Evaluation of two new gadolinium chelates as contrast agents for MRI

Two new gadolinium chelates were investigated for potential use as tissue-specific contrast agents for magnetic resonance imaging. In vitro measurements of stability constants, octanol/water partition coefficients and relaxation times in solutions of water and human serum albumin (HSA) were performed with each new chelate and compared with gadolinium-diethylenetriamine pentaacetic acid, Gd(DTPA). Biodistribution studies and magnetic resonance imaging in rats were used to evaluate the new chelates in vivo. The stability constants (log K) of gadolinium-N,N″-bis(3-hydroxy-6-methyl-2-pyridylmethyl)diethylenetriamine-N,N′,N″-triacetic acid, Gd(DTTA-HP), and gadolinium-1,7-13-triaza-4,10-16-trioxacyclooctadecane-N,N′,N″-triacetic acid, Gd(TTCT), were determined to be 23.65 and 18.07, respectively. These can be compared to a literature value of 22.46 for Gd(DTPA). Octanol/water partition coefficients for both complexes showed they were more lipophilic than Gd(DTPA). Gd(DTTA-HP) exhibited a smaller relaxivity in water but a larger relaxivity in 4% HSA than Gd(DTPA). Gd(TTCT) exhibited a lower relaxivity than Gd(DTPA) in both water and 4% HSA. Both complexes showed similar biodistributions to Gd(DTPA) no carrier-added concentrations. Gd(DTTA-HP) had a greater percent change in signal intensity than Gd(DTPA) on T₁-weighted spin-echo images in the heart, liver, and kidney. Percent change in signal intensity for Gd(TTCT) was lower than Gd(DTPA) in heart, liver, and kidney.     

Differentiation between acutely ischemic myocardium and zones of completed infarction in dogs on the basis of frequency-dependent backscatter

The goal of this work was to determine whether the frequency dependence of apparent backscatter coefficient (not corrected for attenuation within the myocardium) could differentiate completed, remote infarction from acute myocardial injury in vivo. Myocardial infarcts were produced in six dogs by coronary artery occlusion. One to 12 months later, acute ischemic injury was induced in each dog by ligation of a coronary artery that supplied a region of myocardium adjacent to the established infarct. Infarct, ischemic, and normal regions were interrogated with a 5-MHz, circular, 0.5-in. diam, broadband, focused, piezoelectric transducer mounted in a water-filled stand-off device placed against the exposed, beating heart. Apparent backscatter coefficients were measured over the range of frequencies from 3-7 MHz. The frequency dependence was obtained from the slope of log apparent backscatter coefficient versus log frequency. No significant difference in frequency dependence was found between normal and acutely ischemic myocardium for periods of up to 2 h of ischemia. In contrast, frequency dependence in regions of remote infarct (1.8 +/- 0.1, mean +/- standard error) was significantly lower than that in acutely ischemic or nonischemic regions (2.3 +/- 0.1) (p less than 0.01). These results suggest that remote myocardial infarction can be differentiated from acutely injured but still potentially salvageable myocardium in vivo on the basis of the frequency dependence of backscatter.     

Visualization of myocardial infarction and subsequent coronary reperfusion with MRI using a dog model

Twelve anesthetized mongrel dogs underwent left thoracotomy with placement of a removable ligature around the left circumflex coronary artery. Following a 3 to 6 hour delay, ECG-gated spin-echo MRI was performed. The ligature was then removed reperfusing the heart, and after a 10-15 min period, MRI repeated. Finally, post-sacrifice images were obtained, and the hearts chemically stained for infarct evaluation. The MR images were subjectively and quantitatively evaluated for visibility of the endocardial border and of the injured myocardium, and for changes after reperfusion. The injured tissue was variably visible in vivo, the major limitation a result of motion blurring and artifact. The abnormal tissue was easily visible on MRI in 11 animals, and not clearly visible in one. The endocardial border was easily seen in 10 animals. The variation of calculated relaxation times was high for both normal and ischemic/infarcted myocardium in the beating hearts (normal: T1 = 566 +/- 288, T2 = 38 +/- 6; injured myocardium: T1 = 637 +/- 250, T2 = 41 +/- 12) in contrast, relatively stationary skeletal muscle measured in the same images had narrower ranges (T1 = 532 +/- 199, T2 = 28 +/- 2). Changes with reperfusion were seen, but not reliably. The infarcted or ischemic zones were easily visible on post-sacrifice images in all animals imaged. Post-sacrifice relaxation times were T1 = 564 +/- 69 msec, T2 = 39 +/- 3 msec for normal heart muscle, and 725 +/- 114, T2 = 47 +/- 5 for ischemic/infarcted tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic analysis of blood distribution of intravenously administered 153Gd-labeled Gd(DTPA)2- and 99mTc(DTPA) in rats

