Relationship of Dose and Signal Enhancement Properties of Gadoquatrane, a New Tetrameric, Macrocyclic Gadolinium-Based Contrast Agent, Compared With Gadobutrol: A Randomized Crossover Study in Healthy Adults.

OBJECTIVES: To investigate the signal-enhancement properties of the tetrameric gadolinium-based contrast agent (GBCA) gadoquatrane in relation to the administered dose and compare its properties to those of a standard dose of gadobutrol, as a representative of the currently established macrocyclic GBCAs for magnetic resonance imaging. MATERIALS AND METHODS: In this randomized, single-blind, 4 × 4 crossover study, 43 healthy adults (19-50 years of age) received 3 single IV injections of gadoquatrane (0.01, 0.03, and 0.06 mmol gadolinium/kg body weight) and 1 injection of gadobutrol (0.1 mmol gadolinium/kg body weight) in randomized sequence with 1-week washout periods between administrations. The relative signal enhancement (RSE) was determined in predefined areas of interest in magnetic resonance image sets of the head-neck region. RSE-vs-dose curves (dose-response curves) were established by linear regression, and comparator-equivalent doses were determined by Bayesian inverse regression analysis. Further, 3 blood samples were taken after each injection for pharmacokinetic analyses, and safety data were assessed. RESULTS: The RSE increased with gadoquatrane dose. A linear function adequately fitted this relationship. In line with the more than 2-fold higher r1 relaxivity of gadoquatrane per gadolinium ion, gadobutrol-equivalent RSE was achieved with gadoquatrane at less than half the gadolinium dose and less than one eighth of the molecule dose.Administration of gadoquatrane and gadobutrol resulted in very similar dose-normalized gadolinium concentrations in plasma, indicating that the pharmacokinetic profiles are essentially the same. Both contrast agents were well tolerated. Adverse events were rare and not dependent on the dose administered. CONCLUSIONS: Gadoquatrane has the potential to be an effective GBCA that can be used at substantially lower doses in clinical routine than the currently established macrocyclic GBCAs.

Pharmacokinetics, Safety, and Tolerability of the Novel Tetrameric, High-Relaxivity, Macrocyclic Gadolinium-Based Contrast Agent Gadoquatrane in Healthy Adults.

OBJECTIVES: Gadolinium (Gd)-based contrast agents are well established in clinical routine and have been proven safe and effective. However, there is a need for "next-generation" Gd-based contrast agents that would allow lowering the Gd dose used for routine contrast-enhanced magnetic resonance imaging procedures. The objective of this first-in-human study was to investigate the pharmacokinetic profile, safety, and tolerability of gadoquatrane, a novel high-relaxivity Gd-based contrast agent. MATERIALS AND METHODS: This study was conducted in 2018/2019 as a prospective, randomized, single-blind, single-dose, placebo-controlled, escalating-dose study. Healthy volunteers were randomly assigned (6:2) to intravenous administration of gadoquatrane (0.025 to 0.2 mmol Gd/kg body weight) or placebo. Study procedures included collection of blood samples and excreta for pharmacokinetic analyses and safety assessments. RESULTS: Forty-nine healthy study participants (mean age ± SD, 35 ± 6.3 years; 24 female) were evaluated. The effective half-life of gadoquatrane in plasma was short and similar in all dose groups (1.4-1.7 hours). Plasma concentrations around the lower quantitation limit (0.0318 µmol Gd/L) were reached 15-72 hours after administration. The volume of distribution at steady state was ~0.2 L/kg in all dose groups. The clearance (total and renal) was ~0.1 L/h per kilogram in all groups. Across dose groups, the exposure of gadoquatrane increased dose-proportionally. Metabolite profiling revealed no hint of degradation in vivo or release of free Gd. Seven of 36 participants (19.4%) receiving gadoquatrane and 4 of 13 participants (30.8%) receiving placebo experienced mild or moderate treatment-emergent adverse events. No serious adverse events occurred. The analysis of the Gd concentration-QTc interval relationship indicated no risk of QT/QTc prolongation (>10 milliseconds) with gadoquatrane at clinical dose levels. CONCLUSIONS: Gadoquatrane with its high-relaxivity, pharmacokinetic similarity to established Gd-based contrast agents and high tolerability is a promising "next-generation" contrast agent for magnetic resonance imaging.

Preclinical Profile of Gadoquatrane: A Novel Tetrameric, Macrocyclic High Relaxivity Gadolinium-Based Contrast Agent.

