Gadolinium-DOTA enhanced MR imaging of intracranial lesions

Gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (Gd-DOTA) is the first of a new class of macrocyclic paramagnetic magnetic resonance (MR) contrast agents (gadolinium cryptelates) to be used in clinical practice. Gadolinium-DOTA possesses relaxation properties similar to those of gadolinium diethylene triamine pentaacetic acid (Gd-DTPA). We report our initial clinical experience in 38 patients with intracranial lesions studied with MR before and after injection of Gd-DOTA. Diseases included primary and metastatic brain tumor, cerebral infarct, vascular malformation, meningioma, hemangiopericytoma, schwannoma, and pituitary macroadenoma. Gadolinium-DOTA was administered intravenously in a dosage of 0.1 mmol/kg body weight. All studies were performed on a superconductive 0.5 T system. As compared to noncontrast T1- and T2-weighted images (WI), Gd-DOTA enhanced T1 WI were useful in defining the anatomy of malignant intraaxial tumors (high-grade glioma, metastasis) and in tumor versus edema differentiation. Low-grade gliomas did not enhance; in these cases the precontrast T2-weighted sequence was found to be more informative. In post-operative patients, Gd-DOTA allowed us to demonstrate residual tumor or tumor recurrence. Extraaxial tumors (meningioma, hemangiopericytoma, neuroma) enhanced markedly, presumably reflecting tumor vascularity. In our experience, the use of Gd-DOTA improves the anatomic definition of cerebral lesions and in some cases increases both MR sensitivity and specificity. We found Gd-DOTA to be a well tolerated and effective paramagnetic contrast agent. Gadolinium-DOTA can be considered as an alternative water-soluble MR contrast agent to Gd-DTPA.     

Preclinical evaluation of MnDPDP: new paramagnetic hepatobiliary contrast agent for MR imaging

Manganese(II)-N,N'-dipyridoxylethylenediamine-N,N'-diacetate-5,5'-bis (phosphate) (MnDPDP) is a paramagnetic complex designed for use as a hepatobiliary agent. The T1 relaxivity of MnDPDP (2.8 [mmol/L]-1.sec-1 in aqueous solution) was similar to that of gadolinium diethylenetriaminepentaacetic acid (DTPA) (4.5 [mmol/L]-1.sec-1) and gadolinium tetraazocyclodecanetetraacetic acid (DOTA) (3.8 [mmol/L]-1.sec-1). However, in liver tissue the T1 relaxivity of MnDPDP (21.7 [mmol/L]-1.sec-1) was threefold higher than that reported for Gd-DOTA (6.7 [mmol/L]-1.sec-1). Maximum liver T1 relaxation enhancement occurred 30 minutes after injection of MnDPDP, at which time 54MnDPDP biodistribution studies indicated that 13% of total body activity was in the liver. Enhanced (MnDPDP, 50 mumol/kg) MR images showed a fivefold increase in tumor-liver contrast-to-noise ratio over baseline unenhanced images. Results of the authors' acute and subchronic toxicity studies suggest that MnDPDP will be safe at the doses necessary for clinical imaging; at 10 mumol/kg, the safety factor (LD50/effective dose) for MnDPDP is 540, significantly greater than the safety factor of Gd-DTPA (ie, 60-100).     

Evaluation of Gd-DTPA-labeled dextran as an intravascular MR contrast agent: imaging characteristics in normal rat tissues.

Dextran covalently linked to moieties of gadolinium diethylenetriamine pentaacetic acid (DTPA), for use as a macromolecular, intravascular blood pool marker for contrast material-enhanced magnetic resonance (MR) imaging was characterized by means of physicochemical and relaxivity measurements and MR imaging in healthy rats. Dextran labeled with 15 Gd-DTPA moities (molecular weight of approximately 75,000 d) had a T1 relaxivity at 0.25 T and 37 degrees C of 157.1 mmol-1.sec-1 per molecule and 10.5 mmol-1.sec-1 per gadolinium atom, more than twice that of unbound Gd-DTPA. Osmolality was 300-350 mOsm/kg at a gadolinium concentration of 0.01 mmol/L. Tissue enhancement was essentially linearly related to injected dose in the gadolinium dose range of 0.01-0.05 mmol/kg of body weight. Approximate typical enhancement values over baseline for normal tissues at 10 minutes after a gadolinium dose of 0.05 mmol/kg were as follows: cardiac muscle, adrenal gland, and liver, 40%-50%; lungs, 160%-200%; renal cortex, 130%; renal medulla, 240%; spleen, 75%; muscle, 15%; and brain, 5%-10%. Projection-subtraction images showed that dextran-(Gd-DTPA)15 remained intravascular for at least 1 hour after injection. The prolonged and easily appreciated levels of tissue enhancement with dextran-(Gd-DTPA)15, at a gadolinium dose less than that routinely used in Gd-DTPA, indicate further evaluation of this macromolecular marker.     