Rat plasma distribution data obtained following IV administration of 99mTc(DTPA) alone or after co-administration of 99mTc(DTPA) and 153Gd-labeled Gd(DTPA)2- at 0.001, 0.1, and 1.0 mmol Gd/kg were evaluated using compartmental modeling techniques. A three-compartment open model was found to fit the data significantly better (P less than 0.01) than a two- or four-compartment open model. This model incorporates and links the plasma and urine data and includes a delay to account for the transit time through the kidneys/ureters. The two nonplasma compartments of the model were assumed to be related to rapidly and slowly equilibrating tissues. Tc(DTPA) and Gd(DTPA)2- had nearly identical pharmacokinetic profiles in plasma and the rate constants were essentially the same. No significant dose dependent pharmacokinetic differences were found for the range of Gd(DTPA)2- doses tested. Simulations of the proposed three-compartment model were used to generate concentration-time curves for each of the three compartments.     

Quantitative dependence of MR signal intensity on tissue concentration of Gd(HP-DO3A) in the nephrectomized rat.

Cardiac-gated SE 20/224 +/- 20 MR images were obtained from nephrectomized rats before and after intravenously administering 153Gd-Gd(HP-DO3A). The concentration of Gd, [Gd], was linear in dose in myocardium, skeletal muscle, and blood. Under steady-state conditions, where d[Gd]/dt = 0, image intensities (IIN) in regions of interest were compared with the measured [Gd]. IIN was linear in myocardium at less than or equal to 0.61 mumol/g-myocardium (less than or equal to 0.5 mmol/kg dose) and in skeletal muscle at less than or equal to 0.63 mumol/g-muscle (less than or equal to 0.75 mmol/kg). Above 0.6 mumol Gd/g-tissue, IIN did not increase further. The in vivo data were consistent with measured ex vivo and in vivo relaxivities. A 29% greater slope for IIN versus [Gd] in myocardium [14,439 +/- 4350 IIN (mumol/g)] than in muscle [10,258 +/- 5,296 IIN/(mumol/g)] was attributed to a significant difference in blood content: 25% versus 2% weight blood in myocardium and skeletal muscle, respectively. Two components were apparent from plots of ex vivo 1/T1 versus [Gd] in myocardium and muscle, and only one for blood.     

Effectiveness and Toxicity of Several DTPA Broadening Agents for Biological ESR Spectroscopy

The effectiveness of a standard ESR broadening agent, potassium trioxalatochromiate (CrOx), for use with the spin-label tempone, was compared to that of diethylenetriaminepentaacetic acid (DTPA) containing an ion (Gd, Cr, Mn, Fe) with a large magnetic moment. Signal attenuation, line broadening, toxicity, and cell membrane permeability were compared. As a broadening agent, CrOx was most effective, followed by Fe–DTPA. CrOx proved mildly toxic while Gd-DTPA and Fe–DTPA were virtually nontoxic. The human red blood cell membrane was tested for permeability to Fe– and Gd–DTPA and found to be impermeable to both. In situations where toxicity to cells is critical, the DTPA chelates, particularly Fe–DTPA, may prove an acceptable substitute for CrOx.     

The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption

To provide contrast enhancement in magnetic resonance imaging, a new class of compounds has been developed, the paramagnetic metal ion chelates. Gadolinium (Gd) DTPA, a prototype of this class, shows a sufficiently high in vivo stability and low toxicity for use in initial clinical trials. This type of agent, designed for rapid clearance by glomerular filtration, allows the assessment on MRI of renal function, alterations in tissue perfusion, myocardial ischemia, and perhaps most significantly disruption of the blood-brain barrier (BBB). Research at Vanderbilt has demonstrated these applications, with particular emphasis in three areas. Tissue perfusion changes, such as those produced by ligation of the arterial blood supply to portions of the spleen and kidney, cannot easily be detected on unenhanced MRI. These acute tissue infarcts can be readily identified following the administration of Gd DTPA. The question of field strength dependence of Gd DTPA has been addressed by experimentation at 0.15, 0.5, and 1.5 tesla. Furthermore, the ability to detect an alteration of the BBB, when present without associated edema, has been demonstrated with the application of control enhancement. The use of contrast agents in MRI will enhance both the sensitivity and specificity of magnetic resonance imaging.     

