Small Brain Lesion Enhancement and Gadolinium Deposition in the Rat Brain: Comparison Between Gadopiclenol and Gadobenate Dimeglumine.

OBJECTIVES: The aim of the set of studies was to compare gadopiclenol, a new high relaxivity gadolinium (Gd)-based contrast agent (GBCA) to gadobenate dimeglumine in terms of small brain lesion enhancement and Gd retention, including T1 enhancement in the cerebellum. MATERIALS AND METHODS: In a first study, T1 enhancement at 0.1 mmol/kg body weight (bw) of gadopiclenol or gadobenate dimeglumine was evaluated in a small brain lesions rat model at 2.35 T. The 2 GBCAs were injected in an alternated and cross-over manner separated by an interval of 4.4 ± 1.0 hours (minimum, 3.5 hours; maximum, 6.1 hours; n = 6). In a second study, the passage of the GBCAs into cerebrospinal fluid (CSF) was evaluated by measuring the fourth ventricle T1 enhancement in healthy rats at 4.7 T over 23 minutes after a single intravenous (IV) injection of 1.2 mmol/kg bw of gadopiclenol or gadobenate dimeglumine (n = 6/group). In a third study, Gd retention at 1 month was evaluated in healthy rats who had received 20 IV injections of 1 of the 2 GBCAs (0.6 mmol/kg bw) or a similar volume of saline (n = 10/group) over 5 weeks. T1 enhancement of the deep cerebellar nuclei (DCN) was assessed by T1-weighted magnetic resonance imaging at 2.35 T, performed before the injection and thereafter once a week up to 1 month after the last injection. Elemental Gd levels in central nervous system structures, in muscle and in plasma were determined by inductively coupled plasma mass spectrometry (ICP-MS) 1 month after the last injection. RESULTS: The first study in a small brain lesion rat model showed a ≈2-fold higher number of enhanced voxels in lesions with gadopiclenol compared with gadobenate dimeglumine. T1 enhancement of the fourth ventricle was observed in the first minutes after a single IV injection of gadopiclenol or gadobenate dimeglumine (study 2), resulting, in the case of gadopiclenol, in transient enhancement during the injection period of the repeated administrations study (study 3). In terms of Gd retention, T1 enhancement of the DCN was noted in the gadobenate dimeglumine group during the month after the injection period. No such enhancement of the DCN was observed in the gadopiclenol group. Gadolinium concentrations 1 month after the injection period in the gadopiclenol group were slightly increased in plasma and lower by a factor of 2 to 3 in the CNS structures and muscles, compared with gadobenate dimeglumine. CONCLUSIONS: In the small brain lesion rat model, gadopiclenol provides significantly higher enhancement of brain lesions compared with gadobentate dimeglumine at the same dose. After repeated IV injections, as expected for a macrocyclic GBCA, Gd retention is minimalized in the case of gadopiclenol compared with gadobenate dimeglumine, resulting in no T1 hypersignal in the DCN.

Molecular Imaging to Predict Response to Targeted Therapies in Renal Cell Carcinoma.

Molecular magnetic resonance imaging targeted to an endothelial integrin involved in neoangiogenesis was compared to DCE-US and immunochemistry to assess the early response of three different therapeutic agents in renal cell carcinoma. Human A498 renal cells carcinoma was subcutaneously inoculated into 24 nude mice. Mice received either phosphate-buffered saline solution, sunitinib, everolimus, or bevacizumab during 4 days. DCE-US and molecular MRI targeting αvß3 were performed at baseline and 4 days after treatment initiation. PI, AUC, relaxation rate variations ΔR2⁎, and percentage of vessels area quantified on CD31-stained microvessels were compared. Significant decreases were observed for PI and AUC parameters measured by DCE-US for bevacizumab group as early as 4 days, whereas molecular αvß3-targeted MRI was able to detect significant changes in both bevacizumab and everolimus groups. Percentage of CD31-stained microvessels was significantly correlated with DCE-US parameters, PI (R = 0.87, p = 0.0003) and AUC (R = 0.81, p = 0.0013). The percentage of vessel tissue area was significantly reduced (p < 0.01) in both sunitinib and bevacizumab groups. We report an early detection of neoangiogenesis modification after induction of targeted therapies, using DCE-US or αvß3-targeted MRI. We consider these outcomes should encourage clinical trial developments to further evaluate the potential of this molecular MRI technique.

Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats.

