Current and Future MR Contrast Agents: Seeking a Better Chemical Stability and Relaxivity for Optimal Safety and Efficacy.

This review summarizes 30 years of experience in the development and clinical use of magnetic resonance (MR) contrast agents. Despite their undisputable usefulness for disease diagnosis, gadolinium (Gd)-based contrast agents (GBCAs) have gone through 2 major safety crises. Approximately 10 years ago, the regulatory agencies decided to restrict the use of GBCAs to minimize the risk of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Yet, following the recent discovery of Gd retention in brain, the same agencies adopted different positions ranging from suspension of marketing authorizations, changes in GBCA safety labeling, and performing preclinical and clinical studies to assess the potential long-term consequences of Gd accumulation on motor and cognitive functions. Besides, magnetic resonance imaging (MRI) has benefited from MR technological advances, which provide alternative solutions to increase the MR signal, generate new contrasts on MRI scans, and accelerate their acquisition and analysis. Altogether, GBCAs in combination with new MR techniques have found their place in the diagnostic pathway of various diseases. Despite the large research efforts to identify and develop alternative Gd-free MR agents, manganese- and iron-based contrast agents have failed to reach market approval. In this context, the development of next-generation MR contrast agents should focus on high-stability and high-relaxivity GBCAs, such as gadopiclenol, which offer the possibility to adapt the administered Gd dose to each indication while ensuring an optimal patient safety.

Experimental system to detect a labeled cell monolayer in a microfluidic environment.

PURPOSE: To investigate the feasibility of detecting a living cell monolayer labeled with gadoterate (Gd-DOTA) in a microfluidic environment, by micromagnetic resonance imaging (MRI) in a 2.35T small-animal system. The development of new targeted contrast agents (CAs) requires proof-of-concept studies in order to establish the detectability of the CA and to predict the role of biodistribution in its uptake mechanisms. A promising approach is to carefully mimic the in vivo pharmacokinetic context with reduced experimental complexity compared to in vivo situations. MATERIALS AND METHODS: A dedicated experimental system was built by combining a microfluidic slide and a radiofrequency probe based on a 6 mm diameter multiturn transmission-line resonator. Adherent KB cells were incubated with different concentrations of Gd. MRI data were acquired at 2.35T with a 3D gradient echo and a resolution of 12.4 µm perpendicular to the cell layer. The longitudinal relaxation rate, R1 , was measured as a function of the amount of Gd internalized by the cells. RESULTS: R1 measurements for different Gd concentrations per cell were performed using data with an signal-to-noise ratio (SNR) of 100. Relaxation-rate variations ΔR1 of 0.035 s(-1) were measured. A quenching effect was observed at Gd concentrations above 20 fmol/cell. CONCLUSION: Our results suggest that this dedicated experimental system is suitable for specifically assessing new high-relaxivity targeted CAs under real-time uptake conditions.

Ultra-sensitive molecular MRI of cerebrovascular cell activation enables early detection of chronic central nervous system disorders.

Since endothelial cells can be targeted by large contrast-carrying particles, molecular imaging of cerebrovascular cell activation is highly promising to evaluate the underlying inflammation of the central nervous system (CNS). In this study, we aimed to demonstrate that molecular magnetic resonance imaging (MRI) of cerebrovascular cell activation can reveal CNS disorders in the absence of visible lesions and symptoms. To this aim, we optimized contrast carrying particles targeting vascular cell adhesion molecule-1 and MRI protocols through both in vitro and in vivo experiments. Although, pre-contrast MRI images failed to reveal the ongoing pathology, contrast-enhanced MRI revealed hypoperfusion-triggered CNS injury in vascular dementia, unmasked amyloid-induced cerebrovascular activation in Alzheimer's disease and allowed monitoring of disease activity during experimental autoimmune encephalomyelitis. Moreover, contrast-enhanced MRI revealed the cerebrovascular cell activation associated with known risk factors of CNS disorders such as peripheral inflammation, ethanol consumption, hyperglycemia and aging. By providing a dramatically higher sensitivity than previously reported methods and molecular contrast agents, the technology described in the present study opens new avenues of investigation in the field of neuroinflammation.

Tumor imaging using P866, a high-relaxivity gadolinium chelate designed for folate receptor targeting.

The objective of this study was to evaluate the potential of a high-relaxivity macromolecular gadolinium (Gd) chelate to target folate receptors (FRs). P866 is a dimeric high-relaxivity Gd chelate coupled to a folate moiety. Binding affinity, in vivo biodistribution studies in KB tumor-bearing mice at 1, 4, and 24 h, and dynamic contrast-enhanced (DCE)-MRI (2.35 T) over 4 h were assessed. Binding and internalization of P866 through the FR was demonstrated. Due to the high molecular volume of P866, the binding affinity compared to free FA was decreased (K(D) = 59.3 +/- 1.8 nM and 5.9 +/- 0.2 nM, respectively). Tumor/muscle (T/M) uptake was 5.4 +/- 1.0, 4 h after injection of 15 micromol/kg. Competition with free FA was less effective when the dose was increased due to a saturation of FR. At a dose of 5 micromol/kg, a 70% difference in signal enhancement was observed between P866 and the nonspecific reference compound, thus demonstrating the specificity of FR targeting. While this high-relaxivity folate-Gd chelate has demonstrated its potential capacity to target in vivo FR on tumors, the sensitivity is probably limited to a certain extent by the saturation of the FR and by the decrease in the apparent relaxivity of the internalized part of P866 in the tumor cells.

