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Magnetic resonance imaging (MRI) contrast agents are utilized adjunctively to enhance the contrast between normal and abnormal structures on MRI scans. Along with the rapid evolution of the field has come a new appreciation for the medicinal chemistry of this unique class of metallopharmaceuticals. The efficacy of MRI agents is a complex function of chemical, biophysical, and pharmacological properties, which must be married in a package of exquisite safety. This report illustrates the wide range of medicinal chemistry relevant to existing agents that are either approved or in clinical development, as well as concepts, which may result in exciting new pharmaceuticals in the future.

Objective The aim of this study was to assess whether visualisation of in-stent changes can be improved with high-resolution, steady-state, blood pool contrast-enhanced MR angiography compared with first-pass MR angiography. Intra-arterial digital subtraction angiography (DSA) served as the reference standard. Methods Twenty patients after stent placement in the superficial femoral artery (SFA) underwent MRA prior to reintervention. MRA of the SFA includes first-pass MRA as well as 3D high-resolution MRA in the steady state (SS-MRA) after injection of Gadofosveset trisodium. Sensitivity and specificity values for the detection of significant in-stent lesions by means of SS-MRA were calculated at the proximal, middle and distal stent segments in comparison to DSA. Kappa statistics were used to determine agreement between the two techniques. Results Sensitivity and specificity values for the detection of significant stenosis with SS-MRA reached 95% in the proximal, 100% in the middle and 100% in the distal stent segment. Kappa coefficients between SS-MRA and DSA were 0.789, 0.797 and 0.859 for the proximal, middle and distal segments, whereas the Kappa coefficients for FP-MRA were 0,211, 0,200 and 0,594 in these segments, respectively. Conclusion Detection of in stent stenosis is significantly improved using SS MRA, in comparison to state-of-the-art FP-MRA.

Magnetic resonance (MR) angiography has significantly reduced the need for diagnostic conventional angiography and is preferred over CT angiography in children because of its lack of ionizing radiation. The availability of gadofosveset trisodium (the only clinically approved blood pool MR contrast agent) has led to an increase in applications of MR for vascular imaging and an improvement in diagnostic quality of MR angiography. Gadofosveset is a gadolinium-based contrast agent that binds reversibly to albumin, resulting in increased paramagnetic effect and longer intravascular residence. This allows for high-resolution arterial and venous MR angiography, assessment of flow characteristics of vascular malformations, dynamic vascular imaging, and multi-station imaging with a single low-dose gadolinium contrast injection. The purpose of this pictorial essay is to facilitate understanding of the kinetics and safety profile of gadofosveset trisodium, discuss technical aspects of imaging, and illustrate advantages and extracardiac applications in pediatric body imaging.

Background A comprehensive cardiac magnetic resonance (cardiac MR) study including both late gadolinium enhancement (LGE) and MR angiography may be indicated for patients with a history of acquired or congenital heart disease. Objective To study the novel use of an extracellular agent for assessment of LGE combined with a blood pool contrast agent for detailed MR angiography evaluation to yield a comprehensive cardiac MR study in these patients. Materials and methods We reviewed clinical cardiac MR studies utilizing extracellular and blood pool contrast agents and noted demographics, clinical data and adverse events. We rated LGE image quality and MR angiography image quality for each vascular segment and calculated inter-rater variability. We also quantified contrast-to-noise ratio (CNR). Results Thirty-three patients (mean age 13.9 ± 3 years) received an extracellular contrast agent (10 gadobenate dimeglumine, 23 gadopentetate dimeglumine) and blood pool contrast agent (33 gadofosveset trisodium). No adverse events were reported. MRI indications included Kawasaki disease (8), cardiomyopathy and coronary anatomy (15), repaired congenital heart disease (8), and other (2). Mean LGE quality was 2.6 ± 0.6 with 97% diagnostic imaging. LGE quality did not vary by type of contrast agent given ( P  = 0.07). Mean MR angiography quality score was 4.7 ± 0.6, with high inter-rater agreement (k = 0.6–0.8, P  < 0.002). MR angiography quality did not vary by type of contrast agent used ( P  = 0.6). Conclusion Cardiac MR studies utilizing both extracellular and blood pool contrast agents are feasible and safe and provide excellent-quality LGE and MR angiography images. The use of two contrast agents allows for a comprehensive assessment of both myocardial viability and vascular anatomy during the same exam.