Utilization of the nephrectomized mouse for determining threshold effects of MRI contrast agents

The tissue concentration of an extravascularly distributed MRI contrast agent required to achieve a 20% change in the MRI signal intensity (SI) of skeletal muscle was determined using radiolabeled gadoteridol administered to nephrectomized mice. This minimal change in the quantified SI was reliably detected qualitatively in the MR muscle images. MR images of muscle were acquired following each intravenous injection of six sequential doses of 0.8 micromol of 153Gd-labeled gadoteridol. A 2.0 T imaging spectrometer and a T1-weighted spin-echo pulse sequence were used to acquire the MR images. After imaging, the injected 153Gd in muscle was measured, and the 153Gd assay results were used to determine the gadoteridol concentration in muscle following each injection. The muscle concentrations of gadoteridol were then correlated to the quantified enhanced MR SI of muscle. Using the 20% factor, it was concluded that the amount of gadoteridol necessary to achieve a reliable change in the SI of muscle was 33+/-10 nmol/g-skeletal muscle.     

Synthesis, characterization and relaxivity of DTPA double alkyl esters heterocyclic gadolinium(III) complexes

The DTPA ligand modified by heterocyclic compound and linked through double alkyl ester covalent bond was synthesized by acylation reaction between diethylenetriamine pentaacetic (DTPA) bisanhydride and a novel heterocyclic compound. The corresponding paramagnetic Gd(III) complex was gained by the reaction of the DTPA ligand with GdCl3.6H2O. The structure of the ligand and its Gd(III) complex was characterized by elemental analysis, FTIR and 1H NMR, and the longitudinal relaxivity (R1) was measured. Besides, the magnetic resonance imaging of the new Gd(III) complex in vitro was studied. The result suggested that the stability of the complex was well, and when the Gd(III) quantity was identical, the R1 of the Gd(III) complex (5.12 mmol x L(-1) x s(-1)) was higher than the clinical magnetic resonance imaging contrast agent Gd-DTPA (3.64 mmol x L(-1).     

An MRA study of vascular stenosis in a pig model using CH3-DTPA-Gd (NMS60) and Gd-DTPA

PURPOSE: This study used an experimental arterial stenosis model in pigs to evaluate the utility of a new medium-weight MRI contrast agent, NMS60 (a synthetic oligomeric Gd complex containing three Gd(3+) atoms, molecular weight of 2158 Da) compared to Gd-DTPA for contrast-enhanced MRA. MATERIALS AND METHODS: We used six male white hybrid pigs. Under anesthesia, one femoral artery was exposed and an inflatable cuff placed around it. The cuff was tightened around the vessel until 80-90% stenosis was achieved using digital subtraction angiography as a guide. Animals were then immediately transferred to the MRI scanner and images acquired pre- and postcontrast injection (0.1 or 0.2 mmol Gd/kg Gd-DTPA or NMS60, as a rapid bolus) using high-resolution and dynamic MRA. RESULTS: The dynamic MRA scans acquired during contrast bolus injection clearly showed the stenosed femoral artery as a segment of close to zero enhancement during the arterial phase of the bolus transit, while on the high-resolution scans the stenosis was difficult to detect due to venous signal contamination. The signal-to-noise at peak enhancement on the dynamic scans was significantly greater with 0.1 mmol Gd/kg NMS60 compared to 0.1 mmol Gd/kg Gd-DTPA (14.6 vs. 9.9, P < .05) and not significantly greater than 0.2 mmol Gd/kg (14.6 vs. 12.8). DISCUSSION AND CONCLUSION: This new medium-weight contrast agent demonstrated significantly greater enhancement than Gd-DTPA and may be valuable to aid detection of vascular stenosis in humans.     