Enhancing lesions of the brain: intraindividual crossover comparison of contrast enhancement after gadobenate dimeglumine versus established gadolinium comparators

RATIONALE AND OBJECTIVES: Gadobenate dimeglumine (Gd-BOPTA) possesses a two-fold higher T1 relaxivity compared to other available gadolinium contrast agents. The study was conducted to evaluate the benefits of this increased relaxivity for MR imaging of intracranial enhancing brain lesions. MATERIALS AND METHODS: Forty-five patients (31 males, 14 females) with suspected glioma or cerebral metastases were evaluated. Patients received Gd-BOPTA and either Gd-DTPA (n = 23) or Gd-DOTA (n = 22) in fully randomized order at 0.1 mmol/kg body weight and at a flow rate of 2 ml/s. The second agent was administered 1-14 days after the first agent. Images were acquired precontrast (T1wSE, T2wFSE sequences) and at sequential postcontrast time-points (T1wSE sequences at 0, 2, 4, 6, and 8 and 15 min and a T1wSE-MT sequence at 12 min) at 1.0 or 1.5 T using a head coil. Determination of contrast enhancement was performed quantitatively (lesion-to-brain ratio, contrast-to-noise ratio, and percent enhancement) and qualitatively (border delineation, internal morphology, contrast enhancement, and diagnostic preference) by two independent, fully blinded readers. RESULTS: Images from 43/45 patients were available for quantitative assessment. After correction for precontrast values, significantly greater lesion-to-brain ratio (P < .003), contrast-to-noise ratio (P < .03), and percent enhancement (P < .0001) was noted by both readers for Gd-BOPTA-enhanced images at all time-points from 2 min postcontrast. Qualitative assessment of all patients similarly revealed significant preference for Gd-BOPTA for lesion border delineation (P < .004), lesion internal morphology (P < .008), contrast enhancement (P < .0001), and diagnostic preference (P < .0005). CONCLUSIONS: The greater T1 relaxivity of Gd-BOPTA permits improved visualization of intracranial enhancing lesions compared to conventional gadolinium agents.     

Magnetic resonance relaxivity of dendrimer-linked nitroxides.

The relaxivity and bioreduction rates of eight dendrimer-linked nitroxides varying in the number of nitroxides per molecule were measured and the potential use of these compounds as MR contrast agents was demonstrated. The T(1) and T(2) relaxivities, measured at room temperature and 1.5 T, varied linearly with the number of nitroxides per molecule for compounds with up to 16 nitroxides per molecule. Fourth-generation polypropylenimide- (DAB) and third-generation polyamidoamine- (PAMAM) dendrimer-linked nitroxides were found to have greater relaxivity than gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA). The greater number of nitroxides per dendrimer increased relaxivity over that of a single nitroxide, allowing a decreased dose to achieve differential contrast with MR evaluations. Rates of nitroxide bioreduction were below detection threshold using EPR spectroscopy for generation 2 dendrimers and higher. A pilot assessment of in vivo cartilage uptake that compared intraarticular injection of three structurally different dendrimer-linked nitroxides with Gd-DTPA and with saline demonstrated high affinity of the DAB-dendrimer-linked nitroxides for normal rabbit articular cartilage. From these results, it is evident that target-specific dendrimer-linked nitroxides can be designed.     

Effect of field strength on gadolinium enhancement in MR imaging

This studv was designed to evaluate the influence of magnetic field strength on the relative enhancement effect (RE) of gadolinium (Gd)-chelates. Dilution series of two paramagnetic contrast agents (Gd-DTPA and Gd-DOTA) were examined in three commercially available MR systems. operating at different field strengths (02 T, 1. T, and 1.5 T). The RE was plotted against Gd concentration. The highest increases in signal intensity occurred with Gd concentrations of approximately L.0 mmol/L. No significant difference in RE was observed between MR systems ranging in field strength from 0.? T to 1.5 T. The RE of Gd-DTPA and Gd-DOTA was found to he equivalent.     