OBJECTIVES: The purpose of this preclinical study was to investigate whether moderate chronic kidney disease is a factor in potentiating gadolinium (Gd) uptake in the brain. MATERIALS AND METHODS: A comparative study was performed on renally impaired (subtotal nephrectomy) rats versus rats with normal renal function. The animals received 4 daily injections of 0.6 mmol Gd/kg a week for 5 weeks (cumulative dose of 12 mmol Gd/kg) of gadodiamide or saline solution. The MR signal enhancement in the deep cerebellar nuclei was monitored by weekly magnetic resonance imaging examinations. One week after the final injection, the total Gd concentration was determined by inductively coupled plasma mass spectrometry in different regions of the brain including the cerebellum, plasma, cerebrospinal fluid, parietal bone, and femur. RESULTS: After the administration of gadodiamide, the subtotal nephrectomy group presented a significantly higher T1 signal enhancement in the deep cerebellar nuclei and a major increase in the total Gd concentration in all the studied structures, compared with the normal renal function group receiving the same linear Gd-based contrast agent. Those potentiated animals also showed a pronounced hypersignal in the choroid plexus, still persistent 6 days after the last injection, whereas low concentration of Gd was found in the cerebrospinal fluid (<0.05 µmol/L) at this time point. Plasma Gd concentration was then around 1 µmol/L. Interestingly, plasma Gd was predominantly in a dissociated and soluble form (around 90% of total Gd). Total Gd concentrations in the brain, cerebellum, plasma, and bones correlated with creatinine clearance in both the gadodiamide-treated groups. CONCLUSIONS: Renal insufficiency in rats potentiates Gd uptake in the cerebellum, brain, and bones.

Linear Gadolinium-Based Contrast Agents Are Associated With Brain Gadolinium Retention in Healthy Rats.

OBJECTIVES: The aim of this study was to evaluate Gd retention in the deep cerebellar nuclei (DCN) of linear gadolinium-based contrast agents (GBCAs) compared with a macrocyclic contrast agent. MATERIALS AND METHODS: The brain tissue retention of Gd of 3 linear GBCAs (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) and a macrocyclic GBCA (gadoterate meglumine) was compared in healthy rats (n = 8 per group) that received 20 intravenous injections of 0.6 mmol Gd/kg (4 injections per week for 5 weeks). An additional control group with saline was included. T1-weighted magnetic resonance imaging was performed before injection and once a week during the 5 weeks of injections and for another 4 additional weeks after contrast period. Total gadolinium concentration was measured with inductively coupled plasma mass spectrometry. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data. RESULTS: At completion of the injection period, all the linear contrast agents (gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide) induced a significant increase in signal intensity in DCN, unlike the macrocyclic GBCA (gadoterate meglumine) or saline. The T1 hypersignal enhancement kinetic was fast for gadodiamide. Total Gd concentrations for the 3 linear GBCAs groups at week 10 were significantly higher in the cerebellum (1.21 ± 0.48, 1.67 ± 0.17, and 3.75 ± 0.18 nmol/g for gadobenate dimeglumine, gadopentetate dimeglumine, and gadodiamide, respectively) than with the gadoterate meglumine (0.27 ± 0.16 nmol/g, P < 0.05) and saline (0.09 ± 0.12 nmol/g, P < 0.05). No significant difference was observed between the macrocyclic agent and saline. CONCLUSIONS: Repeated administrations of the linear GBCAs gadodiamide, gadobenate dimeglumine, and gadopentetate dimeglumine to healthy rats were associated with progressive and significant T1 signal hyperintensity in the DCN, along with Gd deposition in the cerebellum. This is in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

T1-Weighted Hypersignal in the Deep Cerebellar Nuclei After Repeated Administrations of Gadolinium-Based Contrast Agents in Healthy Rats: Difference Between Linear and Macrocyclic Agents.