OBJECTIVES: The aim of this report was to characterize the key physicochemical, pharmacokinetic (PK), and magnetic resonance imaging (MRI) properties of gadoquatrane (BAY 1747846), a newly designed tetrameric, macrocyclic, extracellular gadolinium-based contrast agent (GBCA) with high relaxivity and stability. MATERIALS AND METHODS: The r1-relaxivities of the tetrameric gadoquatrane at 1.41 and 3.0 T were determined in human plasma and the nuclear magnetic relaxation dispersion profiles in water and plasma. The complex stability was analyzed in human serum over 21 days at pH 7.4 at 37°C and was compared with the linear GBCA gadodiamide and the macrocyclic GBCA (mGBCA) gadobutrol. In addition, zinc transmetallation assay was performed to investigate the kinetic inertness. Protein binding and the blood-to-plasma ratio were determined in vitro using rat and human plasma. The PK profile was evaluated in rats (up to 7 days postinjection). Magnetic resonance imaging properties were investigated using a glioblastoma (GS9L) rat model. RESULTS: The new chemical entity gadoquatrane is a macrocyclic tetrameric Gd complex with one inner sphere water molecule per Gd ( q = 1). Gadoquatrane showed high solubility in buffer (1.43 mol Gd/L, 10 mM Tris-HCl, pH 7.4), high hydrophilicity (logP -4.32 in 1-butanol/water), and negligible protein binding. The r1-relaxivity of gadoquatrane in human plasma per Gd of 11.8 mM -1 ·s -1 (corresponding to 47.2 mM -1 ·s -1 per molecule at 1.41 T at 37°C, pH 7.4) was more than 2-fold (8-fold per molecule) higher compared with established mGBCAs. Nuclear magnetic relaxation dispersion profiles confirmed the more than 2-fold higher r1-relaxivity in human plasma for the clinically relevant magnetic field strengths from 0.47 to 3.0 T. The complex stability of gadoquatrane at physiological conditions was very high. The observed Gd release after 21 days at 37°C in human serum was below the lower limit of quantification. Gadoquatrane showed no Gd 3+ release in the presence of zinc in the transmetallation assay. The PK profile (plasma elimination, biodistribution, recovery) was comparable to that of gadobutrol. In MRI, the quantitative evaluation of the tumor-to-brain contrast in the rat glioblastoma model showed significantly improved contrast enhancement using gadoquatrane compared with gadobutrol at the same Gd dose administered (0.1 mmol Gd/kg body weight). In comparison to gadoterate meglumine, similar contrast enhancement was reached with gadoquatrane with 75% less Gd dose. In terms of the molecule dose, this was reduced by 90% when compared with gadoterate meglumine. Because of its tetrameric structure and hence lower number of molecules per volume, all prepared formulations of gadoquatrane were iso-osmolar to blood. CONCLUSIONS: The tetrameric gadoquatrane is a novel, highly effective mGBCA for use in MRI. Gadoquatrane provides favorable physicochemical properties (high relaxivity and stability, negligible protein binding) while showing essentially the same PK profile (fast extracellular distribution, fast elimination via the kidneys in an unchanged form) to established mGBCAs on the market. Overall, gadoquatrane is an excellent candidate for further clinical development.

Large area ion beam sputtered dielectric ultrafast mirrors for petawatt laser beamlines.

The latest advances in petawatt laser technology within the ELI Beamlines project have stimulated the development of large surface area dielectrically coated mirrors meeting all demanding requirements for guiding the compressed 30 J, 25 fs HAPLS laser beam at 10 Hz repetition rate and a center wavelength of 810 nm entirely in vacuum. We describe the production and evaluation of Ta2O5/HfO2/SiO2 ion beam sputtered coated (440 × 290 × 75) mm3 beam transport mirrors. No crazing was observed after thirty vacuum-air cycles. A laser induced damage threshold of 0.76 J/cm2 (fluence on mirror surface) was achieved and maintained at high shot rates.

Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment.

