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.     

Gd HP-DO3A--experimental evaluation in brain and renal MR

GD HP-DO3A, a neutral (nonionic) IV MR contrast agent presently in clinical trials, was evaluated with respect to imaging characteristics in rats. Following administration of 0.25 mmol/kg I.V., 58 +/- 19%, i.e. (n = 6) enhancement was noted in a brain gliosarcoma model. Meningeal spread of neoplasia could be identified due to its enhancement (69 +/- 26%) in nine animals. The time course of renal enhancement was quantitated at two dosages, 0.05 (n = 4) and 0.25 mmol/kg (n = 8). At the higher dose, enhancement of both cortex and medulla plateaued between 9 and 23 min postinjection. At the lower dose, enhancement of renal medulla was maximum at 2 min postinjection. These enhancement characteristics (both brain and kidney), at equivalent contrast dosages, are comparable to that previously published for Gd-DTPA. However, Gd HP-DO3A has the potential to be utilized clinically at higher doses than Gd-DTPA, with no reported adverse effects in initial trials employing up to 0.3 mmol/kg.     

Biodistribution of GdCl3 and Gd-DTPA and their influence on proton magnetic relaxation in rat tissues

The biodistribution and relative molar effectiveness of the ionic (GdCl3) and chelated (Gd-DTPA) forms of gadolinium (Gd) to enhance proton relaxation rates in rat kidney, liver and spleen were evaluated. Rats were given intravenous injections of either GdCl3 (100 mumol/kg) or Gd-DTPA (178 mumol/kg). Gd-DTPA was primarily contained in the vascular compartment and was quickly accumulated in the kidney after injection with a relaxivity of 4.3 sec-1 (mumol/g kidney)-1. It was eliminated quickly from the body with only 2% of the injected dose remaining after 120 min. After GdCl3 injection, Gd was found primarily in liver and spleen. It accumulated continuously reaching 72% of the injected does in these two tissues after 120 min. Despite this continuous increase in tissue Gd concentration, the relaxation rates showed saturation in liver and spleen. The results suggest that after GdCl3 was injected it distributed either in a protein bound form that was effective at causing relaxation or in a colloid form that was not effective. The biodistribution of GdCl3 was such that it was determined by the phagocytic action of the recticuloendothelial system on a colloid. The biodistribution and tissue relaxivity of Gd-DTPA suggest it will be a useful vascular MRI contrast agent. However, the usefulness of GdCl3 as an MRI contrast agent is limited not only by its acute toxicity but also by its saturable effect on tissue relaxation rates. Consequently, GdCl3 has only a modest influence on tissue relaxivity.     

Dynamic contrast-enhanced MRI of Implanted VX2 tumors in rabbit muscle: comparison of Gd-DTPA and NMS60

We studied the dynamics of injected contrast enhancement in implanted VX2 tumors in rabbit thigh muscle. We compared two contrast agents Gd-DTPA and NMS60, a novel gadolinium containing trimer of molecular weight 2.1 kd. T1-weighted spin echo images were acquired preinjection and at 5-60 min after i.v. injection of 0.1 mmol/kg of agent. Dynamic T1-weighted SPGR images (1.9 s/image) were acquired during the bolus injection. Male NZW rabbits (n = 13) were implanted with approximately 2 x 10(6) VX2 tumor cells and grew tumors of 28+/-27 mL over 12 to 21 days. NMS60 showed significantly greater peak enhancement in muscle, tumor rim, and core compared to DTPA in both T1-weighted and SPGR images. NMS60 also showed delayed peak enhancement in the dynamic scans (compared to Gd-DTPA) and significantly reduced leakage rate constant into the extravascular space for tumor rim (K21 = 5.1 min(-1) vs. 11.5 min(-1) based on a 2 compartment kinetic model). The intermediate weight contrast agent NMS60 offers greater tumor enhancement than Gd-DTPA and may offer improved regional differentiation on the basis of vascular permeability in tumors.     