One of the characteristics of the blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) response to functional challenges of the brain is the poststimulation undershoot, which has been suggested to originate from a delayed recovery of either cerebral blood volume (CBV) or cerebral metabolic rate of oxygen to baseline. Using bolus-tracking MRI in humans, we recently showed that relative CBV rapidly normalizes after the end of stimulation. As this observation contradicts at least part of the blood-pool contrast agent studies performed in animals, we reinvestigated the CBV contribution by dynamic T1-weighted three-dimensional MRI (8 seconds temporal resolution) and Vasovist at 3 T (12 subjects). Initially, we determined the time constants of individual BOLD responses. After injection of Vasovist, CBV-related T1-weighted signal changes revealed a signal increase during visual stimulation (1.7%±0.4%), but no change relative to baseline in the poststimulation phase (0.2%±0.3%). This finding renders the specific nature of the contrast agent unlikely to be responsible for the discrepancy between human and animal studies. With the assumption of normalized cerebral blood flow after stimulus cessation, a normalized CBV lends support to the idea that the BOLD MRI undershoot reflects a prolonged elevation of oxidative metabolism.

The purpose of this study was to compare the image quality of the intravascular contrast agent gadofosveset with the extracellular contrast agent gadoterate meglumine in time-resolved three-dimensional magnetic resonance (MR) angiography of the human arteries of the hand. The value of cuff compression technique for suppression of venous enhancement for both contrast agents was also investigated. Three-dimensional MR angiograms of both hands of 11 healthy volunteers were acquired for each contrast agent at 1.5-T, while subsystolic cuff compression was applied at one side. Quantitative and qualitative evaluation were performed and analyzed with Student’s t -test. Visualization of vessels was superior in the images acquired with gadofosveset, especially in the late phases. Quantitative and qualitative evaluation showed significantly higher values for gadofosveset. The cuff compression at the lower arm proved to be an effective method to enhance arterial vessels. In conclusion the blood pool agent gadofosveset is superior for the dynamic imaging of the vessels of the hand when compared with the extracellular contrast agent gadoterate meglumine. To fully utilize the advantages of intravascular contrast agents, venous overlay has to be delayed or reduced, which can be achieved effectively by subsystolic lower arm cuff compression.

With the development of new magnetic resonance (MR) contrast agents that have longer persistence in the blood, contrast-enhanced magnetic resonance angiography (MRA) facilitates non-invasive imaging of the cardiovascular system at high resolution in large anatomic volumes. These high resolution 'steady state' images have simultaneous enhancement of both the artery and vein blood pools. Consequently, separation of arteries and veins is an emerging challenge in MRA analysis. Because of the complexity of the vascular structure, manual approaches to cardiovascular tree analysis are impractical. A novel, highly-automated low extremity vessel segmentation and display methodology is reported that consists of five main steps: (1) Binary mask generation, (2) tree-structure generation, (3) optimal vessel path calculation, (4) vessel segment labeling, and (5) conflict resolution. The method's performance was tested in computer phantoms and in in vivo data sets. In the computer-generated phantoms, vessel volume errors ranged from 1.0 to 8.8%. In the in vivo data, the labeling errors ranged from 0.1 to 15.5%. The method provided high quality results in individual data sets and demonstrated segmentation robustness.

