High-relaxivity Contrast Agents Research Articles

Computational insight into a mechanistic overview of water exchange kinetics and thermodynamic stabilities of bis and tris-aquated complexes of lanthanides.

A thorough investigation of Ln3+ complexes with more than one inner-sphere water molecule is crucial for designing high relaxivity contrast agents (CAs) used in magnetic resonance imaging (MRI). This study accomplished a comparative stability analysis of two hexadentate (H3cbda and H3dpaa) and two heptadentate (H4peada and H3tpaa) ligands with Ln3+ ions. The higher stability of the hexadentate H3cbda and heptadentate H4peada ligands has been confirmed by the binding affinity and Gibbs free energy analysis in aqueous solution. In addition, energy decomposition analysis (EDA) reveals the higher binding affinity of the peada4- ligand than the cbda3- ligand towards Ln3+ ions due to the higher charge density of the peada4- ligand. Moreover, a mechanistic overview of water exchange kinetics has been carried out based on the strength of the metal-water bond. The strength of the metal-water bond follows the trend Gd-O47 (w) > Gd-O39 (w) > Gd-O36 (w) in the case of the tris-aquated [Gd(cbda)(H2O)3] and Gd-O43 (w) > Gd-O40 (w) for the bis-aquated [Gd(peada)(H2O)2]- complex, which was confirmed by bond length, electron density (ρ), and electron localization function (ELF) at the corresponding bond critical points. Our analysis also predicts that the activation energy barrier decreases with the decrease in bond strength; hence k ex increases. The 17O and 1H hyperfine coupling constant values of all the coordinated water molecules were different, calculated by using the second-order Douglas-Kroll-Hess (DKH2) approach. Furthermore, the ionic nature of the bonding in the metal-ligand (M-L) bond was confirmed by the Quantum Theory of Atoms-In-Molecules (QTAIM) and ELF along with energy decomposition analysis (EDA). We hope that the results can be used as a basis for the design of highly efficient Gd(iii)-based high relaxivity MRI contrast agents for medical applications.

The adjacent effect between Gd(III) and Cu(II) in layered double hydroxide nanoparticles synergistically enhances T1-weighted magnetic resonance imaging contrast.

Magnetic resonance imaging (MRI) is one key technology in modern diagnostic medicine. However, the development of high-relaxivity contrast agents with favorable properties for imaging applications remains a challenging task. In this work, dual Gd(III) and Cu(II) doped-layered double hydroxide (GdCu-LDH) nanoparticles show significantly higher longitudinal relaxivity compared with sole-metal-based LDH (Gd-LDH and Cu-LDH) nanoparticles. This relaxation enhancement in GdCu-LDH is also much greater than the simple addition of the relaxivity rate of the two paramagnetic ions in Gd-LDH and Cu-LDH, presumably attributed to synergistic T1 shortening between adjacent Gd(III) and Cu(II) in the LDH host layers (adjacent effect). Moreover, our GdCu-LDH nanoparticles exhibit a pH-ultrasensitive property in MRI performance and show much clearer MR imaging for tumor tissues in mice than Gd-LDH and Cu-LDH at the equivalent doses. Thus, these novel Gd/Cu-co-doped LDH nanoparticles provide higher potential for accurate cancer diagnosis in clinic application. To the best of our knowledge, this is the first report that two paramagnetic metal ions in one nanoparticle synergistically improve the T1-MRI contrast.

Large Protein Assemblies for High-Relaxivity Contrast Agents: The Case of Gadolinium-Labeled Asparaginase.

Biologics are emerging as the most important class of drugs and are used to treat a large variety of pathologies. Most of biologics are proteins administered in large amounts, either by intramuscular injection or by intravenous infusion. Asparaginase is a large tetrameric protein assembly, currently used against acute lymphoblastic leukemia. Here, a gadolinium(III)-DOTA derivative has been conjugated to asparaginase, and its relaxation properties have been investigated to assess its efficiency as a possible theranostic agent. The field-dependent 1H longitudinal relaxation measurements of water solutions of gadolinium(III)-labeled asparaginase indicate a very large increase in the relaxivity of this paramagnetic protein complex with respect to small gadolinium chelates, opening up the possibility of its use as an MRI contrast agent.