OBJECTIVES: To prospectively compare in healthy rats the effect of multiple injections of macrocyclic (gadoterate meglumine) and linear (gadodiamide) gadolinium-based contrast agents (GBCAs) on T1-weighted signal intensity in the deep cerebellar nuclei (DCN), including the dentate nucleus. MATERIALS AND METHODS: Healthy rats (n = 7/group) received 20 intravenous injections of 0.6 mmol of gadolinium (Gd) per kilogram (4 injections per week during 5 weeks) of gadodiamide, gadoterate meglumine, or hyperosmolar saline (control group). Brain T1-weighted magnetic resonance imaging was performed before and once a week during the 5 weeks of injections and during 5 additional weeks (treatment-free period). Gadolinium concentrations were measured with inductively coupled plasma mass spectrometry in plasma and brain. Blinded qualitative and quantitative evaluations of the T1 signal intensity in DCN were performed, as well as a statistical analysis on quantitative data. RESULTS: A significant and persistent T1 signal hyperintensity in DCN was observed only in gadodiamide-treated rats. The DCN-to-cerebellar cortex signal ratio was significantly increased from the 12th injection of gadodiamide (1.070 ± 0.024) compared to the gadoterate meglumine group (1.000 ± 0.033; P < 0.001) and control group (1.019 ± 0.022; P < 0.001) and did not significantly decrease during the treatment-free period. Total Gd concentrations in the gadodiamide group were significantly higher in the cerebellum (3.66 ± 0.91 nmol/g) compared with the gadoterate meglumine (0.26 ± 0.12 nmol/g; P < 0.05) and control (0.06 ± 0.10 nmol/g; P < 0.05) groups. CONCLUSIONS: Repeated administrations of the linear GBCA gadodiamide to healthy rats are associated with progressive and persistent T1 signal hyperintensity in the DCN, with Gd deposition in the cerebellum in contrast with the macrocyclic GBCA gadoterate meglumine for which no effect was observed.

Rapid-clearance iron nanoparticles for inflammation imaging of atherosclerotic plaque: initial experience in animal model.

PURPOSE: To evaluate the use of a recently developed fast-clearing ultrasmall superparamagnetic iron oxide (USPIO) for detection of vascular inflammation in atherosclerotic plaque. MATERIALS AND METHODS: The study protocol was approved by the animal experimentation ethics committee. A recently introduced USPIO, P904, and a reference-standard USPIO, ferumoxtran-10, were tested in a rabbit model of induced aortic atherosclerosis. In vivo magnetic resonance (MR) angiography and T2*-weighted plaque MR imaging were performed at baseline and after administration of P904 and ferumoxtran-10 (administered dose for both, 1000 micromol of iron per kilogram of body weight) in 26 hyperlipidemic New Zealand white rabbits. The variation in vessel wall area over time was evaluated with nonparametric testing. Ex vivo MR imaging findings were compared with iron content at linear regression analysis. RESULTS: With in vivo MR imaging, plaque analysis was possible as early as 24 hours after P904 injection. The authors observed a 27.75% increase in vessel wall area due to susceptibility artifacts on day 2 (P = .04) and a 38.81% increase on day 3 (P = .04) after P904 administration compared with a 44.5% increase in vessel wall area on day 7 (P = .04) and a 34.8% increase on day 10 (P = .22) after ferumoxtran-10 administration. These susceptibility artifacts were correlated with intraplaque iron uptake in the corresponding histologic slices. The number of pixels with signal loss on the ex vivo MR images was linearly correlated with the logarithm of the iron concentration (P = .0001; R(2) = 0.93). CONCLUSION: Plaque inflammation in rabbits can be detected earlier with P904 than with ferumoxtran-10 owing to the faster blood pharmacokinetics and the early uptake of P904 in the reticuloendothelial system. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/252/2/401/DC1.

How to compare the efficiency of albumin-bound and nonalbumin-bound contrast agents in vivo: the concept of dynamic relaxivity.