Neurotoxicity of gadolinium contrast agents for magnetic resonance imaging in rats with osmotically disrupted blood-brain barrier

The neurotoxicity of intravenously injected Gadolinium (Gd) complexes to rats with disrupted blood-brain barrier (BBB) was evaluated. After disruption of the BBB by infusion of mannitol solution, one of several contrast agents tested was injected intravenously at a dose of 1 or 3 mmol Gd/kg, and neurological symptoms were graded. The concentrations of Gd in brain and plasma were also measured. Injection of Gd-DTPA at a dose of 3 mmol Gd/kg did not change behavior. On the other hand, Gd-DTPA-BMA, Gd-DO3A-butrol, and Gd-DO3A-HP each induced behavioral impairments, and some animals died within 1 h after injection. Gd-DO3A-HP showed lethal effect even at a dose of 1 mmol/kg. The concentration of Gd in the brain of the animals injected with Gd-DO3A-HP at 3 mmol Gd/kg was essentially the same as that of animals injected with Gd-DTPA at the same dose. The neurotoxicity of the contrast agents tested was graded as follows: Gd-DTPA ≤ Gd-DTPA-BMA = Gd-DO3A-butrol < Gd-DO3A-HP.     

Gd-enhanced MR imaging of brain metastases: Contrast as a function of dose and lesion size

MR imaging contrast of brain metastases after cumulative doses of gadolinium chelate is quantitated and compared in order to assess the clinical utility of high dosage. T1-weighted spin-echo MR images of 39 patients with metastatic brain tumors were made before and after each of three equal doses cumulating to 0.1, 0.2 and 0.3 mmol Gd-complex per kg body weight. Quantitation of MRI contrast was limited to homogeneous brain metastases larger than 3 mm (n = 246). Post-Gd MRI contrast doubled with dose escalation from 0.1 to 0.3 mmol/kg and also increased with lesion size, by a factor of 2.5 between metastases of 3 and 16 mm diameter, that is after correcting for partial volume effect. At 0.2 and 0.3 mmol/kg the respective numbers of visible metastases increased by 15% and 43% compared with 0.1 mmol/kg (p < 0.0001, both). Image contrast figures differed significantly between doses (p = 0.018). Both the number of metastases and the image contrast is significantly higher when dose escalation is performed. It is indicated that the number of detected metastases will increase further at Gd doses beyond 0.3 mmol/kg. Post-Gd MRI contrast increases with lesion size, to an extent that can not be attributed to partial volume attenuation.     

A comparative evaluation of CH3-DTPA-Gd (NMS60) for contrast-enhanced magnetic resonance angiography

In a canine model the signal dynamics of a new oligomer-based MR contrast agent (NMS60, 2158 Da) were compared to Gd-DTPA to investigate the agents' potential for magnetic resonance angiography (MRA). Twelve male mongrel dogs were imaged sequentially under anesthesia with two different MRA sequences (Tlw 3DSPGR). Initial enhancement was measured every 9 s for eight points in time. Thereafter, spatial highly resolved MRAs were obtained at 5, 10, 15, 20, 30, 45, and 60 min post-injection of two different dosages. Over the first 20 s following bolus administration the average arterial enhancement of 0.1 mmol(Gd)kg NMS60 was 44% greater than Gd-DTPA. Twenty minutes post-injection the relative signal intensity of NMS60 was as high as the peak signal intensity with Gd-DTPA at the same dosage level (0.1 mmol(Gd)/kg). In the animals that received NMS60 injections the vascular conspicuity was overly superior to those who received Gd-DTPA. No significant toxicity effects were noted for either dosage level. The intermediate weight contrast agent NMS60 offers greater vascular enhancement and retention time than Gd-DTPA. For a given set of optimized imaging parameters this offers improved spatial details, less arterial/venous overlap, and better vascular contrast.     