Utility of Contrast-Enhanced T2 FLAIR for Imaging Brain Metastases Using a Half-dose High-Relaxivity Contrast Agent.

Efficient detection of metastases is important for patient' treatment. This prospective study was to explore the clinical value of contrast-enhanced T2 FLAIR in imaging brain metastases using half-dose gadobenate dimeglumine. In vitro signal intensity of various gadolinium concentrations was explored by spin-echo T1-weighted imaging and T2 FLAIR. Then, 46 patients with lung cancer underwent nonenhanced T2 FLAIR before administration of half-dose gadobenate dimeglumine and 3 consecutive contrast-enhanced T2 FLAIR sequences followed by 1 spin-echo T1WI after administration of half-dose gadobenate dimeglumine. After an additional dose of 0.05 mmol/kg, 3D brain volume imaging was performed. All brain metastases were classified as follows: solid-enhancing, ≥ 5 mm (group A); ring-enhancing, ≥ 5 mm (group B); and lesion diameter of <5 mm (group C). The contrast ratio of the lesions on 3 consecutive phases of contrast-enhanced T2 FLAIR was measured, and the percentage increase of contrast-enhanced T2 FLAIR among the 3 groups was compared. In vitro, the maximal signal intensity was achieved in T2 FLAIR at one-eighth to one-half of the contrast concentration needed for maximal signal intensity in T1WI. In vivo, the mean contrast ratio values of metastases on contrast-enhanced T2 FLAIR for the 3 consecutive phases ranged from 63.64% to 83.05%. The percentage increase (PI) values of contrast-enhanced T2 FLAIR were as follows: PIA < PIB (P = .001) and PIA < PIC (P < .001). The degree of enhancement of brain metastases on contrast-enhanced T2 FLAIR was lower than on 3D brain volume imaging (P < .001) in group A, and higher than on 3D brain volume imaging (P < .001) in group C. Small or ring-enhancing metastases can be better visualized on delayed contrast-enhanced T2 FLAIR using a half-dose high-relaxivity contrast agent.

Steady State Magnetic Resonance Angiography of the Thoracic Aorta Using Inversion-recovery Steady-State Free Precession and a High Relaxivity Contrast Agent.

To evaluate image quality and aortic dimension measurement accuracy of high resolution, motion compensated steady-state magnetic resonance angiography (SS-MRA) with a high relaxivity, extracellular fluid gadolinium-based contrast agent compared with standard first-pass contrast enhanced MRA (FP-CEMRA) in patients with thoracic aortic aneurysms. Sixty-nine patients (mean age, 51.7 y, 25% female) diagnosed with thoracic aortic aneurysms who underwent MRA on a 1.5 T scanner using FP-CEMRA and SS-MRA techniques were retrospectively identified. Quantitative analysis was performed by measuring the aortic diameters at 6 locations within the thoracic aorta for each technique. Two radiologists independently performed the qualitative analysis by assessing the image quality (1 to 5), presence of artifact (1 to 4), signal-to-noise (1 to 4), contrast-to-noise (1 to 4), and wall conspicuity (1 to 4) in the aorta at 4 different locations: the aortic root, the ascending aorta, the aortic arch, and the descending aorta. The aortic dimensions obtained by SS-MRA had a good correlation with FP-CEMRA. Means for the aortic diameters between the FP-CEMRA and the SS-MRA at all 6 locations demonstrated minimal mean differences (0.013 to 0.044 mm).Qualitative assessment of aorta at 4 locations by 2 reviewers demonstrated that SS-MRA had on average superior image quality at the aortic root and ascending aorta for both reviewers (P<0.05) and at the descending aorta for one reader (P<0.05). Otherwise, both techniques were comparable at the ascending aorta. SS-MRA demonstrated less artifact at the aortic root and the ascending aorta (P<0.05). Aortic dimension measurements provided by SS-MRA with a high relaxivity, extracellular fluid gadolinium-based contrast agent are comparable to the conventional FP-CEMRA. Furthermore, SS-MRA qualitatively demonstrated comparable to better overall image quality than FP-CEMRA at different aortic locations. Therefore, SS-MRA may provide a comparable alternative, or complementary examination to conventional FP-CEMRA in patients who have difficulty breath holding, or in situations where contrast bolus timing was poor.