Calcium binding by gadolinium-based MR contrast agents

PURPOSE: This study was conducted to characterize the alterations in ionic sodium, potassium, and calcium by gadolinium-based MR contrast agents. MATERIALS AND METHODS: An electrolyte solution (ES) containing 1.2 mM/L calcium ions,120 mM/L sodium, and 4.0 mM/L potassium were diluted with various gadolinium compounds and alterations in ionized electrolytes were measured using an ion-specific electrometer. Gadolinium compounds including Gd-DTPA, Gd-DOTA, gadoteridol, gadodiamide, meglumine/sodium diatrizoate (76% Urografin), and isotonic saline as a control were investigated. The dilution ranged from 5% (ES/test solution = 100/5) to 100%. Alterations of ionic electrolytes were measured. Calcium-binding capacities caused by each gadolinium compound also were measured. RESULTS: The alterations of ionic sodium and potassium by gadolinium compound were similar to those of isotonic saline. A significant reduction in ionized calcium was observed with Gd-DTPA and Gd-DOTA in comparison with gadoteridol and gadodiamide. CONCLUSION: Ionic gadolinium compounds induced significant reductions of calcium ions in vitro compared with non-ionic gadolinium compounds.     

Signal modulation in (1)H magnetic resonance spectroscopy using contrast agents: proton relaxivities of choline, creatine, and N-acetylaspartate.

The effect of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) on the proton relaxation properties of choline, creatine and N-acetylaspartate has been assessed quantitatively. The compounds studied, either directly or indirectly as chemical constituents of other compounds, contribute to proton MR spectroscopy observable metabolite resonances. The longitudinal and transverse Gd-DTPA proton relaxivities of the methyl groups of choline, creatine, and N-acetylaspartate have been determined at 1.5 T. The longitudinal relaxivity of lactate has also been measured. Longitudinal and transverse relaxivity values were found to vary in the order N-acetylaspartate < creatine < choline. Using choline as an example, the maximum possible signal enhancement predicted in vivo in the presence of 0.5 mM Gd-DTPA (using a T(1)-weighted sequence, TR = 888 msec, TE = 20 msec) was found to be approximately 100 %. For a T(2)-weighted sequence (TR = 3000 msec, TE = 270 msec) a maximum signal loss of 53 % was calculated. The present study indicates why the use of contrast agents in spectroscopic investigations may lead to significant changes in signal intensities. Magn Reson Med 42:1155-1158, 1999.     

In vivo measurements of relaxivities in the rat kidney cortex

The aim of this study was to implement a novel noninvasive method to derive the in vivo T1 relaxivity (R1) and T2 relaxivity (R2) in the rat kidney cortex. A two-compartment gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) distribution model was established to estimate the bolus and infusion dosages of Gd-DTPA necessary for obtaining the required steady-state concentration levels. After a single bolus injection of (99m)Tc-DTPA, several blood samples were collected. Based on considerations from the applied two-compartment model, a steady-state concentration was predicted approximately 5-10 minutes after the bolus injection. The plasma concentration levels of Gd-DTPA were measured by simultaneous injection of (99m)Tc-DTPA. Three regions in the cortex (upper, central, and lower) of both rat kidneys were used. A statistical evaluation resulted in the following in vivo relaxivities found at 7 T: R1 = 1.04 +/- 0.08 mM(-1)s(-1) and R2 = 10.78 +/- 0.83 mM(-1)s(-1). Using a 95% confidence interval, no intracortical differences were detected. The relaxivities R1 and R2 calculated in the intact rat kidney cortex were distinctly different from relaxivities found in human plasma: (22 degrees C) 4.42 +/- 0.07 mM(-1)s(-1) (r2> 0.98) and R2 = 5.75 +/- 0.17 mM(-1)s(-1) (r2> 0.98), respectively. The measurements showed a marked difference between in vitro and in vivo relaxivities. Comparison of the distribution rates in pig, human, and rats shows a distinct proportionality between size and renal function.     