OBJECTIVES: : The purpose of this study was to determine the pharmacokinetics (PKs), imaging properties, and safety of the liver-specific magnetic resonance (MR) imaging contrast agent gadoxetic acid disodium (Gd-EOB-DTPA) in subjects with various levels of hepatic impairment, renal impairment, or coexisting hepatic and renal impairment. MATERIALS AND METHODS: : In this single-center, open-label, parallel-group study, patients with varying degrees of renal and/or hepatic impairment were compared with healthy subjects matched for age, gender, and weight (control group). All subjects received a single intravenous bolus of Gd-EOB-DTPA (Primovist, Eovist, EOB-Primovist) 25 µmol/kg body weight. Samples of serum, urine, and feces were collected for PK analysis. MR imaging was performed before dosing and at preset times after dose administration to determine enhancement relative to predose signal intensity values. Safety was assessed by monitoring adverse events, laboratory values, vital signs, cardiac rhythm, oxygen saturation, and by physical examination findings. RESULTS: : Gd-EOB-DTPA was well tolerated by all subjects. Total clearance of Gd-EOB-DTPA did not significantly change in patients with mild and moderate hepatic impairment (Child-Pugh A and B), compared with the control group. Mean urinary excretion was increased and mean fecal excretion was decreased in patients with hepatic impairment. Renal excretion was increased to between 72% and 96% of the dose administered in patients with very high bilirubin levels (>3 mg/dL), compared with 48% in the control group. Total clearance of Gd-EOB-DTPA was significantly reduced to 140 ± 45 mL/min and terminal elimination half-life (t1/2) was slightly, but not significantly, increased to 2.6 ± 0.9 hours in patients with severe hepatic impairment (Child-Pugh C), compared with the control group (209 ± 37 mL/min and 1.8 ± 0.2 hours, respectively). Liver MR signal enhancement (area under the curve of relative enhancement [%] over time) was similar in patients with mild and moderate hepatic impairment and in those in the control group, but was decreased by 38% in patients with severe hepatic impairment, compared with control. Peak liver enhancement, however, was still at a high level (118% ± 57%). PK and imaging parameters were not significantly affected in patients with moderate renal impairment (creatinine clearance, 30-50 mL/min). In patients with end-stage renal failure (ESRF), however, the PK profile of Gd-EOB-DTPA was significantly different, with an increased t1/2 (20.0 ± 7.0 hours vs. 1.8 ± 0.2 hours in the control group). During a 3-hour dialysis session that started 1 hour after administration of the intravenous dose, the serum levels in patients with ESRF declined by between 71% and 88% as a result of elimination by hemodialysis and parallel hepatobiliary excretion. This is comparable with the decline observed in healthy subjects (85%) during the 1- to 4-hour interval after injection. CONCLUSIONS: : The results of the present study show that in humans with moderate renal impairment and mild-to-moderate hepatic impairment, no relevant changes in PK parameters, such as total clearance and t1/2, develop as a result of increased renal excretion to compensate in the case of hepatic impairment (or increased hepatic elimination in the case of renal impairment). The t1/2 of Gd-EOB-DTPA was markedly altered only in patients with ESRF. The high MR signal enhancement profile, observed even in patients with severe hepatic impairment, indicates that there is no need to adjust the dose of Gd-EOB-DTPA.

Prediction of antiangiogenic treatment efficacy by iron oxide enhanced parametric magnetic resonance imaging.

RATIONALE AND OBJECTIVES: Tools for monitoring modern target-specific antiangiogenic and antivascular therapies are highly desirable because treatment strategies are time consuming, expensive, and yet sometimes ineffective. Therefore, the aim of this experimental study was to evaluate the predictive value of steady-state ultrasmall particles of iron oxide (USPIO; SH U 555 C)-enhanced magnetic resonance imaging (MRI) for early assessment of antivascular tumor-treatment effectiveness. METHODS: Mice were inoculated with an HT-1080 fibrosarcoma xenograft and subjected to target-specific antivascular therapy using a selective thrombogenic vascular-targeting agent (truncated tissue factor fused to RGD peptide) or saline as control. Four to 8 hours after treatment, the USPIO-induced change in the transverse relaxation rate DeltaR2* was measured by MRI, and the vascular volume fraction (VVF) was calculated by calibrating DeltaR2* of the tumor by DeltaR2* of muscle tissue. Treatment response was defined by histologic grading of vascular thrombosis and tumor necrosis. RESULTS: After thrombogenic treatment, half of the HT-1080 xenograft-bearing animals showed only minor (=nonresponder) whereas the other half showed extensive tumor thrombosis (=responders). For responders, a significant decrease of DeltaR2* and VVF was observed compared with the control group (DeltaR2*: controls: 16 +/- 1 s-1 vs. responder: 4 +/- 2 s-1; P < 0.001) whereas DeltaR2* and VVF remained nearly unchanged for nonresponders (DeltaR2*: nonresponder 14 +/- 2 s-1). VVF and DeltaR2* values correlated inversely with the histologic grading of vascular thrombosis and tumor necrosis (VVF: r = -0.8; DeltaR2*: r = -0.71; P < 0.01). CONCLUSION: USPIO-enhanced MRI allows a noninvasive, early assessment of treatment efficacy of thrombogenic vascular-targeting agents.

