Hanns-Joachim Weinmann

Comparison of Magnetic Properties of Mri Contrast Media Solutions at Different Magnetic Field Strengths

Rationale and Objectives:To characterize and compare commercially available contrast media (CM) for magnetic resonance imaging (MRI) in terms of their relaxivity at magnetic field strengths ranging from 0.47 T to 4.7 T at physiological temperatures in water and in plasma. Relaxivities also were quantified in whole blood at1.5 T. Methods:Relaxivities of MRI-CM were determined by nuclear magnetic resonance (NMR) spectroscopy at 0.47 T and MRI phantom measurements at 1.5 T, 3 T, and 4.7 T, respectively. Both longitudinal (T1) and transverse relaxation times (T2) were measured by appropriate spin-echo sequences. Nuclear magnetic resonance dispersion (NMRD) profiles were also determined for all agents in water and in plasma. Results:Significant dependencies of relaxivities on the field strength and solvents were quantified. Protein binding leads to both increased field strength and solvent dependencies and hence to significantly altered T1 relaxivity values at higher magnetic field strengths. Conclusions:Awareness of the field strength and solvent associated with relaxivity data is crucial for the comparison and evaluation of relaxivity values. Data observed at 0.47 T can thus be misleading and should be replaced by relaxivities measured at 1.5 T and at 3 T in plasma at physiological temperature.

Stability of Gadolinium-Based Magnetic Resonance Imaging Contrast Agents in Human Serum at 37°C

Objectives:Assessment of the complex stability and Gd3+ dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37°C. Methods and Results:The kinetic profiles of Gd3+ dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37°C. The initial rates of Gd3+ release and the amounts of Gd3+ released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd3+ dissociation was also investigated. The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37°C [% Gd3+ release after 15 days and initial rate (%/d) (95% confidence interval) in brackets]. Nonionic Linear GBCAs:Optimark [21 (19–22) %, 0.44 (0.40–0.51) %/d) and Omniscan [20 (17–20) %, 0.16 (0.15–0.17) %/d]. Ionic Linear GBCAs:Magnevist [1.9 (1.2–2.0) %, 0.16 (0.12–0.36) %/d], Multihance [1.9 (1.3–2.1) %, 0.18 (0.13–0.38) %/d], Vasovist [1.8 (1.4–1.9) %, 0.12 (0.11–0.18) %/d], and Primovist [1.1 (0.76–1.2) %, 0.07 (0.05–0.08) %/d]. Macrocyclic GBCAs:Gadovist, Prohance, and Dotarem (all < limit of quantification of 0.1%, <0.007%/d). In the presence of additional 10 mmol/L phosphate in serum, the initial Gd3+ release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd3+ released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd3+ released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd3+ from the 3 macrocyclic GBCAs. Conclusions:The release of Gd3+ from all linear Gd complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.

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.

Lipid-Rich Atherosclerotic Plaques Detected by Gadofluorine-Enhanced In Vivo Magnetic Resonance Imaging

Background—MRI of specific components in atherosclerotic plaque may provide information on plaque stability and its potential to rupture. We evaluated gadofluorine in atherosclerotic rabbits using a new MR sequence that allows plaque detection within 1 hour after injection and assessed enhancement in lipid-rich and non–lipid-rich plaques. Methods and Results—Twelve rabbits with aortic plaque and 6 controls underwent MRI before and up to 24 hours after gadofluorine injection (50 μmol/kg). Two T1-weighted, segmented gradient-echo sequences (TFL) were compared to enhance vessel wall delineation after injection: (1) an inversion-recovery prepulse (IR-TFL) or (2) a combination of inversion-recovery and diffusion-based flow suppression prepulses (IR-DIFF-TFL). With the use of IR-TFL at 1 hour after injection, the vessel wall was not delineated because of poor flow suppression; at 24 hours after injection, the enhancement was 37% (P<0.01). IR-DIFF-TFL showed significant enhancement after versus before contrast (1 hour: 164% [P<0.005]; 24 hours: 207% [P<0.001]). At 1 hour and 24 hours after injection, the contrast-to-noise ratio was higher with the use of IR-DIFF-TFL than with IR-TFL (1 hour: 13.0±7.7 versus −19.8±10.3 [P<0.001]; 24 hours: 15.2±5.9 versus 11.4±8.9, respectively [P=0.052]). There was no enhancement in the vessel wall after gadofluorine injection in the control group. A strong correlation was found (r2=0.87; P<0.001) between the lipid-rich areas in histological sections and signal intensity in corresponding MR images. This suggests a high affinity of gadofluorine for lipid-rich plaques. Conclusions—Gadofluorine-enhanced MRI improves atherosclerotic plaque detection. The IR-DIFF-TFL method allows early detection of atherosclerotic plaque within 1 hour after gadofluorine injection.