Albumin labeled with Gd-DTPA. An intravascular contrast-enhancing agent for magnetic resonance blood pool imaging: preparation and characterization

A paramagnetic-labeled macromolecule, albumin-(Gd-DTPA), was prepared for use as an intravascular contrast agent for magnetic resonance imaging. An average of 19 Gd-DTPA chelates were covalently conjugated to human serum albumin through the bifunctional anhydride of DTPA. The albumin-(Gd-DTPA) was characterized with use of high-performance liquid chromatography, sodium dodecyl sulfate gel electrophoresis, atomic absorption, biuret and Bradford protein tests, and by its effect on proton relaxation (relaxivity). The average molecular weight was 92,000 daltons, indicating the albumin conjugate was predominantly monomeric. The T1 relaxivity of albumin-(Gd-DTPA) was 273 mM-1 sec-1 relative to carrier concentration, which corresponds to a relaxivity of 14.9 mM-1 sec-1 relative to gadolinium concentration. The average conditional stability constant for albumin-bound Gd-DTPA chelate was log K = 20.0. Spin-echo images of rats demonstrated persistent enhancement of vascular tissues and slowly flowing blood. Application of albumin-(Gd-DTPA) may augment the MR assessments of blood volume, tissue perfusion, and flow characteristics.     

Stability of MRI paramagnetic contrast media: a proton relaxometric protocol for transmetallation assessment

RATIONALE AND OBJECTIVES: The suitability of paramagnetic complexes as magnetic resonance contrast agents depends on various factors such as their relaxivity, stability, selectivity, and the inertness toward transmetallation by endogenous ions. The transmetallation of a series of 18 gadolinium complexes by the Zn2+ ion was studied in vitro by proton relaxometry. METHODS: Transmetallation was analyzed through the evolution of the paramagnetic longitudinal relaxation rate of water protons at 37 degrees C in pH = 7 phosphate buffer solutions containing 2.5 mmol/L of the gadolinium complexes and 2.5 mmol/L zinc chloride. The measurements were performed at 0.47 T over a period of at least 3 days. RESULTS: The results confirm the high stability of macrocyclic systems and a high sensitivity of Gd-diethylenetriamine-pentaacetic acid (DTPA) derivatives to transmetallation by Zn2+ ions. The decreasing order of stability with respect to metal exchange is as follows: Gd-macrocyclics > Gd-C-functionalized DTPA > Gd-DTPA > primary and secondary Gd-DTPA bisamides. The ternary bisamide analyzed in this study [Gd-DTPA-1,11-bisbismethylamino-1,11-dioxo-3,6,9-triaza-3,6,9-tris(carboxymethyl)undecane] is more stable than the parent compound Gd-DTPA. CONCLUSIONS: A simple relaxometric protocol has been successfully developed to study the in vitro transmetallation process of gadolinium complexes. The importance of the functionalization and substitution of the DTPA-like complexes is clearly shown.     

AUR Memorial Award 1991. Immunogenicity of gadolinium-based contrast agents for magnetic resonance imaging. Induction and characterization of antibodies in animals.

To evaluate the immunogenic potential of gadolinium-based magnetic resonance imaging (MRI) contrast agents, Sprague-Dawley rats were sensitized with gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) dimeglumine and with Gd-DTPA covalently linked to either human serum albumin, dextran, or polylysine. IgG antibodies directed against Gd-DTPA were detected in immune sera by an enzyme-linked immunosorbent assay (ELISA), and were confirmed by competitive inhibition of antibody binding using free Gd-DTPA dimeglumine. Antiserum induced by immunization with human serum albumin-(Gd-DTPA) was characterized by a monophasic competition curve with 50% inhibition (IC50) = 5.5 x 10(-4) M when Gd-DTPA dimeglumine was used as both the well-coating and the displacing agent in a competition ELISA. Antiserum induced by Gd-DTPA dimeglumine alone was characterized by a biphasic competition curve with IC50 = 6.5 x 10(-7) M and 7.9 x 10(-4) M. Antisera obtained after exposure to either dextran-(Gd-DTPA) or polylysine-(Gd-DTPA) were of insufficient titer for characterization. The detection of antibodies specific for Gd-DTPA suggests in vivo protein binding with formation of hapten-carrier conjugates. This hypothesis is supported by increased relaxivity values observed when Gd-DTPA dimeglumine is incubated in serum rather than in water. Gd-DTPA dimeglumine and albumin-(Gd-DTPA) are immunogenic in rats under idealized experimental conditions. Additional studies will be necessary to determine the potential for immunologic response in humans to gadolinium chelates under conditions of exposure inherent in clinical use.     

