaving the infarcted zone as a positively enhanced "hot spot." Delineation of the infarcted region persisted for 6 to 8 seconds. The infarcted zone detected with MRI corresponded to that observed at autopsy. CONCLUSIONS Regions of acute myocardial infarction can be detected as negatively enhanced "cold spots" or positively enhanced "hot spots" by studying the first-pass dynamics of Gd-BOPTA/Dimeg through hearts with regional ischemia by use of single shot EPI.