Antiangiogenic tumor treatment: early noninvasive monitoring with USPIO-enhanced MR imaging in mice.

PURPOSE: To prospectively investigate steady-state blood volume measurements for early quantitative monitoring of antiangiogenic treatment with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS: The institutional animal care committee approved all experiments. HT-1080 fibrosarcoma-bearing nude mice were injected with a thrombogenic vascular targeting agent (VTA) (11 nude mice, 20 tumors) or saline (12 nude mice, 20 tumors). USPIO-enhanced (SH U 555C) MR imaging was performed after the VTA was administered. USPIO-induced changes in tissue R2* (DeltaR2*) were measured with a T2-weighted dual-echo echo-planar imaging sequence, and the vascular volume fraction (VVF) was calculated. Parametric DeltaR2* maps were analyzed with respect to tumor perfusion patterns. Correlative histologic analysis was performed for grading of tissue thrombosis, and tissue perfusion was quantified with fluorescent microbeads. Unpaired Student t test and Spearman nonparametric correlation coefficient were used for statistical analysis. RESULTS: The DeltaR2* values were significantly (P < .001) reduced shortly after treatment initiation (mean DeltaR2*, 0.017 msec(-1) +/- 0.0014 [standard error] in control animals vs 0.005 msec(-1) +/- 0.0007 in animals that received VTA), which was also reflected by a decrease in the VVF (2.47% +/- 0.18 vs 0.41% +/- 0.48, P < .001). Histologic analysis revealed various degrees of tumor thrombosis after VTA treatment that correlated inversely with the DeltaR2* values (r = -0.83). Moreover, tumor perfusion measurements corroborated the MR results, indicating a significant reduction in tissue perfusion after VTA treatment (mean tissue fluorescence, 570.4 arbitrary units [au] per gram +/- 27 vs 161.7 au/g +/- 17; P < .05). CONCLUSION: USPIO-enhanced MR imaging enables early monitoring of antiangiogenic treatment of tumors.

Effect of field strengths on magnetic resonance angiography: comparison of an ultrasmall superparamagnetic iron oxide blood-pool contrast agent and gadopentetate dimeglumine in rabbits at 1.5 and 3.0 tesla.

OBJECTIVES: We sought to compare the intravascular enhancement of an ultrasmall superparamagnetic iron oxide (USPIO) blood-pool contrast agent to gadopentetate dimeglumine for contrast-enhanced magnetic resonance angiography (CE-MRA) at field strengths of 1.5 and 3.0 T in rabbits. MATERIALS AND METHODS: CE-MRA at 1.5 and 3.0 T was performed at several time points (50 seconds and 5, 10, 20, and 30 minutes) after the manual intravenous injection of 40 micromol Fe/kg body weight of an USPIO (SH U 555 C; Schering AG, Berlin, Germany) and 100 micromol/kg body weight gadopentetate dimeglumine (Magnevist; Schering AG, Berlin, Germany). MRA was performed with comparable acquisition parameters at both field strengths (Turbo-gradient sequence; 1.5 T: TR/TE/alpha: 5.5/1.7 milliseconds/40 degrees ; 3.0 T: TR/TE/alpha: 5.1/1.8 milliseconds/40 degrees ) on clinical imaging systems (both: Gyroscan Intera, Philips Medical Systems, Best, The Netherlands). At either field strength, 6 rabbits were studied with both contrast agents (n = 24 in total). Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated from signal intensity measurements in the abdominal aorta. RESULTS: Compared with 1.5 T, the SNR and CNR of gadopentetate dimeglumine significantly increased at 3.0 T by a factor of 2.2 and 2.3, respectively (P or= 0.05). At both field strength and either time point, CNR and SNR of SH U 555 C were significantly higher compared with gadopentetate dimeglumine at 3.0 T (P

Synthesis of two 3,5-disubstituted sulfonamide catechol ligands and evaluation of their iron(III) complexes for use as MRI contrast agents.

Two 3,5-disubstituted sulfonamide catechol ligands were synthesized. Tris(ligand) iron(III) complexes were prepared and investigated as MRI contrast agents. Longitudinal relaxivity (r1) values were determined for the complexes. The r1 values in water were substantially higher than those of typical six-coordinate iron(III) complexes. The r1 values in plasma under the same conditions increased. The iron(III) complexes were administered to rats, and the kidney and liver signal intensities were measured by T1-weighted MR imaging experiments.

High-dose Gd-DTPA vs. Bis-Gd-mesoporphyrin for monitoring laser-induced tissue necrosis.