Potential use of a diluted high-relaxivity gadolinium-based intra-articular contrast agent for magnetic resonance arthrography: an in-vitro study

BackgroundMagnetic resonance arthrography (MRA) requires intra-articular injection of gadolinium-based diluted paramagnetic contrast material. To our knowledge, gadobenate dimeglumine (Gd-BOPTA) has never been used for intra-articular applications. Our aim was to test in vitro different concentrations of Gd-BOPTA to be potentially used to perform MRA.MethodsGd-BOPTA was diluted in saline (NaCl 0.9%) to achieve different concentrations (4 mmol/l; 2 mmol/l; 1 mmol/l; 0.67 mmol/l; 0.5 mmol/l). Six sets of five sterile pipes were prepared with 5 ml of each solution, five sets added with 0.5 ml of fresh synovial fluid. Two separate pipes were prepared with 5 ml of gadopentetate dimeglumine (Gd-DTPA) at 2 mmol/l, one pipe added with 0.5 ml of synovial fluid. Pipes were imaged using a T1-weighted sequence at 1.5 T. For each pipe, signal intensity (SI) in arbitrary units (au) was measured.ResultsSI reproducibility range was 86–99%. Mean Gd-BOPTA SI in pipes containing synovial fluid increased from 1236 ± 8au (0.5 mmol/l) up to 1610 ± 44au (1 mmol/l) and down to 1405 ± 33au (4 mmol/l). Mean Gd-BOPTA SI in pipes without synovial fluid increased from 1184 ± 29au (0.5 mmol/l) up to 1530 ± 38au (1 mmol/l), and down to 1347 ± 39au (4 mmol/l). SI of pipes without synovial fluid was lower than that of pipes with synovial fluid for both Gd-BOPTA and Gd-DTPA (P ≤ 0.002). Regarding pipes with synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1246 ± 27au. Compared with Gd-BOPTA, SI was not different at 0.5 mmol/l (− 0.2%, P = 0.587) while it was higher (P < 0.001) at all other concentrations (range + 13.3%[4 mmol/l] − + 28.3%[1 mmol/l]). Regarding pipes without synovial fluid, mean Gd-DTPA SI at 2 mmol/l was 1275 ± 56au. Compared with Gd-BOPTA, SI was lower at 0.5 mmol/l (− 6.8%,P < 0.001), while it was higher (P < 0.001) at all other concentrations (range + 6.1%[4 mmol/l] − + 19.6% [1 mmol/l]).ConclusionsIn vitro, Gd-BOPTA at 1 mmol/ had a + 28% SI increase in comparison to Gd-DTPA 2 mmol/l. SI similar to Gd-DTPA can be obtained using one fourth concentration of Gd-BOPTA.

Characterization of a Manganese‐Containing Nanoparticle as an MRI Contrast Agent

We present relaxivity and physicochemical data for a high relaxivity, manganese‐containing, nanoparticle‐based, and tumor selective MRI contrast agent, SN132D. The nanoparticles have a diameter of 5–6 nm, selected to give a compromise between renal excretion and tumor contrast, based on the Enhanced Permeability and Retention effect. The per manganese relaxivity (r1) is 24.8 ± 0.2 mm–1 Mn s–1 at 1.5 T and 37 °C in water, corresponding to per nanoparticle relaxivity of 347 ± 3 mm–1 s–1. The NMRD profiles in both water and serum showed a peak in r1 in the frequency range 20–40 MHz, which is characteristic of slowly moving paramagnetic systems. The r1 decreases when the temperature is increased from 25 °C to 37 °C, indicating fast exchange dynamics of the coordinated water molecules. The exchange time constant of the whole water molecule, τMO, was 6 ns. The r1 in serum is significantly higher than in water, due to an increase in medium viscosity and chelation of 18.9 ± 2.0 % of MnII ions to human serum components, most likely human serum albumin. The r1 is stable in the pH range 3–10. The per Mn relaxivity is among the highest reported for Mn‐containing systems and far higher than those of the clinically used gadolinium‐based contrast agents.

Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]−. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.

Improved coronary magnetic resonance angiography using gadobenate dimeglumine in pediatric congenital heart disease

BackgroundCMRA in pediatrics remains challenging due to the smaller vessel size, high heart rates (HR), potential image degradation caused by limited patient cooperation and long acquisition times. High-relaxivity contrast agents have been shown to improve coronary imaging in adults, but limited data is available in children. We sought to investigate whether gadobenate dimeglumine (Gd-BOPTA) together with self-navigated inversion-prepared coronary magnetic resonance angiography (CMRA) sequence design improves coronary image quality in pediatric patients. MethodsForty consecutive patients (mean age 6±2.8years; 73% males) were prospectively recruited for a 1.5-T MRI study under general anesthesia. Two electrocardiographic-triggered free breathing steady-state free precession (SSFP) angiography sequences (A and B) with isotropic spatial resolution (1.3mm3) were acquired using a recently developed image-based self-navigation technique. Sequence A was acquired prior to contrast administration using T2 magnetization preparation (T2prep). Sequence B was acquired 5–8min after a bolus of Gd-BOPTA with the T2prep replaced by an inversion recovery (IR) pulse to null the signal from the myocardium. Scan time, signal-to noise and contrast-to-noise ratios (SNR and CNR), vessel wall sharpness (VWS) and qualitative visual score for each sequence were compared. ResultsScan time was similar for both sequences (5.3±1.8 vs 5.2±1.5min, p=.532) and average heart rate (78±14.7 vs 78±14.5bpm, p=.443) remained constant throughout both acquisitions. Sequence B resulted in higher SNR (12.6±4.4 vs 31.1±7.4, p<.001) and CNR (9.0±1.8 vs 13.5±3.7, p<.001) and provided improved coronary visualization in all coronary territories (VWS A=0.53±0.07 vs B=0.56±0.07, p=.001; and visual scoring A=3.8±0.59 vs B=4.1±0.53, p<.001). The number of non-diagnostic coronary segments was lower for sequence B [A=42 (13.1%) segments vs B=33 (10.3%) segments; p=.002], and contrary to the pre-contrast sequence, never involved a proximal segment. These results were independent of the patients' age, body surface area and HR. ConclusionsThe use of Gd-BOPTA with a 3D IR SSFP CMRA sequence results in improved coronary visualization in small infants and young children with high HR within a clinically acceptable scan time.

T2*-Correction in Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Glioblastoma From a Half Dose of High-Relaxivity Contrast Agent.

The aim of this study was to evaluate the arterial input function (AIF) and tissue enhancement time curve (tissue function [TF]) obtained after the administration of a half-dose gadobenate dimeglumine (0.05-mmol/kg body weight [bw]) compared with a full dose (0.1-mmol/kg bw) of a standard-relaxivity contrast agent. We enrolled 40 adult patients with glioblastoma in an interindividual comparative study. Patients were randomized to 1 of the 2 study arms: 20 patients received 0.1-mmol/kg bw of gadoterate; the other 20 patients received 0.05-mmol/kg bw of gadobenate. The patients underwent dynamic contrast-enhanced magnetic resonance imaging examinations. Arterial input function, tissue enhancement time curve (TF), tumor transfer rate (K), and tumor extracellular-extravascular volume fraction (Ve) were calculated for each patients. Averaged AIF, TF, K, and Ve of both groups were compared. A significant difference (P = 0.001) between the peak AIF values obtained with the 2 different gadolinium-based contrast agents was observed. No difference was found between TFs (P = 0.35). Comparison on kinetic parameters revealed a significant difference for K (P = 0.047) but no difference for Ve (P = 0.74). The administration of half dose of the high-relaxivity contrast agent gadobenate is effective in improving AIF by reducing T2*-shortening effects on dynamic contrast-enhanced magnetic resonance imaging and ensuring at the same time an adequate signal enhancement in tumor tissue. The use of 0.05-mmol/kg bw of gadobenate not only is feasible but also can lead to a better estimation of K based on a more accurate AIF assessment.

Ultrashort echo time magnetic resonance imaging of the lung using a high-relaxivity t1 blood-pool contrast agent.