Evaluation of matrix metalloproteinases in atherosclerosis using a novel noninvasive imaging approach.

OBJECTIVE: Despite great advances in our knowledge, atherosclerosis continues to kill more people than any other disease in the Western world. This is because our means of identifying truly vulnerable patients is limited. Prediction of atherosclerotic plaque rupture may be addressed by MRI of activated matrix metalloproteinases (MMPs), a family of enzymes that have been implicated in the vulnerability of plaques prone to rupture. This study evaluated the ability of the novel gadolinium-based MRI contrast agent P947 to target MMPs in atherosclerotic plaques. METHODS AND RESULTS: The affinity of P947 toward activated MMPs was demonstrated in vitro. The affinity and specificity of P947 toward matrix metalloproteinase (MMP)-rich plaques was evaluated both in vivo using ApoE-/- mice and ex vivo in hyperlipidemic rabbits. Gadolinium content quantification and MRI showed a preferential accumulation of P947 in atherosclerotic lesions compared with the nontargeted reference compound, Gd-DOTA. The ex vivo assay on rabbit plaques revealed a higher uptake of P947. Moreover, using human carotid artery endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich and MMP-poor plaques. An in vivo MRI investigation in mice revealed that P947 greatly improved the ability to visualize and delineate atherosclerotic plaques. CONCLUSIONS: P947 may be a useful tool for the detection and characterization of the MMP-rich atherosclerotic plaques.

Magnetic resonance imaging of myocardial perfusion and viability using a blood pool contrast agent.

RATIONALE AND OBJECTIVES: A comprehensive cardiac magnetic resonance (MR) examination should comprise imaging of myocardial perfusion, viability, and the coronary arteries. Blood pool contrast agents (BPCAs) improve coronary MR angiography, whereas their potential for imaging of perfusion and viability is unknown. The abilities to noninvasively image myocardial perfusion and viability using the BPCA P792 (Guerbet, France) were tested in a closed-chest model of nonreperfused myocardial infarction in 5 pigs. MATERIALS AND METHODS: Two to 3 days after instrumentation, myocardial perfusion imaging with a saturation-recovery steady-state free precession technique and viability imaging with an inversion-recovery fast low-angle shot sequence were conducted on a 1.5-T MR scanner using the extracellular contrast agents (ECCA) Gd-DOTA (0.1 mmol Gd/kg) and blood pool contrast agent (BPCA) P792 (0.013 mmol Gd/kg). RESULTS: Perfusion defects were visualized in all pigs with good correlation between the ECCA and the BPCA (1.77 +/- 1.16 cm2 vs. 1.80 +/- 1.19 cm2, r = 0.959, P < 0.01). Reduced myocardial perfusion was detected using the ECCA up to 80 seconds after injection. In contrast, BPCA administration enabled visualization of perfusion defects on equilibrium perfusion imaging in all cases for 10 minutes. The size of myocardial infarction detected with viability MR imaging correlated well between the standard method (ECCA) and delayed-enhancement imaging with the BPCA (5.40 +/- 3.16 versus 5.52 +/- 3.13 cm3, r = 0.994, P < 0.002). CONCLUSIONS: The BPCA investigated in this study allows both reliable detection of perfusion defects on first pass and equilibrium perfusion imaging and characterization of viability after myocardial infarction. Thus, this contrast agent is suitable for a comprehensive cardiac MR examination.

Assessment of myocardial infarction in pigs using a rapid clearance blood pool contrast medium.

Delayed enhancement MRI using extracellular contrast media allows reliable detection of myocardial infarction. If blood pool contrast media like P792 (Vistarem, Guerbet, France), in addition to improving coronary MR angiography, can be shown to also produce delayed enhancement in myocardial infarction they could improve the prerequisites for a comprehensive cardiac MR examination. In this study reperfused myocardial infarction in five minipigs was imaged with an inversion-recovery fast low-angle shot sequence using P792 (0.013 mmol Gd/kg) and the extracellular contrast medium Gd-DOTA (Dotarem, 0.1 mmol Gd/kg, Guerbet). The infarction size determined on MRI using P792 (7.55 +/- 2.31 cm(2)) highly correlated both with histomorphometry (7.81 +/- 2.18 cm(2), r = 0.991, P < 0.002) and with MRI using Gd-DOTA (7.85 +/- 2.35 cm(2), r = 0.978, P < 0.005). Bland-Altman analysis showed that the limit of agreement of MRI using P792 compared to histomorphometry was 3.3 +/- 7.6% of the infarction size. The contrast-to-noise ratio between infarcted and remote myocardium was not significantly different between Gd-DOTA (5.9 +/- 2.4) and P792 (4.4 +/- 1.1, P = 0.5). The blood pool contrast medium P792 allows reliable assessment of viability with good contrast and accuracy.