The purpose of this study was to assess the accuracy of fractional blood volume (vb) estimates in low-perfused and low-vascularized tissue using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The results of different MRI methods were compared with histology to evaluate the accuracy of these methods under clinical conditions. vb was estimated by DCE-MRI using a 3D gradient echo sequence with k-space undersampling in five muscle groups in the hind leg of 9 female pigs. Two gadolinium-based contrast agents (CA) were used: a rapidly extravasating, extracellular, gadolinium-based, low-molecular-weight contrast agent (LMCA, gadoterate meglumine) and an extracellular, gadolinium-based, albumin-binding, slowly extravasating blood pool contrast agent (BPCA, gadofosveset trisodium). LMCA data were evaluated using the extended Tofts model (ETM) and the two-compartment exchange model (2CXM). The images acquired with administration of the BPCA were used to evaluate the accuracy of vb estimation with a bolus deconvolution technique (BD) and a method we call equilibrium MRI (EqMRI). The latter calculates the ratio of the magnitude of the relaxation rate change in the tissue curve at an approximate equilibrium state to the height of the same area of the arterial input function (AIF). Immunohistochemical staining with isolectin was used to label endothelium. A light microscope was used to estimate the fractional vascular area by relating the vascular region to the total tissue region (immunohistochemical vessel staining, IHVS). In addition, the percentage fraction of vascular volume was determined by multiplying the microvascular density (MVD) with the average estimated capillary lumen, [Formula: see text], where d = 8μm is the assumed capillary diameter (microvascular density estimation, MVDE). Except for ETM values, highly significant correlations were found between most of the MRI methods investigated. In the cranial thigh, for example, the vb medians (interquartile range, IQRs) of IHVS, MVDE, BD, EqMRI, 2CXM and ETM were vb = 0.7(0.3)%, 1.1(0.4)%, 1.1(0.4)%, 1.4(0.3)%, 1.2(1.8)% and 0.1(0.2)%, respectively. Variances, expressed by the difference between third and first quartiles (IQR) were highest for the 2CXM for all muscle groups. High correlations between the values in four muscle groups-medial, cranial, lateral thigh and lower leg - estimated with MRI and histology were found between BD and EqMRI, MVDE and 2CXM and IHVS and ETM. Except for the ETM, no significant differences between the vb medians of all MRI methods were revealed with the Wilcoxon rank sum test. The same holds for all muscle regions using the 2CXM and MVDE. Except for cranial thigh muscle, no significant difference was found between EqMRI and MVDE. And except for the cranial thigh and the lower leg muscle, there was also no significant difference between the vb medians of BD and MVDE. Overall, there was good vb agreement between histology and the BPCA MRI methods and the 2CXM LMCA approach with the exception of the ETM method. Although LMCA models have the advantage of providing excellent curve fits and can in principle determine more physiological parameters than BPCA methods, they yield more inaccurate results.

Contrast-enhanced magnetic resonance angiography (CE-MRA) with standard extracellular contrast material is well established for vascular imaging. Recently, the first blood pool contrast agent (BPA) has become clinically available. This paper reviews characteristics and classification of BPA as well as first clinical experience in various vascular territories. BPAs comprise gadolinium-based compounds, synthetic compounds, and ultrasmall superparamagnetic iron-oxide (USPIO) particles. Such BPAs are retained in blood with a prolonged time-window of enhancement as compared to extracellular gadolinium chelates. Promising results from USPIO at first-pass and steady-state angiography have been published, but no USPIO is approved yet. Gadofosveset is the first clinically approved BPA. After bolus injection, gadofosveset binds noncovalently to serum-albumine, thus enhancing relaxivity. First published results from carotid, coronary, renal, and peripheral angiography are encouraging; particularly helpful is prolonged enhancement during steady state. More BPAs have been clinically evaluated, but no approval has been granted. Bolus-injectable BPAs allow for first-pass CE-MRA similar to standard extracellular contrast media, but with higher relaxivity, allowing lower doses and reduced injection rates. An additional feature of BPA is the steady-state phase with a broad time window enabling high-resolution angiography or double-gated angiography of coronary arteries to compensate for the complex motion pattern.

PurposeThe ability to non-invasively image myocardial microvascular dilation and constriction is essential to assessing intact function and dysfunction. Yet, conventional measurements based on blood oxygenation are not specific to changes in blood volume. The purpose of this study was to extend to the heart a blood-pool MRI approach for assessing vasomodulation in the presence of blood gas changes and investigate if sex-related differences exist.MethodsAnimals [five male and five female healthy Sprague Dawley rats (200–500 g)] were intubated, ventilated, and cycled through room air (normoxia) and hypercapnia (10% CO2) in 10-minute cycles after i.v. injection of blood-pool agent Ablavar (0.3 mmol/kg). Pre-contrast T1 maps and T1-weighted 3D CINE were acquired on a 3 Tesla preclinical MRI scanner, followed by repeated 3D CINE every 5 min until the end of the gas regime. Invasive laser Doppler flowmetry of myocardial perfusion was performed to corroborate MRI results.ResultsMyocardial microvascular dilation to hypercapnia and constriction to normoxia were readily visualized on T1 maps. Over 10 min of hypercapnia, female myocardial T1 reduced by 20% (vasodilation), while no significant change was observed in the male myocardium. After return to normoxia, myocardial T1 increased (vasoconstriction) in both sexes (18% in females and 16% in males). Laser Doppler perfusion measurements confirmed vasomodulatory responses observed on MRI.ConclusionBlood-pool MRI is sensitive and specific to vasomodulation in the myocardial microcirculation. Sex-related differences exist in the healthy myocardium in response to mild hypercapnic stimuli.