Hepatic metastases: liposomal Gd-DTPA-enhanced MR imaging

Liposomal gadolinium diethylenetriaminepentaacetic acid (DTPA) encapsulated within 70- and 400-nm vesicles was tested as a contrast agent for magnetic resonance (MR) imaging of the liver in rats with hepatic metastases. Liposomal Gd-DTPA caused significant improvement in contrast between liver and tumor (P less than .005) on T1-weighted MR images. Smaller 70-nm liposomal Gd-DTPA vesicles caused greater contrast enhancement, reflecting the larger surface-area-to-volume ratio of the smaller vesicles. Liposomal Gd-DTPA-enhanced images permitted significant improvement in metastasis detection by five blinded radiologists (P less than .005). By comparison, free Gd-DTPA without liposomes caused a statistically significant reduction in contrast between tumor and liver and reduced lesion detection (P less than .01). Liposomal Gd-DTPA also resulted in sustained vascular enhancement for 1 hour after administration. The results suggest that paramagnetic liposomes may become a useful MR imaging contrast agent.     

Pilot MR evaluation of pharmacokinetics and relaxivity of specific blood pool agents for MR angiography

RATIONALE AND OBJECTIVES: To evaluate the use of two new blood pool contrast agents (P760, P775) compared with a low-molecular-weight gadolinium chelate in MR angiography. METHODS: The r1 efficiency of P760 was evaluated in vitro at 1.5 T; 3D abdominal contrast-enhanced MR angiography with qualitative analysis was compared in four rabbits after injection of incremental doses of P760 and in one rabbit after Gd-DOTA. A dynamic MR study was performed using a 2D T1-weighted turbo-flash MR sequence after injection of P760, P775, and Gd-DOTA. Each compound was tested at equivalent doses in three rabbits to assess r1 efficiency. Quantitative analysis of signal intensity in the aorta, the inferior vena cava, the renal cortex, and the medulla was performed. RESULTS: In vitro, the r1 efficiency of P760 was 23.3 mmol(-1) x L x sec(-1) at 1.5 T. Injection of a dose of P760 10 times less than Gd-DOTA allowed similar vessel visualization. The signal intensity peak and first-pass contrast kinetics in the aorta and the inferior vena cava were similar with the three products. Compared with P760 and Gd-DOTA, P775 allowed a greater renal cortex signal intensity at the first pass and a faster decrease on delayed images. CONCLUSIONS: The superior r1 efficiency of P760 and P775 was confirmed in vitro and in vivo at 1.5 T compared with Gd-DOTA, and P775 proved to be a rapid-clearance blood pool agent.     

Comparison of Gd-BOPTA with Gd-DTPA in MR imaging of rat liver

A new lipophilic compound, gadolinium benzyloxypropionictetraacetate (BOPTA), with a high rate of biliary excretion was assessed as a magnetic resonance (MR) hepatospecific contrast-enhancing agent and compared with Gd-DTPA (diethylenetriaminepentaacetic acid) in MR imaging of normal rats. T1-weighted spin-echo images obtained before and after administration of each contrast agent at doses of 0.25, 0.5, and 1.0 mmol/kg showed greater enhancement of the liver with Gd-BOPTA than with Gd-DTPA, with the advantage more evident at lower doses. Images obtained with an inversion recovery sequence at the null value of rat liver parenchyma after injection of 0.1- and 0.5-mmol/kg doses of the contrast agent provided better evidence of the greater and longer-lasting hepatic enhancement due to Gd-BOPTA when compared with that of Gd-DTPA. Gd-BOPTA is a potentially good contrast agent for obtaining prolonged enhancement of the liver, permitting studies during the long time needed to acquire conventional T1-weighted images.     

Pineapple juice labeled with gadolinium: a convenient oral contrast for magnetic resonance cholangiopancreatography

The aim of our study was to prepare in vitro a pineapple juice (PJ) solution labeled with a minimal gadolinium concentration working as a negative contrast agent in heavily T2-weighted imaging and to assess that solution in vivo as a negative oral contrast agent for magnetic resonance cholangiopancreatography (MRCP). Three PJs were compared in vitro according to their T2. Increasing concentrations of gadolinium (Gd)-DOTA in PJ were assessed in vitro for T2 reduction. Single-shot turbo spin echo T2-weighted MR cholangiopancreatograms were obtained for 35 patients with suspected biliopancreatic duct disease, before and after ingestion of the PJ/Gd-DOTA solution. Signal intensity (SI) measurements of gastroduodenal lumens, pancreatobiliary ducts, and image quality scores were obtained systematically before and after contrast ingestion. The in vitro selected Gd-DOTA concentration in the PJ was 2.76 mmol/l. Ingestion of 180 ml of PJ labeled with 1 ml of Gd-DOTA eliminated efficiently the gastroduodenal SI in MRCP, improving significantly the rates of complete visualization of the pancreatobiliary ducts (P<0.01) and the MRCP image quality scores (P<0.05). All patients easily ingested the contrast solution and found the solution palatable. PJ labeled with gadolinium constituted an efficient and convenient negative oral contrast agent for MRCP.     