RATIONALE AND OBJECTIVES: The objective of this study was to compare, in a rabbit experimental model that mimics a magnetic resonance (MR) angiographic protocol, the efficiency of the following types of compound on the MR signal: (1) a nonalbumin-bound blood pool contrast agent: P792; (2) a weak albumin-bound extracellular contrast agent: Gd-BOPTA; and (3) a strong albumin-bound blood pool contrast agent: MS325. METHODS: The 2 main phases of early distribution after contrast agent injection, ie, the bolus phase (0-15 seconds postinjection) and the postbolus phase (1-5 minutes postinjection) were investigated by measuring Gd blood concentrations in the first 5 minutes postinjection. In the case of MS325 and Gd-BOPTA, the percentage of the free and bound forms were calculated throughout the pharmacokinetic profile. The dynamic relaxivity at 60 MHz in plasma of each contrast agent was determined in the 2 phases after contrast agent injection, ie, the bolus phase and the postbolus phase. RESULTS: Injected under similar conditions, the 3 contrast agents had a comparable profile during the bolus phase (0-15 seconds postinjection). At 1 minute postinjection, only 38% of Gd-BOPTA remained in the blood, whereas 85% of P792 was still present in the blood. MS-325 had an intermediate position with 61% remaining in the blood. During the postbolus phase, the various compounds demonstrated similar behavior: the plasma concentration of P792 was higher than that of MS325 and Gd-BOPTA, ie, Ci/C0 (P792)>Ci/C0 (MS325)>Ci/C0 (Gd-BOPTA). At the peak of the bolus, 75% of MS325 and 93% of Gd-BOPTA was present in free form. This proportion decreased progressively during the postbolus phase, because 5 minutes postinjection, 23% of the free form remained for MS325 and 82% for Gd BOPTA. A significant decrease in dynamic r1 relaxivity was observed at 60 MHz for the products that bind to albumin (Gd-BOPTA and MS325) during the bolus phase. The dynamic relaxivity for MS325 at the bolus phase was 8.6 mMs and 5.2 mMs for Gd-BOPTA. At the postbolus phase, the dynamic relaxivity increased (17.3 mMs for MS325 and 6.7 mMs for Gd-BOPTA). The dynamic relaxivity of P792, which does not bind to albumin, was constantly equal to 26 mMs at each time point of the pharmacokinetic profile (bolus and postbolus phase). CONCLUSIONS: The physicochemical measurements of relaxivity in plasma are made in vitro at a fixed concentration of gadolinium and the value of relaxivity is not necessarily an accurate reflection of the efficiency of the contrast agent in vivo, especially for contrast agents that bind to albumin. Indeed, in vivo, the proportion of free and bound forms of albumin-binding contrast agents varies according to the pharmacokinetic profile, and the relaxivities of albumin-bound and free contrast agents are different. Consequently, the concept of dynamic relaxivity was introduced to compare the efficiency of MS325, Gd-BOPTA, and P792 in vivo. The variation of the dynamic relaxivity of MS325 and Gd-BOPTA between the bolus and postbolus phase is significant (101% for MS325 and 29% for Gd-BOPTA) as a result of the variation in the quantity of bound and free forms during the pharmacokinetic profile. The blood pool agent P792 has different properties, which result from its intravascular retention and its lack of albumin binding. Indeed, contrary to Gd-BOPTA and MS325, the dynamic relaxivity of P792 is higher at the bolus phase (26 mMs) and does not vary during the pharmacokinetic profile. The impact of these different dynamic relaxivities should be integrated in the analysis of the performance of the different classes of contrast agents in clinical MRA protocols.

Optimization of a blood pool contrast agent injection protocol for MR angiography.

PURPOSE: To design an ideal first-pass profile for MR angiography (MRA) by optimizing a multiphasic injection protocol based on two experimental animal models. MATERIALS AND METHODS: An equivalent contrast-enhanced (CE) MRA injection protocol was developed with controlled injection modalities (injection rate, volume, and dose) in rabbits and pigs. P792, a blood pool contrast agent, was injected in 17 male New Zealand rabbits and five farm pigs with variable injection schemes (mono- and multiphasic). From the gadolinium (Gd) blood concentration data, a simulation of an MR acquisition was performed to evaluate the impact of such an injection protocol on MR arterial signal and to select the best injection protocol. RESULTS: An empirical relationship between the arterial peak concentration and the injection parameters was found in the rabbits and pigs, allowing precise prediction of the first-pass profile. Of the four injection scheme strategies tested (standard bolus and bi-, tri-, and multiphasic injection protocols), the multiphasic "ramp" injection protocol provided the most optimal contrast agent pharmacokinetics with a durable plateau of concentration. CONCLUSION: Ramp injection protocol provides an optimized first-pass profile for CE-MRA.

Dark lumen magnetic resonance colonography in a rodent polyp model: initial experience and demonstration of feasibility.

PURPOSE: We sought to assess dark lumen magnetic resonance (MR) colonography for the detection of colon polyps in a rodent model with histology as the gold standard. MATERIAL AND METHODS: Fourteen male Wistar rats were subjected to carcinogenic N-methyl-N'-nitro-N-nitrosoguanidine at the age of 4 months to induce colon neoplasms. MR imaging was performed after a time interval of 1 year. Preparation and data acquisition was performed with the animals under full anesthesia. After a body-warm saline enema images were acquired on a clinical 1.5-T whole-body MR system using a standard extremity coil. Plain and contrast-enhanced (0.3 mmol/kg; Gd-DOTA; Dotarem, Guerbet, France) 3-dimensional T1-weighted gradient recall echo images were acquired. Two radiologists analyzed the MR data sets in consensus for lesion depiction. Contrast uptake in colonic wall and polyps was quantitatively assessed by signal-to-noise ratio and contrast-to-noise ratio measurements and compared using a Wilcoxon-Mann-Whitney U test with statistical significance at a P value < 0.05. Finally, all animals were killed, and the MR imaging results were compared with pathologic findings. Sensitivity and specificity were calculated. RESULTS: By pathology, a total of 15 polyps were found in 9 of 14 rats. MR colonography detected 13 of 15 polyps measuring between 4 and 11 mm (mean 7 +/- 0.6 mm) in 8 of 9 animals, resulting in a sensitivity and specificity of 0.87 and 1.0, respectively. Compared with the precontrast data, all polyps showed a statistically significant increase in signal-to-noise ratio (78.2 +/- 6.3 to 167.4 +/- 17.7) and contrast-to-noise ratio (45.4 +/- 5.2 to 124.6 +/- 11.2). CONCLUSION: MR colonography with a dark colon lumen and a bright, contrast-enhanced colon wall appears well suited for the detection of colonic lesions in a rodent model.