PURPOSE: To compare Bis-Gd-mesoporphyrin (Bis-Gd-MP), a contrast agent with a reported high affinity to necrotic tissue, with high-dose gadopentate dimeglumin (Gd-DTPA) for defining laser-induced muscle and liver necrosis by contrast-enhanced (CE) MRI. MATERIALS AND METHODS: Laser-induced interstitial thermotherapy (LITT) was performed in the muscle and liver tissue of New Zealand White rabbits (1500 J and 2100 J; n=80 lesions). The animals were randomly assigned to a group that received 0.3 mmol/kg bw Gd-DTPA or a group that received 0.05 mmol/kg bw Bis-Gd-MP. Following contrast injection, dynamic MRI was performed on muscle lesions with a T1-weighted, two-dimensional, fast low-angle shot (FLASH) sequence. The liver and muscle lesions were then repeatedly imaged for six hours after contrast injection using a T1-weighted spin-echo (SE) sequence. Central and peripheral lesion enhancement was determined and correlated with gross pathology and microscopy findings. RESULTS: Both contrast agents allowed precise determination of lesion diameters with an average accuracy of 6.8%+/-1.3%. Rim enhancement during dynamic MRI was superior for Gd-DTPA (P<0.001) and revealed slightly higher lesion diameters compared to the results of follow-up MR studies. A persistent enhancement of necrotic liver and muscle tissue was observed for both contrast agents throughout the observation period, suggesting that simple diffusion-type processes may underlie the supposed affinity of Bis-Gd-MP for tissue necrosis. CONCLUSION: Bis-Gd-MP and Gd-DTPA are equally well suited for postinterventional lesion assessment in LITT.

Cell tagging with clinically approved iron oxides: feasibility and effect of lipofection, particle size, and surface coating on labeling efficiency.

PURPOSE: To evaluate the effect of lipofection, particle size, and surface coating on labeling efficiency of mammalian cells with superparamagnetic iron oxides (SPIOs). MATERIALS AND METHODS: Institutional Review Board approval was not required. Different human cell lines (lung and breast cancer, fibrosarcoma, leukocytes) were tagged by using carboxydextran-coated SPIOs of various hydrodynamic diameters (17-65 nm) and a dextran-coated iron oxide (150 nm). Cells were incubated with increasing concentrations of iron (0.01-1.00 mg of iron [Fe] per milliliter), including or excluding a transfection medium (TM). Cellular iron uptake was analyzed qualitatively at light and electron microscopy and was quantified at atomic emission spectroscopy. Cell visibility was assessed with gradient- and spin-echo magnetic resonance (MR) imaging. Effects of iron concentration in the medium and of lipofection on cellular SPIO uptake were analyzed with analysis of variance and two-tailed Student t test, respectively. RESULTS: Iron oxide uptake increased in a dose-dependent manner with higher iron concentrations in the medium. The TM significantly increased the iron load of cells (up to 2.6-fold, P < .05). For carboxydextran-coated SPIOs, larger particle size resulted in improved cellular uptake (65 nm, 4.37 microg +/- 0.08 Fe per 100 000 cells; 17 nm, 2.14 microg +/- 0.06 Fe per 100 000 cells; P < .05). Despite larger particle size, dextran-coated iron oxides did not differ from large carboxydextran-coated particles (150 nm, 3.81 microg +/- 0.46 Fe per 100 000 cells; 65 nm, 4.37 microg +/- 0.08 Fe per 100 000 cells; P > .05). As few as 10 000 cells could be detected with clinically available MR techniques by using this approach. CONCLUSION: Lipofection-based cell tagging is a simple method for efficient cell labeling with clinically approved iron oxide-based contrast agents. Large particle size and carboxydextran coating are preferable for cell tagging with endocytosis- and lipofection-based methods.

First-pass and equilibrium-MRA of the aortoiliac region with a superparamagnetic iron oxide blood pool MR contrast agent (SH U 555 C): results of a human pilot study.