The lung remains one of the most challenging organs to image using magnetic resonance imaging (MRI) due to intrinsic rapid signal decay. However, unlike conventional modalities such as computed tomography, MRI does not involve radiation and can provide functional and morphologic information on a regional basis. Here we demonstrate proof of concept for a new MRI approach to achieve substantial gains in a signal to noise ratio (SNR) in the lung parenchyma: contrast-enhanced ultrashort echo time (UTE) imaging following intravenous injection of a high-relaxivity blood-pool manganese porphyrin T1 contrast agent. The new contrast agent increased relative enhancement of the lung parenchyma by over 10-fold compared to gadolinium diethylene triamine pentaacetic acid (Gd-DTPA), and the use of UTE boosted the SNR by a factor of 4 over conventional T1-weighted gradient echo acquisitions. The new agent also maintains steady enhancement over at least 60 minutes, thus providing a long time window for obtaining high-resolution, high-quality images and the ability to measure a number of physiologic parameters.

Ultra low-dose of gadobenate dimeglumine for late gadolinium enhancement (LGE) imaging in acute myocardial infarction: A feasibility study

PurposeTo assess the feasibility of using an ultra-low dose (0.05mmol/kg of body weight [BW]) of high relaxivity contrast agent for late gadolinium enhancement (LGE) imaging in patients with acute myocardial infarction (AMI). Materials and methods17 consecutive patients (mean age, 60.1±10.3 years) with ST-segment elevation AMI underwent two randomized cardiac magnetic resonance studies (exam intervals between 24 and 48h) on a 1.5T unit during the first week after the event using gadobenate dimeglumine (Gd-BOPTA) at the dose of 0.1mmol/kg BW (standard dose or SD group) and 0.05mmol/kg BW (half dose or HD group). Image quality was qualitatively assessed. Quantitative analysis of LGE were performed by measuring signal intensity (SI), signal-to-noise ratio (SNR) in the infarcted myocardium (IM), non-infarcted myocardium (N-IM) and left ventricular cavity (LVC) in images acquired at 1, 3, 5, 10, 15 and 20min after administration of Gd-BOPTA using both contrast media protocol. Contrast-to-noise ratio (CNR) between IM and N-IM (CNR IM/N-IM) and between IM and LVC (CNR IM/LVC) were also quantified for each time point. Moreover the extent of infarcted myocardium was measured. Results102 LGE images were evaluated for each dose group. Quality score was significantly higher for SD at 1, 15 and 20min (0.002<p<0.046) and for HD at 5min (p=0.013). SNR has been higher in the SD group compared to the HD group even though not statistically significant at any time-point for both IM (SD vs. HD: 87.7±73 vs. 65±66; 0.15<p<0.38) and N-IM (SD vs. HD: 22±61 vs. 9.9±6.5; 0.09<p<0.43). LVC SNR was significantly higher with SD at 10min (p=0.03), 15min (p=0.001) and 20min (p=0.004). CNR between the IM and N-IM was significantly higher using SD compared to HD (1382.24±1049 vs. 695.4±500; 0.000<p<0.028) at 10, 15 and 20min. No significant differences in CNR IM/LVC were noted for HD acquired 5min after CM administration compared to SD acquired at 10 (p=0.34), 15 (p=0.96) and 20 (p=0.41) min, and between HD at 10min compared to SD acquired at 15min (p=0.78) and 20min (p=0.32). Good correlation between SD and HD (0.56<r2<0.85, p<0.024) was found at all time-points in the measuring of IA. ConclusionThe use of a 0.05mmol/kg dose of gadobenate dimeglumine is feasible for LGE imaging of acute MI and the best image quality is obtained at 5min after contrast administration. It could be beneficial in patient with renal failure and a solution to improve the identification of subendocardial infarction reducing examination time, costs and total gadolinium load. However, the standard dose of 0.1mmol/kg provides overall better image quality, with the best performance obtained at the delay of 10min or more after Gd-BOPTA administration, and it should be routinely preferred.