T2-based area-at-risk and edema are influenced by ischemic duration in acute myocardial infarction

The purpose of our study was to assess whether T2 MRI identifies the infarcted myocardium or the true area-at-risk (AAR) and whether edema is present in the salvageable region following acute myocardial infarction (MI). The study involved a porcine model of MI with a coronary occlusion model of either 60 min or 90 min. Imaging was performed on a 3T MRI pre-occlusion and at day 3 post-MI. Prior-MI, myocardial perfusion territory (MPT) maps were obtained under MRI via direct intracoronary injection of contrast agent. Post-MI, edema extent was quantified by T2 mapping while infarction and microvascular obstruction (MVO) were assessed by late gadolinium enhancement (LGE). Anatomically registered short-axis slices were analyzed for MPT, T2-AAR and infarct areas and T2 relaxation values. Animals were divided into groups with (MVO+) and without MVO (MVO-). T2-AAR area was significantly greater than infarct area in both groups. In the MVO+ group, T2-AAR and MPT were comparable and highly correlated, whereas, in the MVO- group, T2-AAR significantly underestimated MPT without any trend. T2 values in the salvageable myocardium were found to be significantly higher than those in remote myocardium. Our methodology offers the advantage that all images are acquired within the same MRI reference as opposed to complex co-registration with gross pathology. Our study suggests that edema may expand beyond the infarct zone over the entire ischemic bed. T2-AAR may be more clinically relevant than true AAR by perfusion territory since it identifies the “salvageable” myocardium.     

DTPA双酰胺杂环钆(Ⅲ)配合物的合成、表征与弛豫效能

通过二乙三胺五乙酸(DTPA)酸酐与一种新型杂环化合物的酰化反应,得到了双酰胺共价键链接、杂环化合物修饰的DTPA配体。再与GdCl₃·6H₂O反应得到相应的顺磁性钆(Ⅲ)配合物。通过元素分析、FTIR、1H NMR等手段表征了配体和金属配合物的结构,进而测定了配合物的纵向弛豫率(R₁)。结果表明,配合物分子稳定性很好,且在同等含钆量条件下,这种新型钆(Ⅲ)金属配合物的R₁(5.12 mmol·L-1·s-1)高于临床应用的磁共振成像对比剂Gd-DTPA(3.64 mmol·L-1·s-1)。     

Effect of hyperosmotic mannitol on magnetic resonance relaxation parameters in reperfused canine myocardial infarction

To determine how administration of a hyperosmotic agent alters regional nuclear magnetic resonance (NMR) relaxation parameters and imaging characteristics in ischemic-reperfused myocardium, 7 dogs were infused with mannitol for 15 minutes before and after the release of a 3 hour left anterior descending coronary artery (LAD) occlusion. Nine control animals received normal saline during the 3 hour occlusion and 1 hour reperfusion periods. Normal posterior left ventricular (LV) wall and the ischemic anterior LV wall (risk area) myocardium was sampled for calculation of segmental microsphere myocardial blood flow, % tissue water content, NMR relaxation times (T1, T2) and myocyte ultrastructure using electron microscopy. Mean infarct T1 values were 14% greater than normal segments in saline-treated controls, but only 5% greater after mannitol. The difference in tissue water content between infarcted and normal segments was 4% in saline-treated (83 vs. 79%) compared to 2% in mannitol-treated dogs (79 vs. 77%). T1, T2 and % water content of control infarct segments were greater than treated infarcts (p less than 0.01). T1 and T2 rose as occlusion flow fell below 0.5 ml/min/g in control hearts but did not rise until flows were reduced to 0.1 ml/min/g in mannitol-treated hearts. Areas of increased signal in T1 and T2 NMR images correlated well with histochemical infarct volume (r = 0.98, SEE = 1.1 cc) in mannitol-treated dogs, but infarct borders were qualitatively less well-defined than in controls. We concluded that mannitol (1) diminishes tissue edema and reduces NMR relaxation parameters (T1, T2) in infarcted myocardium; and (2) attenuates the rise in T1 and T2 and ultrastructural myocyte injury in ischemic-reperfused myocardium.     