The purpose of this study was to study different doses for first-pass and equilibrium phase MRA of aortoiliac vessels with a superparamagnetic iron oxide (SPIO) intravascular MR contrast agent (SH U 555 C) after single i.v. bolus injection. Sixteen healthy volunteers were prospectively enrolled into this single-blind, placebo-controlled clinical trial. SHU 555 C was injected as an i.v. bolus at stepwise increased dose levels of 5, 10, 20 and 40 micromol Fe/kg bodyweight (b.w.) corresponding to injection volumes of 0.01, 0.02, 0.04 and 0.08 ml/kg b.w. Serial high-resolution three-dimensional MRA of the aortoiliac vessels was acquired during first-pass and equilibrium, at 6 min intervals up to 42 min after contrast application using a breath-hold three-dimensional FLASH sequence on a 1.5 T scanner. Intravascular enhancement was calculated within the abdominal aorta and the inferior vena cava and a statistical analysis for significant differences in vessel enhancement was performed during the bolus and equilibrium phases. The visibility of vessels was ranked and effects of potential artifacts on image quality were graded for each time point and dose group. SH U 555 C showed a dose-dependent intravascular enhancement during the observation period (42 min). The highest dose of 40 micromol Fe/kg b.w. revealed the highest image quality during first-pass and equilibrium phases. The intravascular enhancement in the aorta increased dose-dependently from 5 to 40 micromol kg b.w. during first-pass and equilibrium phases (p<0.05). Intravascular signal inhomogeneities were observed at lower doses and decreased with increasing doses. First-pass MRA was diagnostic at doses of 10, 20 and 40 micromol Fe/kg b.w. For equilibrium MRA, a dose of 40 micromol Fe/kg b.w. was considered to be diagnostic. SH U 555 C proved to be a contrast agent with a high T1-effect suitable for both first-pass MRA comparable to gadolinium-enhanced MRA and high resolution equilibrium MRA up to 42 min post-injection (p.i.).

Accentuation of high susceptibility of hypertrophied myocardium to ischemia: complementary assessment of Gadophrin-enhancement and left ventricular function with MRI.

The aim of the study was to compare infarction size and left ventricular (LV) function in normal and hypertrophied hearts after brief ischemia using Gadophrin-enhancement and functional assessment by MRI. Rats (n = 20) were assigned to aortic banding to induce LV hypertrophy or control. Eight weeks later, rats were subjected to 25 min of regional myocardial ischemia followed by 3 hr of reperfusion. The necrosis-specific agent Gadophrin-3 was injected to delineate infarcted myocardium on MRI. Effects of aortic banding and ischemia on LV mass and function were determined. At postmortem, areas at risk and infarction were measured. Close correlation was found between LV mass measured with MRI and at postmortem (r = 0.98). LV mass measured with MRI was significantly greater (0.81 +/- 0.02 g) in animals with aortic banding compared to control (0.62 +/- 0.02 g; P < 0.001). Infarction size was larger in hypertrophied hearts (19.0 +/- 1.4% / 18.3 +/- 1.5%) than in control (9.8 +/- 1.7% / 9.2 +/- 2.0%) on Gadophrin-enhanced MRI and at postmortem, respectively. Similarly, greater impairment in ejection fraction was observed in hypertrophied hearts with MRI (39 +/- 4% vs. 49 +/- 2%; P = 0.02). Gadophrin-3 provides accurate estimation of infarct size in hypertrophied hearts. Hypertrophied hearts are more sensitive to ischemia than nonhypertrophied hearts. The complementary assessment of Gadophrin-enhancement and LV function with MRI provides unique information about myocardium sensitivity to ischemia.

Myocardial perfusion and MR angiography of chest with SH U 555 C: results of placebo-controlled clinical phase i study.

PURPOSE: To evaluate SH U 555 C for contrast material-enhanced three-dimensional magnetic resonance (MR) angiography of the chest and myocardial perfusion. MATERIALS AND METHODS: For chest MR angiography, SH U 555 C was intravenously injected at four doses (5, 10, 20, and 40 micromol iron [Fe] per kilogram of body weight) into three healthy volunteers per dose group, and placebo (saline) was injected into one additional volunteer per dose group (16 subjects). With a body phased-array coil, serial high-spatial-resolution breath-hold three-dimensional MR angiography of the chest was performed at baseline, first pass, and 6, 12, 18, 24, 30, 36, and 42 minutes after injection. SH U 555 C (40 micromol Fe/kg) was injected into four additional volunteers to evaluate cardiac perfusion. Signal intensity (SI) was measured in vessels, cardiac chambers, and myocardium to calculate relative SI changes during time. Analysis of variance for multiple comparisons was applied for statistical analysis. Two readers assessed image quality. Subjects were monitored for side effects (cardiovascular reactions) for 24 hours. RESULTS: SH U 555 C showed a dose-dependent increase in SI enhancement during first pass and equilibrium phase. SH U 555 C showed dose-dependent increase (range, 259% +/- 160 [SD] at 5 micromol Fe/kg to 907% +/- 370 at 40 micromol Fe/kg) for thoracic aorta during first pass. Intravascular SI did not significantly decrease with time during equilibrium phase within arterial and venous vessels. Image quality remained stable and was diagnostic for highest dose group to 30 minutes, with good to excellent contrast even in smaller blood vessels. For cardiac perfusion, SH U 555 C showed peak enhancement during first pass through right and left ventricles, as well as stable SI during equilibrium phase within cardiac chambers and myocardium. Peak enhancement during first pass was limited due to susceptibility effects, which were more pronounced in right ventricle than in left. Contrast agent was well tolerated, and no cardiovascular reactions occurred. CONCLUSION: SH U 555 C bolus injected at highest dose of 40 micromol Fe/kg has capability for depiction at first-pass MR angiography and for cardiac perfusion.