Assessment of nonischemic fibrosis in hypertrophic cardiomyopathy: Comparison of gadopentetate dimeglumine and gadobenate dimeglumine for enhanced cardiovascular magnetic resonance imaging

To compare whether the higher relaxivity contrast agent gadobenate is superior for the identification of nonischemic late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM) compared to standard relaxivity agents such as gadopentetate. Fifteen patients with HCM and positive LGE based on routine cardiac magnetic resonance (CMR) with 0.2 mmol/kg gadopentetate were enrolled. Each patient thereafter underwent a second enhanced CMR exam with 0.2 mmol/kg gadobenate using the same CMR protocol. LGE was assessed in a short axis stack acquired after contrast administration using an inversion recovery gradient echo sequence. Two independent blinded readers quantified LGE by manual planimetry. The signal intensities of injured myocardium, remote myocardium, left ventricular cavity, and air were measured in identical locations using anatomical landmarks and dedicated software. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. No adverse events related to contrast administration occurred. Gadobenate dimeglumine showed a higher SNR of injured myocardium (45.4 ± 24.0 vs. 31.1 ± 16.6, P = 0.002) and a higher CNR between remote and injured myocardium (37.6 ± 25.0 vs. 26.5 ± 17.6, P = 0.006) compared to gadopentetate dimeglumine. The amount of LGE (based on the same postprocessing criteria and definitions) was higher with gadobenate dimeglumine (12.7 ± 8.5 g vs. 9.4 ± 5.6 g, P = 0.005). There was no difference in intra- and interobserver variability between gadopentetate dimeglumine and gadobenate dimeglumine. CMR with the high relaxivity contrast agent gadobenate dimeglumine reveals significantly more tissue with LGE in patients with HCM.

Gd(DOTAla): A Single Amino Acid Gd-complex as a Modular Tool for High Relaxivity MR Contrast Agent Development

MR imaging at high magnetic fields benefits from an increased signal-to-noise ratio; however T(1)-based MR contrast agents show decreasing relaxivity (r(1)) at higher fields. High field, high relaxivity contrast agents can be designed by carefully controlling the rotational dynamics of the molecule. To this end, we investigated applications of the alanine analogue of Gd(DOTA), Gd(DOTAla). Fmoc-protected DOTAla suitable for solid phase peptide synthesis was synthesized and integrated into polypeptide structures. Gd(III) coordination results in very rigid attachment of the metal chelate to the peptide backbone through both the amino acid side chain and coordination of the amide carbonyl. Linear and cyclic monomers (GdL1, GdC1), dimers (Gd(2)L2, Gd(2)C2), and trimers (Gd(3)L3, Gd(3)C3) were prepared and relaxivities were determined at different field strengths ranging from 0.47 to 11.7 T. Amide carbonyl coordination was indirectly confirmed by determination of the hydration number q for the EuL1 integrated into a peptide backbone, q = 0.96 ± 0.09. The water residency time of GdL1 at 37 °C was optimal for relaxivity, τ(M) = 17 ± 2 ns. Increased molecular size leads to increased per Gd relaxivity (from r(1) = 7.5 for GdL1 to 12.9 mM(-1) s(-1) for Gd(3)L3 at 1.4 T, 37 °C). The cyclic, multimeric derivatives exhibited slightly higher relaxivities than the corresponding linearized multimers (Gd(2)C2: r(1) = 10.5 mM(-1) s(-1) versus Gd(2)C2-red r(1) = 9 mM(-1) s(-1) at 1.4 T, 37 °C). Overall, all six synthesized Gd complexes had higher relaxivities at low, intermediate, and high fields than the clinically used small molecule contrast agent [Gd(HP-DO3A)(H(2)O)].

Magnetic Resonance Imaging Techniques in the Evaluation of Stroke and Neurovascular Disease

Early intervention remains vital in the management of acute stroke. The goals of imaging techniques are to establish a diagnosis as early as possible and to obtain accurate information about the intracranial vasculature and brain perfusion to guide therapeutic decisionmaking. Magnetic resonance imaging (MRI) and contrast-enhanced magnetic resonance angiography (CE-MRA) are valuable techniques in the evaluation of acute stroke and can provide diagnostic information on the underlying pathophysiological changes. Gadolinium-based contrast agents (GBCAs) facilitate the diagnosis of ischaemic stroke by accentuating abnormal flow kinetics and the diagnosis of nonischaemic stroke by assisting in the detection and characterisation of intracranial aneurysms and arteriovenous malformations (AVMs). Contrast agents may also be employed in the characterisation of vascular atherosclerotic plaque. Gadobutrol (Gadovist®, Gadavist®) is a high relaxivity contrast agent which combines an excellent safety profile and proven high efficacy. As the only high concentration contrast media it allows to inject at a small and compact bolus, which has a direct impact on the performance of MRA or perfusion MRI procedure.