A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium-based contrast media.

Objectives:Several recent publications have suggested an association between the administration of gadolinium (Gd)-based contrast agents and the occurrence of Nephrogenic Systemic Fibrosis (NSF), an acquired disorder marked by skin thickening and fibrosis occurring in patients with severe renal dysfunction. The aim of this study was to establish a preclinical experimental setting to investigate the possible link between NSF and Gd-based contrast agents, and specifically the role of Gd and/or depletion of endogenous metal ions as possible triggers for NSF. Materials and Methods:Thirty-five healthy male rats received repeated intravenous injections of Magnevist (gadopentetate dimeglumine; Gd-DTPA), Omniscan (gadodiamide; Gd-DTPA-BMA), or gadodiamide without caldiamide at a dose of 2.5 mmol Gd/kg body weight over at least 20 days to simulate the exposure to Gd-containing contrast agents in patients with severe renal dysfunction. In addition, caldiamide (the excess ligand in Omniscan) and Gd-ethylenediamine tetraacetic acid (Gd-EDTA) as a positive control, and saline as a negative control were studied. Histopathologic and immunohistochemical analysis of the skin was performed. Gd and zinc concentrations were measured in skin, femur, and liver tissue by atomic emission spectrometry. Results:Rats receiving Gd-EDTA, gadodiamide without caldiamide, and Omniscan developed epidermal ulceration and acanthosis, dermo-epidermal clefts, minimal-to-slight dermal fibrosis, and increased dermal infiltration of different cells, partly positive for CD34 fibrocytes. No such NSF-like macroscopic lesions were observed in the saline, caldiamide, and Magnevist groups. High Gd concentrations in the skin were found in the Gd-EDTA, gadodiamide without caldiamide, and Omniscan groups. In the Magnevist group, Gd levels in the skin were 10-times lower than in the Omniscan-treated animals but elevated compared with saline. Conclusions:A preclinical experimental setting has been established where NSF-like lesions could be observed. The link between the application of Gd-based contrast media and the induction of NSF-like lesions was established. The data indicate that the observed skin lesions are related to the release of Gd and not to the depletion of endogenous ions. The investigations further suggest potential importance of the stability of Gd-based contrast agents.

In vivo and in vitro evaluation of Gd-DTPA-polylysine as a macromolecular contrast agent for magnetic resonance imaging

Polylysine covalently linked to moieties of gadopentetate (Gd-DTPA), for use as a macromolecular blood pool marker for contrast material-enhanced magnetic resonance imaging (MRI), was characterized by means of physicochemical measurements and pharmacokinetics in rats and rabbits and compared with Gd-DTPA. Gd-DTPA-polylysine was composed of a series of polymers of different molecular sizes that on average were labeled with 60 to 70 Gd-DTPA moieties (average molecular weight, 48,700 daltons [D]). For the macromolecular compound Gd-DTPA-polylysine, relaxivity was three times higher than that of Gd-DTPA. The LD50 value of 17 mmol/kg reflects a fairly high acute intravenous tolerance of the macromolecular compound in mice. Even though the volume of distribution of Gd-DTPA-polylysine in rabbits approached the extracellular fluid space (indicating that the macromolecular compound was also leaking slowly into the interstitial space), the half-life of distribution of the macromolecular compound in the extracellular fluid space was significantly prolonged, thus making the compound suitable as a blood pool marker for MRI. In rats the elimination of Gd-DTPA-polylysine occurred predominantly via the renal route. High-pressure liquid chromatography-size-exclusion chromatography of the fractionated urine samples revealed that the renal clearance must be the integral sum of the separate clearances of each molecular weight species. No biodegradation of the polypeptide was observed, and biodistribution studies revealed only minimal retention of Gd in the body of the rat.