Experimental cerebral infarction in the rat: utility of Gd-DOTA for MR imaging

Nineteen rats presenting a very small (about 2-mm diameter), superficial cerebral infarction were studied with MR-imaging (1.89 Tesla) before and after injection of Gd-DOTA. Fifteen rats examined 1 or 2 hr, and 2, 3, 4, 5, 7, or 10 days after lesion induction, received 0.5 mmol Gd-DOTA/kg body weight. Four other rats presenting a 4-day-old lesion, received 0.1, 0.2, or 0.6 mmol Gd-DOTA/kg. Each rat underwent one imaging study comprising T2-weighted spin-echo (SE) images (3000/100) with subsequent injection of Gd-DOTA followed by 12 consecutive series of T1-weighted SE images (320/40), each taking 6 min. Using 0.5 mmol Gd-DOTA/kg, early (immediate) and long-lasting (more than 1 hour) visualization of lesions of varying age (1 hr to up to 10 days) was possible and at appropriate time intervals after injection, the visualization of the lesion was clearer and more complete than with T2-weighted images. Even in the rats studied with smaller doses of the contrast agent (0.1 or 0.2 mmol/kg), postcontrast T1-weighted images provided superior delineation of the lesions as compared to T2-weighted images.     

The effect of Gd-DTPA on T(1)-weighted choline signal in human brain tumours

The influence of Gd-DTPA on T(1)-weighted (T(1)W) proton MR spectra has been investigated in 19 patients with histologically verified low (n = 13) or high-grade (n = 6) gliomas. Repeat measurements were performed on 9 patients (7 low-grade and 2 high-grade), with 28 examinations performed in total. Comparison of spectra obtained before and after 0.2 mmol/kg Gd-DTPA showed contrast agent induced broadening of the choline signal without significant signal area change. Lack of enhancement of the choline signal with the T(1)-weighted acquisitions implies that the contrast agent and the trimethylamine-containing species do not undergo significant direct interaction. Contrast agent induced changes in the choline signal observed in this and previous studies may, therefore, be attributable to T2*/susceptibility-based effects.     

Optimization of contrast dosage for gadolinium-enhanced 3D MRA of the pulmonary and renal arteries

To determine the minimal contrast dosage required for diagnostic contrast-enhanced three-dimensional (3D) magnetic resonance angiography (MRA) image quality of the pulmonary (PAs) or renal arteries (RAs). In 12 volunteers (10 females, 2 males; mean age 24 years) imaging was performed with 4 different dosages: 0.05, 0.1, 0.2 and 0.3 mmol/kg of body weight (BW) 0.5 M gadolinium (Gd) contrast agent. The PAs and RAs were evaluated separately each in groups of six volunteers. Qualitative and quantitative signal-to-noise ratio (SNR) image analysis was performed. For the PAs, the increases in signal-to-noise ratio were paralleled by increases in image quality ratings. For the PAs, with the use of 0.05 mmol/kg, only 50.3% of all segments were rated diagnostic, whereas with higher dosages the percentage rose to 89.2% for 0.1 mmol/kg, 98.2% for 0.2 mmol/kg. and 99.1% for 0.3 mmol/kg. For the RAs, 0.3 mmol/kg provided no significant increase in singal-to-noise ratio compared to 0.2 mmol/kg (p = 0.4). Only by a dosage of 0.2 and 0.3 mmol/kg, all evaluated segments were diagnostic evaluable. A dose of 0.2 mmol/kg is required for proper assessment of the RAs or PAs.     

An investigation of the toxicity of gadolinium based MRI contrast agents using neutron activation analysis

The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 +/- 0.17 ppm and 0.47 +/- 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 +/- 0.46 ppm for the bolus and 1.24 +/- 0.39 ppm for the bolus/constant infusion strategy and 0.16 +/- 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.     

Quantitative assessment of Gd-DTPA contrast agent from signal enhancement: an in-vitro study