Detection of atherosclerotic plaque with Gadofluorine-enhanced magnetic resonance imaging.

BACKGROUND: The purpose of this study was to visualize atherosclerotic plaques independently of luminal narrowing using T1-weighted contrast-enhanced MRI. METHODS AND RESULTS: Eight Watanabe heritable hyperlipidemic (WHHL) rabbits, aged 9 to 18 months, and 8 age-matched controls (New Zealand White rabbits) underwent MRI of the aortic arch before and up to 48 hours after injection of 100 micromol/kg Gadofluorine (Schering AG). Additionally, 8 WHHL rabbits were examined with Magnevist (Schering AG). A half-Fourier acquisition single-shot turbo-spin-echo (HASTE) sequence and a T1-weighted inversion-recovery turbo fast, low-angle shot sequence were used for data acquisition. Immediately after the MR examination, the animals were killed, the aorta was stained with Sudan red, and ex vivo imaging of the stained aortic specimens was performed. Additionally, gadolinium concentrations in plaque (Sudan-positive) and normal (Sudan-negative) aortic wall segments were measured. Plain MR imaging revealed no plaques in the aortic arch in either animal group. Enhancement occurred in the aortic wall of all WHHL rabbits examined with Gadofluorine but not in the vessel wall of animals examined with Magnevist and the control group. Sudan red staining demonstrated multiple plaques in the aortic arch of all WHHL rabbits. Ex vivo imaging demonstrated that the area of hyperenhancement matched the area of plaques stained with Sudan red. The gadolinium concentration was 7+/-5 nmol/g for normal aortic wall of the control group and 368+/-30 nmol/g for aortic wall with plaque in WHHL. CONCLUSIONS: Gadofluorine enhances the imaging of atherosclerotic plaques and enables improved plaque detection of even nonstenotic lesions that are not visible on unenhanced MRI.

Detection and quantification of breast tumor necrosis with MR imaging: value of the necrosis-avid contrast agent Gadophrin-3.

RATIONALE AND OBJECTIVES: The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis. MATERIALS AND METHODS: Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings. RESULTS: In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis. CONCLUSION: Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.

Tissue-specific MR contrast agents.

The purpose of this review is to outline recent trends in contrast agent development for magnetic resonance imaging. Up to now, small molecular weight gadolinium chelates are the workhorse in contrast enhanced MRI. These first generation MR contrast agents distribute into the intravascular and interstitial space, thus allowing the evaluation of physiological parameters, such as the status or existence of the blood-brain-barrier or the renal function. Shortly after the first clinical use of paramagnetic metallochelates in 1983, compounds were suggested for liver imaging and enhancing a cardiac infarct. Meanwhile, liver specific contrast agents based on gadolinium, manganese or iron become reality. Dedicated blood pool agents will be available within the next years. These gadolinium or iron agents will be beneficial for longer lasting MRA procedures, such as cardiac imaging. Contrast enhanced lymphography after interstitial or intravenous injection will be another major step forward in diagnostic imaging. Metastatic involvement will be seen either after the injection of ultrasmall superparamagnetic iron oxides or dedicated gadolinium chelates. The accumulation of both compound classes is triggered by an uptake into macrophages. It is likely that similar agents will augment MRI of atheriosclerotic plaques, a systemic inflammatory disease of the arterial wall. Thrombus-specific agents based on small gadolinium labeled peptides are on the horizon. It is very obvious that the future of cardiovascular MRI will benefit from the development of new paramagnetic and superparamagnetic substances. The expectations for new tumor-, pathology- or receptor-specific agents are high. However, is not likely that such a compound will be available for daily routine MRI within the next decade.

MR image-guided endovascular procedures with the ultrasmall superparamagnetic iron oxide SH U 555 C as an intravascular contrast agent: study in pigs.