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 &mgr;mol/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.

Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions.

Recent reports suggest that nephrogenic systemic fibrosis (NSF) is associated with the administration of gadolinium (Gd)-based contrast agents (GBCAs) and in particular with the stability of the Gd-complex. The aim of this investigation was to compare GBCAs and their potential to trigger NSF. Forty-two healthy male rats received repeated intravenous injections of six different GBCAs at high doses to simulate the exposure seen in patients with severe renal dysfunction. Histopathological and immunohistochemical analysis of the skin was performed, and the concentrations of Gd, zinc and copper were measured in several tissues by inductive coupled plasma atomic emission spectroscopy. Macroscopic and histological skin changes similar to those seen in NSF patients were only observed in rats receiving Omniscan. In addition, very high concentrations of Gd were observed in the animals treated with Omniscan, and, to a lesser extent, in animals treated with OptiMARK. Significantly lower levels of Gd were found after the treatment with ionic linear agents and even less after the treatment with macrocyclic agents. The data in this investigation strongly suggest that the stability of the Gd-complex is a key factor for the development of NSF-like symptoms in this experimental setting.

Simultaneous MRI Measurement of Blood Flow, Blood Volume, and Capillary Permeability in Mammary Tumors Using Two Different Contrast Agents

A technique for the simultaneous measurement of three vascular parameters: blood flow (Fρ), blood volume (vb), and the capillary permeability‐surface area product (PSρ) in breast tumors using dynamic contrast‐enhanced magnetic resonance imaging (MRI) is presented. Features of the technique include measurement of precontrast tumor T1, rapid temporal sampling, measurement of the arterial input function, and use of a distributed parameter tracer kinetic model. Parameter measurements are compared that were determined using two contrast agents of different molecular weights, gadolinium‐diethylene triamine pentaacetic acid (Gd‐DTPA; 0.6 kDa) and Gadomer‐17 (17 kDa), in 18 spontaneous canine mammary tumors. Measurements of Fρ and vb corresponded well with literature values, and the mean PSρ measured using Gd‐DTPA was a factor of 15 higher than that measured using Gadomer‐17. J. Magn. Reson. Imaging 2000;12:991–1003.

Pharmacokinetics of Gadomer-17, a new dendritic magnetic resonance contrast agent

Rationale and objectives: Gadomer-17 is a new magnetic resonance (MR) contrast medium presently in clinical development. It is a dendritic gadolinium (Gd) chelate carrying 24 Gd ions. This study investigated the pharmacokinetic behavior of this contrast medium. Methods: The pharmacokinetics of Gadomer-17 were investigated in different species (rat, rabbit, dog, monkey) for up to 7 days after intravenous (i.v.) injection of 25–100 μmol/kg body weight. In addition, elimination and biodistribution were evaluated after single i.v. injection of Gadomer-17 in rats. Results: After i.v. injection Gadomer-17 distributes almost exclusively within the intravascular space without significant diffusion into the interstitial space. The volume of distribution (Vc) in the initial or α-phase ranged from 0.04 1/kg (rats, rabbits) to 0.06 1 kg (monkeys) and 0.07 1/kg (dogs), which reflects mainly the plasma volume. The blood/plasma concentration profile was found to be biphasic. The volume of distribution at a steady state is clearly smaller than that of other contrast media, which distribute to the extracellular space. After single i.v. injection in rats, the dendritic contrast medium was rapidly and completely eliminated from the body, mainly via glomerular filtration. No long-term accumulation or retention of the nonmetabolized agent was detectable in organs or tissues. Conclusions: Gadomer-17 is a promising new MR contrast medium that has an intravascular distribution and a rapid renal elimination.