Comparison of different types of blood pool agents (P792, MS325, USPIO) in a rabbit MR angiography-like protocol.

RATIONALE AND OBJECTIVES: The objective of this study is to determine the influence of the pharmacokinetic behaviors of different classes of blood pool agents (BPA) on a rabbit experimental model that mimics a magnetic resonance angiographic protocol. BPA were as follows: P792, a macromolecular agent (RCBPA), USPIO, an ultrasmall superparamagnetic iron oxide particle agent (SCBPA), and MS-325, a small gadolinium chelate that expresses intravascular behavior by reversible albumin binding. METHODS: The 2 main phases of early distribution following contrast agent injection, that is, the bolus phase and the steady-state phase, are investigated by measuring Gd or Fe blood concentrations in the first 5 minutes postinjection. T1 relaxation times and r1 relaxivity were calculated at each time point of blood sampling. Furthermore, in the case of MS-325, the concentrations of the free and bound forms were calculated, according to the measured concentrations and the apparent r1 relaxivities. RESULTS: Injected under similar conditions, the 3 BPA have, during the bolus phase, a comparable profile to Gd-DOTA. Signal enhancement was maximum during this short bolus phase, as were the T1 relaxation times under 30 ms for all agents. At 1 minute postinjection, P792 (r1 = 39 seconds(-1) x mmol/L(-1), 20 MHz) demonstrated the same pharmacokinetic behavior as USPIO (r1 = 33 seconds(-1) x mmol/L(-1), 20 MHz): C1 minute/C0 values were 91 +/- 6% and 92 +/- 12%, respectively. Immediately after the injection at clinical dose, 74% of MS-325 was in free form, resulting in an apparent r1 relaxivity of only 13 seconds(-1) x mmol/L(-1) (20 MHz); 1 minute postinjection, the C1 minute/C0 value of 61 +/- 4% was the lowest as compared with P792 and USPIO and the bound form represented 75% of the MS-325 molecules. CONCLUSIONS: The BPA P792 and USPIO have favorable properties that result from their intravascular retention and their lack of extravasation, allowing optimal contrast between the vessel and the adjacent tissue for several minutes postinjection. Combining a rapid body clearance and a marked T1 effect, P792 presents optimal blood pool characteristics for angiographic applications. During the bolus phase, MS-325 is mainly in free form, which presents the disadvantage of increasing the tissue signal background, due to extravasation of the free form.

MR angiography with a new rapid-clearance blood pool agent: Initial experience in rabbits.

The purpose of this study was to assess a new Gd-based macromolecular intravascular contrast agent (P792, Vistarem(R); Laboratoire Guerbet, Aulnay sous Bois, France) for MR angiography (MRA). P792 is a macrocyclic gadolinium compound based on a gadoterate meglumine structure substituted by hydrophilic arms. In vitro imaging of phantoms containing varying concentrations of P792 and gadoterate meglumine (Gd-DOTA) was performed. In rabbits (N = 5), arterial concentrations for P792 and Gd-DOTA were determined, and in vivo 3D MRA was performed. For gadolinium concentrations ranging from 200 to 3000 micromol/l, in vitro imaging showed higher SNR values for P792 compared to Gd-DOTA. Determination of arterial Gd concentration showed comparable bolus phase curves for P792 and Gd-DOTA. With P792, higher concentrations were obtained due to a restricted diffusion into the interstitial space. P792 allowed acquisition of high-quality MR angiograms. Image quality was rated as superior for P792 in the post-bolus phase images. In conclusion, P792 appears to be well suited for high-quality first-pass and equilibrium-phase MRA. The intravascular properties lead to an excellent signal in the vasculature, with limited background enhancement. Since the agent is rapidly renally excreted, it should be well suited for perfusion and permeability imaging.