Magnetic resonance imaging with superparamagnetic iron oxide particles for the detection of myocardial reperfusion

The effect of superparamagnetic iron oxide particles on magnetic resonance myocardial signal intensity was examined in order to define the ability of this agent to identify normal, ischemic, and reperfused myocardium. Data were obtained from 6 normal rats (group 1) and from 6 heterotopic isogenic rat heart transplants (group 2) at 4.7 T with a multislice spin-echo sequence. Images were acquired in (a) normal rats before and after the infusion of 36 μmol Fe/kg of AMI-25 (group 1) and (b) rat heart transplants during control, global myocardial ischemia (before and after the injection of 72 μmol Fe/kg of AMI-25), and following reperfusion (group 2). Myocardial signal intensity decreased by 36 ± 4%, p < 0.001, following contrast infusion in normal hearts (group 1). The intensity remained constant in the rat heart transplants (group 2) during coronary occlusion, both before and after the infusion of AMI-25 and decreased by 61 ± 7%, p < 0.001, upon reperfusion. The larger effect of AMI-25 in reperfused as compared to normal myocardium suggests the presence of ischemia-induced hyperemia. There was no significant difference (analysis of variance) among intensities from different myocardial regions in either group at any stage of the experiment. We conclude that the use of AMI-25 permits identification of normal, ischemic, and reperfused myocardium and may therefore be helpful for the early detection of reperfusion following thrombolytic therapy for acute myocardial infarction.     

Reaction of gadolinium chelates with endogenously available ions

The extent of reaction of 153Gd-radiolabeled Gd(L) chelates with 25 mM CO23- (25 mF), PO34-, Zn2+ and Cu2+ at pH 7 was determined for L = EDTA, DTPA, DOTA, HP-DO3A, and DO3A. Gd(EDTA)- and Gd(DTPA)2- reacted (greater than 20% in 10 min) with Cu2+ and Zn2+ in the presence of PO34-. These double replacement reactions yielded precipitated GdPO4 and chelated Cu(L). Gd(HP-DO3A), Gd(DO3A) and Gd(DOTA)- were inert to reaction with all four ions at room temperature (less than or equal to 1% reaction detected). The thermodynamic binding constants of the ligands for Gd3+ and Cu2+ were found to be equal (10(20) M-1) for DO3A, while DOTA and HP-DO3A favored Gd3+ over Cu2+ by greater than or equal to 10(2) M-1. The low order of reactivity of Gd(DOTA)- and Gd(HP-DO3A) was anticipated by the binding constants, but the lack of reactivity of Gd(DO3A) is attributed to kinetic inertia. This latter property, desirable in MRI contrast agents, is promoted by the conformational stability of the tetraazacyclododecane macrocycle, which forms the backbone of the ligand. It is concluded that this class of chelates is exceptionally inert in solutions of endogenously available ions, and that thermodynamics alone is an insufficient predictor of the reactivity of the highly inert Gd complexes based on the tetraazamacrocycle.     

Magnetic resonance imaging of coronary arteries and heart valves in a living mouse: techniques and preliminary results

New investigations in MRI of a mouse heart showed high-contrast cardiac images and thereby the possibility of doing functional cardiac studies of in vivo mice. But is MRI, in addition, capable of visualizing microstructures such as the coronary arteries and the heart valves of a living mouse? To answer this question, 2D and 3D gradient echo sequences with and without flow compensation were used to image the coronary arteries. To increase signal-to-noise ratio, a birdcage resonator was optimized for mouse heart imaging. Contrast between blood and myocardium was achieved through the inflow effect. A segmented three-dimensional FLASH sequence acquired with a multiple overlap thin slab technique showed the best results. With this technique an isotropic resolution of 100 microm was achieved. The left coronary artery could be visualized up to the apex of the heart. This is demonstrated with short axis views and 3D surface reconstructions of the mouse heart. The four cardiac valves were also visible with the 3D method.     

Quantification of myocardial viability distribution with Gd(DTPA) bolus-enhanced, signal intensity-based percent infarct mapping

Introduction

A substantial, common shortcoming of the currently used semiautomated techniques for the quantification of myocardial infarct with delayed enhancement magnetic resonance imaging is the assumption that the whole myocardial slab that corresponds to the hyperenhanced tomographic area is 100% nonviable. This assumption is, however, incorrect. To resolve this conflict, we have recently proposed the signal intensity percent-infarct mapping method and validated it in an ex vivo, canine experiment. The purpose of the current study has been the validation of the signal intensity percent-infarct mapping method in vivo, using a porcine model of reperfused myocardial infarct.

