Wolfgang Ebert

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.

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.

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.

Imaging of Myocardial Infarction: Comparison of Magnevist and Gadophrin-3 in Rabbits

OBJECTIVESnThis study was designed to determine the enhancement profile of a necrosis-specific contrast agent (gadophrin III) in comparison to a standard extracellular agent on T1-weighted magnetic resonance (MR) images in acute and chronic myocardial infarctions (MIs).nnnBACKGROUNDnContrast-enhanced MR imaging demonstrated the ability to accurately quantify infarct size; however, some controversies persist about which contrast medium is best suited.nnnMETHODSnFifteen rabbits underwent thoracotomy and permanent occlusion of a branch of the left coronary artery. Two animals died before imaging, eight were examined 48 h after occlusion and five animals were imaged six weeks following induction of infarction. All animals received 50 micromol/kg of gadophrin-3 24 h before the MR examination. Continuous short-axis views were collected using an inversion recovery turbo fast low angle shot sequence. Imaging was repeated 5 to 10 min following additional injection of 100 micromol/kg of Magnevist. The area of hyperenhancement demarcated following gadophrin-3 injection was compared with the region of hyperenhancement seen on gadophrin-3 plus Magnevist enhanced image using triphenyltetrazolium chloride (TTC) staining as the standard of reference.nnnRESULTSnIn acute MI the mean difference in size of hyperenhancement seen on the two different in vivo MR scans was -1.8 +/- 6.0 mm(2) (p > 0.05). Both measurements showed excellent agreement with TTC staining. Chronic MIs showed no enhancement with gadophrin-3, whereas application of Magnevist resulted in hyperenhancement. CONCLUSIONS; Standard extracellular contrast agents do not overestimate the size of acute MI. The combination of gadophrin-3 and Magnevist can distinguish acute and chronic myocardial injury because chronic MIs do not enhance with gadophrin-3.

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

RATIONALE AND OBJECTIVESnThe 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.nnnMATERIALS AND METHODSnTwenty 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.nnnRESULTSnIn 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.nnnCONCLUSIONnGadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.

Gadomer-17-enhanced 3D navigator-echo MR angiography of the pulmonary arteries in pigs

Abstract. The goal of this study was visualisation and quality assessment of the pulmonary arteries in pigs with modified navigator-echo magnetic resonance angiography using an intravascular contrast agent. Five sedated pigs were examined in a clinical 1.5-T system with modified three-dimensional navigator-echo magnetic resonance angiography (slice thickness 3xa0mm, pixel size 2.4×1.8xa0mm2) to evaluate the pulmonary arteries. Using a phased-array four-element thorax coil the entire thorax was scanned before and after intravenous infusion of a gadolinium-based intravascular contrast agent. Assessment of image quality, enhancement-related contrast-to-noise ratio (CNR) measurements and improvement of visibility of peripheral pulmonary vessels was performed. Improvement of quality using Gadomer-17 was found for smaller vessels; pulmonary trunks and the main pulmonary arteries were sufficiently imaged without enhancement. Mean rise of CNR measured in the pulmonary trunks was 28.64% (P=0.0002), mean rise of CNR in the main pulmonary arteries and the segmental arteries were 79.6% and 148.2%, respectively. Mean distance between the visible peripheral end of 60 sub-segmental arteries and the inner thoracic wall was 12.2±0.4xa0mm, and was significantly (P=0.00002) reduced after contrast infusion to 8.0±0.4xa0mm. The combination of inherent flow sensitivity of navigator-echo angiography and Gadomer-17 proved effective for imaging of the pulmonary arteries. In contrast to standard contrast-enhanced pulmonary MRA studies, breath holding is not required. Further studies and the evaluation of findings of patients suffering from pulmonary embolism are needed to evaluate the possible benefits of a higher spatial resolution which is achievable using navigator-echo techniques in contrast to the higher temporal resolution of ultra-fast pulmonary MRA.

First-pass and equilibrium phase MRA following intravenous bolus injection of SH U 555 C: Phase I clinical trial in elderly volunteers with risk factors for arterial vascular disease

Various types of intravascular contrast agents, either based on the binding of paramagnetic chelates to carriers such as synthetic polymers or biological macromolecules or on ultrasmall particles of superparamagnetic iron oxides (USPIO), are currently investigated in experimental and clinical studies (1–9). USPIO offer an increased r1/ r2-ratio and a prolonged intravascular retention compared to small particles of iron oxides (SPIO), which were designed as T2*-contrast agents for imaging of the reticuloendothelial system (RES). Therefore, USPIO provide the potential for use as an intravascular contrast agent for T1-weighted MRI (2–6). The purpose of our study was to evaluate imaging properties of different doses of a new ultra-small iron oxide MR contrast agent (SH U 555 C, Schering AG, Germany) for first-pass and equilibrium phase MRA of aortoiliac vessels in elderly male volunteers with risk factors for arterial vascular diseases. MATERIALS AND METHODS

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. Magn Reson Med 51:552–558, 2004.

Comparative studies on the efficacy of MRI contrast agents in MRA

Values for the signal intensity (SI) of plasma samples spiked with different concentrations (0.005–25 mmol/L) of various paramagnetic agents (gadopentetate dimeglumine [Magnevist; Schering AG, Berlin, Germany]; gadoxetic acid [Eovist; Schering AG]; Gadomer-17 [Schering AG]; gadobenate dimeglumine [MultiHance; Bracco, Milan, Italy]; MS-325 [EPIX Medical, Cambridge, Mass); and the ultrasmall superparamagnetic iron oxide [USPIO], SH U 555C [Schering AG]) were measured at 1.5 T (Allegra; Siemens AG, Erlangen, Germany). A three-dimensional (3D) MRA sequence (4.7/1.89 [repetition time msec/echo time msec], 25° flip angle) was used. The SI values of the maximum intensity projections (MIP) were measured, and the apparent T1 and T2* relaxivities were calculated from the SI-versus-concentration curves using the known dependence of the SI from sequence parameters and relaxation times (1). MRA studies using a superconducting MR imager (Allegra; Siemens AG) were performed in rabbits after intravenous injection of two dose regimens. The contrast agents were injected after starting the imaging sequence to achieve optimum bolus concentrations during the k space of the sequence. Additional images were taken at 3, 10, and 30 minutes after dosing. A dose of 0.2 mmol/kg was used for all agents to allow a comparison of the various agents with the currently performed practice with extracellular gadolinium chelates (eg, Magnevist). A second dose was adjusted to the calculated T1 relaxivity of Magnevist in plasma.

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

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.