Gold nanoparticles functionalised with stable, fast water exchanging Gd3+ chelates as high relaxivity contrast agents for MRI

Gold nanoparticles functionalized with Gd(3+) chelates displaying fast water exchange, superb pH stability and inertness towards transmetalation with Zn(2+) have been prepared and characterized as a new high relaxivity (29 mM(-1) s(-1), 30 MHz, 25 °C) contrast agent potentially safe for in vivo MRI applications. The Lipari-Szabo treatment for internal rotation was used to evaluate the effect of linker flexibility on the relaxivity of the gold nanoparticles. The effect of fast water exchange on the relaxivity of gold nanoparticles functionalized with Gd(3+) chelates is also addressed in this communication.

Cardiac MRI to investigate myocardial scar and coronary venous anatomy using a slow infusion of dimeglumine gadobenate in patients undergoing assessment for cardiac resynchronization therapy

To evaluate a cardiac MR (CMR) examination with slow infusion of a high-relaxivity contrast agent to visualize coronary venous anatomy (CVA) and myocardial scar in heart failure patients awaiting cardiac resynchronization therapy (CRT). Fourteen patients awaiting CRT (seven ischemic cardiomyopathy (ICM) and seven non-ICM) and two with normal LV function underwent CMR on a 1.5 Tesla (T) MR scanner. Dimeglumine-gadobenate was slowly infused. Bolus arrival in the LV was measured by a dynamic electrocardiogram (ECG) -triggered inversion recovery (IR) scan subsequent to starting an ECG-triggered respiratory-navigated three-dimensional (3D) SSFP MR scan with IR preparation to acquire systolic whole-heart anatomy for vein visualization. Delayed contrast-enhanced MR scan was performed to assess myocardial scar. CVA obtained by CMR was compared with X-ray venography in 11 patients. CVA and scar were segmented and registered for visual inspection. For all subjects, there was excellent visualization of the CVA. All ICM and one non-ICM patient showed scar. There was excellent correlation between veins seen by CMR and venography. We have demonstrated that slow infusion protocol of dimeglumine-gadobenate can be used to assess both CVA and myocardial scar in a single MR examination. Furthermore, an image overlay technique has been used to show the relationship of scar to the CVA.

High-Relaxivity Magnetic Resonance Imaging Contrast Agents Part 2

The observed relaxivity of gadolinium-based contrast agents has contributions from the water molecule(s) that bind directly to the gadolinium ion (inner-sphere water), long-lived water molecules and exchangeable protons that make up the second-sphere of coordination, and water molecules that diffuse near the contrast agent (outer-sphere). Inner- and second-sphere relaxivity can both be increased by optimization of the lifetimes of the water molecules and protons in these coordination spheres, the rotational motion of the complex, and the electronic relaxation of the gadolinium ion. We sought to identify new high-relaxivity contrast agents by systematically varying the donor atoms that bind directly to gadolinium to increase inner-sphere relaxivity and concurrently including substituents that influence the second-sphere relaxivity. Twenty gadolinium-1,4,7,10-tetraazacyclo-dodecane-N,N',N″,N'″-tetraacetato derivatives were prepared and their relaxivity determined in presence and absence of human serum albumin as a function of temperature and magnetic field. Data was analyzed to extract the underlying molecular parameters influencing relaxivity. Each compound had a common albumin-binding group and an inner-sphere donor set comprising the 4 tertiary amine N atoms from cyclen, an α-substituted acetate oxygen atom, 2 amide oxygen atoms, an inner-sphere water oxygen atom, and a variable donor group. Each amide nitrogen was substituted with different groups to promote hydrogen bonding with second-sphere water molecules. Relativities at 0.47 and 1.4 T, 37°C, in serum albumin ranged from 16.0 to 58.1 mM(-1)s(-1) and from 12.3 to 34.8 mM(-1)s(-1), respectively. The reduction of inner-sphere water exchange typical of amide donor groups could be offset by incorporating a phosphonate or phenolate oxygen atom donor in the first coordination sphere, resulting in higher relaxivity. Amide nitrogen substitution with pendant phosphonate or carboxylate groups increased relaxivity by as much as 88% compared with the N-methyl amide analog. Second-sphere relaxivity contributed as much as 24 and 14 mM(-1)s(-1) at 0.47 and 1.4 T, respectively. Water/proton exchange dynamics in the inner- and second-coordination sphere can be predictably tuned by choice of donor atoms and second-sphere substituents, resulting in high-relaxivity agents.