Methods

In swines (n=6), reperfused myocardial infarct was generated occluding for 90 min by an angioplasty balloon either the left anterior descending or the left circumflex coronary artery. To obtain DE images, Gd(DTPA) enhanced inversion-recovery fast gradient-echo acquisitions were carried out on day 28 after myocardial infarction. Scanning started 15 min after intravenous injection of 0.2 mmol/kg Gd(DTPA). At the end of the MRI session, the animal was sacrificed and 2,3,5-triphenyltetrazolium chloride staining was used to validate the existence and to determine the accurate size of the myocardial infarct. Tissue samples were taken and stained with hematoxylin-eosin and Masson's trichrome for histological assessment of the infarct and the periinfarct zone. The signal intensity percent-infarct mapping data were compared with corresponding data from the delayed enhancement images analyzed with SI_remote+2S.D. thresholding, and with corresponding triphenyltetrazolium-chloride staining data using Friedman's repeated measure analysis of variance on ranks.

Results

The infarct volume determined by the triphenyltetrazolium chloride, SI_remote+2S.D. and signal intensity percent-infarct mapping methods was 3.04 ml [2.74, 3.45], 13.62 ml [9.06, 18.45] and 4.27 ml [3.45, 6.33], respectively. Median infarct volume determined by SI_remote+2S.D. significantly differed from that determined by triphenyltetrazolium chloride (P<.05). The Bland-Altman overall bias was 12.49% of the volume of the left ventricle. Median infarct volume determined by signal intensity percent-infarct mapping, however, did not differ significantly (NS) from that obtained by triphenyltetrazolium chloride. Signal intensity percent-infarct mapping yielded only a 1.99% Bland-Altman overall bias of the left ventricular volume.

Conclusions

This in vivo study in the porcine reperfused myocardial infarct model demonstrates that signal intensity percent-infarct mapping is a highly accurate method for the determination of the extent of myocardial infarct. MRI images for signal intensity percent-infarct mapping are obtained with the pulse sequence of conventional delayed enhancement imaging and are acquired within clinically acceptable scanning time. This makes signal intensity percent-infarct mapping a practical method for clinical implementation.     

The relationship between collagen and ultrasonic attenuation in myocardial tissue.

The relationship between ultrasonic attenuation and collagen content is examined in hearts from normal dogs and in hearts from dogs subjected to ischemic injury by coronary occlusion as an approach toward elucidating the physical mechanisms responsible for the attenuation of soft tissue. Increased ultrasonic attenuation is shown to correlate well with increased collagen concentration determined biochemically in regions of ischemic injury studied 2, 4, and 6 weeks following occlusion. Extrapolation of experimentally determined relationship between attenuation and collagen concentration suggests that collagen is responsible for not more than 15% of the attenuation observed in normal myocardium. These results indicate that collagen appears to be the principal determinant of the elevated attenuation detected in regions of myocardial infarction, but is apparently not the primary determinant of the attenuation of normal myocardium.     

Cardiac-synchronized gadolinium-enhanced MR angiography: preliminary experience for the evaluation of the thoracic aorta

Gadolinium (Gd)-enhanced three-dimensional breath-hold magnetic resonance cardiac-synchronized angiography was performed in 13 patients suspected or known to have thoracic aortic disease. High-quality angiograms of the ascending/descending thoracic aorta and coronary arteries were obtained with this method. MR angiograms were compared with Gd-enhanced angiograms obtained without cardiac synchronization. Synchronized imaging showed significantly better aortic valve leaflet and proximal coronary artery depiction. Synchronization reduced motion artifacts, allowing better visualization of the aortic root and proximal coronary arteries.     

DTPA双酯Gd (Ⅲ)配合物的合成及其弛豫率

二乙三胺五乙酸双酐与甘醇单醚反应,得到含多氨基多羧基双酯配体,配体与GdCl₃·6H₂O反应生成非离子配合物.配体及配合物用IR、¹H NMR和元素分析进行了表征,并测试了配合物的驰豫率,其中3种配合物的弛豫率比已用于临床诊断的Gd (DTPA)强,