Proton relaxation enhancement of albumin, immunoglobulin G, and fibrinogen labeled with Gd-DTPA

Bovine serum albumin, immunoglobulin G, and fibrinogen were labeled with Gd-DTPA using a bifunctional chelating agent DTPA anhydride. The protein-(Gd-DTPA) conjugates had 1.4- to 2.0-fold greater longitudinal relaxivities at 0.02 and 0.44 T than the relaxivity of plain Gd-DTPA. The increase of longitudinal relaxivity was not directly related to the size of carrier protein. Up to 50 Gd-DTPA chelates per protein, longitudinal relaxivity of the conjugates was proportional to the concentration of Gd and independent of the Gd/protein ratio.     

Tissue relaxation enhancement after intravenous administration of (ITCB-DTPA)-gadolinum conjugated albumin, an intravascular magnetic resonance imaging contrast agent

Gadolinium-isothiocyanato-benzyl-diethylenetriamine pentaacetic acid (ITCB-DTPA-Gd), a derivative of Gd-DTPA, was multiply conjugated to bovine serum albumin (BSA). In the synthesis of BSA-(ITCB-DTPA-Gd) conjugate, none of the five carboxylate groups of DTPA is functionalized for protein-chelate linkage. The rationale for this modification is to improve the affinity for Gd3+. We obtained a high-stability constant for the complex, comparable to unbound Gd-DTPA. Also, the complex had a T1 relaxivity as high as 30.3 seconds-1mmol-1 at 29 MHz (at 24 degrees C). At this field strength, and T1 of rat blood declined 91% after injection of 300 mg/kg of BSA-(ITCB-DTPA-Gd), corresponding to a Gd dose of 0.02 mmol/kg, while at 0.86 MHz it declined 64%. The shortening of T1 in vitro of blood, as well as spleen, lungs, and kidneys, persisted for 60 minutes. Better enhancement on post-contrast magnetic resonance images of rats was obtained at 1.0 T than at 0.04 T. Tissues with rich vascularization and large venous structures were well displayed at the higher field.     

Gd-DTPA relaxivity depends on macromolecular content.

Gd-DTPA T(1) relaxivity of water protons was measured at 1.5 T and room temperature as a function of macromolecular content in model systems. Gd-DTPA relaxivity was found to increase with macromolecular concentration. The results of this study indicate that the Gd-DTPA relaxivity in tissue extracellular compartment could be as much as 30-70% higher than that of Gd-DTPA in saline. Quantitative MR analyses that use T(1) as an estimation of local Gd-DTPA concentration require a priori determination of the Gd relaxivity in tissue.     

MRI of acute myocardial ischemia: comparing a new contrast agent, Gd-DTPA-24-cascade-polymer, with Gd-DTPA

A new macromolecular contrast agent, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA)-24-cascade-polymer, was compared with Gd-DTPA for time-dependent delineation of acute myocardial ischemia. Acute myocardial ischemia was produced in 12 rats by occluding the anterior branch of the left coronary artery for 20-40 minutes. Dynamic spin-echo magnetic resonance imaging (MRI) was performed for 30 minutes after injection of Gd-DTPA (n = 6) or the cascade polymer (n = 6) using equimolar doses (0.1 mmol of Gd/kg). The contrast agent-induced changes in signal intensity (deltaSI) in normal and ischemic myocardium were observed. In normal myocardium, both contrast agents caused a sharp increase in deltaSI, followed by a decline to baseline values over the 30-minute period. Enhancement in the ischemic myocardium was attenuated. Gd-DTPA showed greater deltaSI in ischemic myocardium than the cascade polymer, which gave rise to virtually no enhancement. Significant differences (P<0.05) in signal enhancement between normal and ischemic myocardium persisted for only 6 minutes using Gd-DTPA but for 18 minutes with the cascade polymer. Use of Gd-DTPA-24-cascade-polymer extends the temporal window of dynamic contrast-enhanced MRI for the differentiation of ischemic and normal myocardium. Identification of the ischemic zone is easier with the cascade polymer, which demonstrates virtually no signal enhancement in this territory.