PURPOSE: To evaluate the feasibility of using the ultrasmall superparamagnetic iron oxide (USPIO) SH U 555 C as an intravascular contrast agent for magnetic resonance (MR) image-guided vascular procedures with an open MR imaging system. MATERIALS AND METHODS: All experiments were performed with MR imaging at 0.2 T. MR image-guided interventions were performed in USPIO-enhanced vessels in four pigs. With near real-time MR image guidance (acquisition time, 0.64 second per section), the splenic and renal arteries were consecutively catheterized by using a susceptibility artifact-based catheter-guide wire combination. Angioplasty and stent implantation were performed four times in the renal artery and twice in the iliac artery. Intraaortal signal intensity (SI) was measured during the interventions. RESULTS: After administration of SH U 555 C (40 micromol of iron per kilogram of body weight), a three-dimensional MR angiographic sequence was performed that allowed visualization of the abdominal and pelvic vessels that were as small as 2 mm in diameter. Catheterization, angioplasty, and stent implantation were successfully guided in the USPIO-enhanced vasculature. Sixty minutes after contrast agent injection, the mean aortic SI was 70% of the maximum measured enhancement levels. CONCLUSION: One intravenous injection of SH U 555 C enabled long, continuous intravascular SI enhancement at MR angiography, and, in combination with susceptibility artifact-based device tracking, the injection allowed the performance of MR imaging-guided intravascular interventions in an open MR imaging system.

Use of a blood-pool contrast agent for MR-guided vascular procedures: feasibility of ultrasmall superparamagnetic iron oxide particles.

RATIONALE AND OBJECTIVES: The purpose of this study was to examine the dose dependency of the intravascular signal intensity after injection of ultrasmall superparamagnetic iron oxide (USPIO) particles (SH U 555 C) in a rabbit model studied with a low-field-strength magnetic resonance (MR) imaging system. The results were used to facilitate MR-guided vascular procedures in a pig. MATERIALS AND METHODS: All experiments were performed at 0.2 T. To determine the optimum USPIO (or SH U 555 C) dose for intravascular interventions, the authors acquired coronal three-dimensional MR angiographic images in 12 rabbits after injection of four dose levels (10, 20, 30, and 40 micromol of iron per kilogram body weight). The intraaortic signal intensities were measured in user-defined regions of interest. For numerical analysis, signal intensity enhancement was computed. Subsequently MR image-guided procedures were performed in USPIO-enhanced vessels in one pig. RESULTS: The signal intensity evaluation shows a clear-cut dose dependence in both early and late phases after administration of SH U 555 C. A high-spatial-resolution MR angiogram acquired 20 minutes after injection yielded the best results with the highest dose (40 micromol of iron per kilogram); at that dose, intravascular enhancement was sufficient for vascular procedures for 60 minutes after injection. CONCLUSION: SH U 555 C is a promising contrast agent for MR angiography and MR-guided vascular procedures in an open low-field-strength MR imager.

Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid interaction with clinical drugs in rats.

RATIONALE AND OBJECTIVES: To investigate whether the hepatic enhancement characteristics of Gd-EOB-DTPA are influenced by the preapplication of a variety of commonly used clinical pharmaceuticals (eg, antibiotics, antineoplastic drugs, corticosteroids, antiarrhythmia drugs, antianxiety drugs, scopolamine, and xanthine derivatives). MATERIALS AND METHODS: Eleven commercially available drugs (prednisolone, rifampicin, doxorubicin hydrochloride, cisplatin, propranolol hydrochloride, scopolamine butylbromide, theophylline, ampicillin, cefotaxime sodium, verapamil hydrochloride, and diazepam) were intravenously (IV) injected in rats at three to five times the clinical dose (n = 3 or 6 per drug). A control group of rats was given saline (n = 6). Gd-EOB-DTPA (25 micromol Gd/kg IV) was administered to rats 30 minutes after the injections of the clinical drugs. Liver MR imaging was performed with a 2.0 T animal imager before and up to 60 minutes after injection. Enhancement (ENH) (%) and area under the data from time versus enhancement curve (AUD) were calculated. RESULTS Rifampicin was the only drug that significantly decreased the hepatic enhancement by Gd-EOB-DTPA. Both the maximum enhancement of the liver and the AUD were significantly reduced when rifampicin was preinjected. Preinjection of prednisolone, doxorubicin hydrochloride, cisplatin or propranolol hydrochloride yielded a slightly but significant increased maximum enhancement of the liver. Furthermore, the enhancement declined more slowly when these drugs were preadministered, yielding a large AUD. None of the other drugs showed a significant effect on hepatic enhancement. CONCLUSION: Rifampicin exerted a clinically significant decrease on hepatic enhancement by Gd-EOB-DTPA. Prednisolone, doxorubicin hydrochloride, cisplatin, or propranolol hydrochloride slightly but significantly increased the hepatic enhancement by Gd-EOB-DTPA.