Comparison of the high relaxivity Gd chelates P1152 and Gd‐BOPTA for contrast‐enhanced MR angiography in rabbits at 1.5 Tesla and 3.0 Tesla

To compare signal-enhancing properties of the high relaxivity Gd chelates P1152 and Gd-BOPTA for contrast-enhanced MR angiography (CE-MRA) in rabbits at 1.5 Tesla (T) and 3.0T. Three-dimensional CE-MRA of the abdominal vasculature was performed in six rabbits using both contrast agents at a dose of 0.1 mmol/kg. Data acquisition was carried out during first pass and up to 10 min after contrast material administration. CNR was determined in aorta, vena cava, and renal cortex. Image quality (5-point scale, 5 = best) of first pass MR angiograms was rated by two radiologists. During first pass CNR of the aorta was 55.1 +/- 5.8 (P1152) and 40.3 +/- 3.9 (Gd-BOPTA) at 1.5T (P < 0.05), and 114.9 +/- 9.9 (P1152) and 73.5 +/- 8.1 (Gd-BOPTA) at 3.0T (P < 0.05). Both contrast agents showed a comparable decline of CNR within 10 min. Image quality was rated 4.8 +/- 0.40 (P1152) and 4.5 +/- 0.50 (Gd-BOPTA) at 1.5T (P = 0.17), and 4.8 +/- 0.37 (P1152) and 4.7 +/- 0.47 (Gd-BOPTA) at 3.0T (P = 0.61). The high relaxivity Gd-chelate P1152 offers potential to improve image contrast for CE-MRA compared with a clinically approved high relaxivity contrast agent.

Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial MRI late gadolinium enhancement

Objectives To investigate the time-course of late gadolinium enhancement of infarcted myocardium using gadobenate dimeglumine at different dosages and administration regimens. Materials and methods After institutional review board approval and informed consent, we studied 13 patients (aged 63 ± 11 years) with chronic myocardial infarction. They underwent two gadobenate dimeglumine-enhanced MR examinations (interval 24–48 h) using short-axis inversion-recovery gradient-echo sequences, with the following two different protocols, in randomized order: 0.05 mmol/kg and imaging at the 2.5th, 5th, 7.5th and 10th minute plus 0.05 mmol/kg and imaging at the 12.5th, 15th, 17.5th and 20th minute; the same as before but using 0.1 mmol/kg for both contrast injections. Contrast-to-noise ratios (CNRs) between infarcted myocardium, non-infarcted myocardium and left ventricle cavity were calculated for each time-point (2.5-min steps). Friedman ANOVA was used for comparing the CNR time-course; Wilcoxon test for comparing CNR at the 10th and the 20th minute. Results The CNR between infarcted and non-infarcted myocardium obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than that obtained at the 10th minute with 0.05 mmol/kg ( P = 0.033) while not significantly different from that obtained at the 10th (0.1 mm/kg) or at the 20th minute with 0.1 plus 0.1 mmol/kg. The CNR between infarcted myocardium and the left ventricle cavity obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than all other measured values ( P ≤ 0.017). Conclusion Using gadobenate dimeglumine, 0.05 plus 0.05 mmol/kg allows for a higher CNR between infarcted myocardium and the left ventricle cavity allowing for reliable assessment of the sub-endocardial infarctions.