Quantitative determination of in-vivo gadolinium diethylenetriamine-pentaacid (Gd-DTPA) concentration is attractive in various studies involving perfusion, tracer kinetics and permeability constants. Using a 1.5 T clinical system and a 7 T small-bore system, we evaluated a method for absolute determination of Gd-DTPA concentrations in plasma solutions. Different solutions of Gd-DTPA and (99m)Tc-DTPA were mixed in human plasma and concentrations in the range of 0-5.0 mmol/l (1.5 T system) or 0-3.0 mmol/l (7 T system) of Gd-DTPA were divided into thirteen tubes. All MRI measurements were carried out using conventional sequences (SE, FLASH and GRASS). The MR measured intensity was converted to Gd-DTPA concentration by mathematical interpretation of the sequences. All MRI sequences showed, that the measured concentrations of Gd-DTPA revealed a slight non-linear difference compared with the calculated Gd-DTPA concentrations determined by the plasma (99m)Tc-DTPA using gamma counting. This non-linearity was most pronounced at high Gd-DTPA concentrations, suggesting that the discrepancy could be a result of an increased plasma relaxivity at higher concentrations. Adjustment of measured Gd-DTPA concentration was therefore performed using a selected power function, A[Gd-DTPA](a), which yielded the best linear relationship. Regression analysis showed that the scaling constant (A) varied from 0.11 to 97.45 and the power constant (a) varied from 0.83 to 1.6. Based on these constants, the MRI measured concentrations of Gd-DTPA did not differ from the calculated concentrations of Gd-DTPA obtained from reference measurements of (99m)Tc-DTPA. In the 1.5 T system, a linear relationship (r(2) > or = 0.95) was demonstrated in the range of 0-5.0 mmol/l Gd-DTPA, and in the 7 T system, a linear relationship (r(2) > or = 0.92) was demonstrated in the range of 0-3.0 mmol/l Gd-DTPA. Additionally, the effect of signal-to-noise on measured concentrations of Gd-DTPA was simulated using MR data of the mixed solutions of Gd-DTPA in plasma and the analytical expression of the pulse sequences. The simulations showed that the concentrations were most sensitive to noise in the GRASS sequence. In conclusion, this study demonstrates a novel approach to quantify accurately the Gd-DTPA concentration directly from MRI signal data using different routine sequences.     

Step-down infusions of Gd-DTPA yield greater contrast-enhanced magnetic resonance images of BBB damage in acute stroke than bolus injections

A rat model of transient suture occlusion of one middle cerebral artery (MCA) was used to create a unilateral reperfused cerebral ischemic infarct with blood-brain barrier (BBB) opening. Opening of the BBB was visualized and quantitated by magnetic resonance (MR) contrast enhancement with a Look-Locker T(1)-weighted sequence either following an intravenous bolus injection (n=7) or during a step-down infusion (n=7) of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). Blood levels of Gd-DTPA after either input were monitored via changes in sagittal sinus relaxation rate. Blood-to-brain influx constants (K(i)) were calculated by Patlak plots. On the basis of the MRI parameters and lesion size, the ischemic injury was determined to be similar in the two groups. The bolus injection input produced a sharp rise in blood levels of Gd-DTPA that declined quickly, whereas the step-down infusion led to a sharp rise that was maintained relatively constant for the period of imaging. Visual contrast enhancement and signal-to-noise (S/N) ratios were better with the step-down method (S/N=1.8) than with bolus injection (S/N=1.3). The K(i) values were not significantly different between the two groups (P>.05) and were around 0.005 ml/(g min). The major reason for the better imaging of BBB opening by the step-down infusion was the higher amounts of Gd-DTPA in plasma and tissue during most of the experimental period. These results suggest that step-down MR contrast agent (MRCA) administration schedule may be more advantageous for detection and delineation of acute BBB injury than the usually used bolus injections.     

MRI of liver tumors using gadolinium-DOTA: prospective study comparing spin-echo long TR-te sequence and CT

Thirty-nine patients with liver tumors were examined using MRI at 0.5 T before and after intravenous bolus injection of either 0.1 mmol/kg (n = 18) or 0.2 mmol/kg (n = 21) of Gadolinium-Dota, using spin-echo T1-and T2-weighted sequences before injections and spin-echo or gradient-echo sequences after injection. When contrast-to-noise (C/N) data were normalized relative to time, optimal mean C/N was observed after gadolinium injection. However, subjective study and case-by-case C/N measurement showed better contrast for SE 2000/60 and CT with injection in 62% and 42% of cases, respectively.     

Signal Intensity for Contrast Enhancement as a Function of the Molarity of Gadolinium-Based MRI Contrast Media

Gadolinium is the central metal that is used as magnetic resonance imaging (MRI) contrast media. Because the metal has toxicity on its own, it causes fibrosis or sclerosis of skin or internal organs, which may lead to disability in joint movement, or even death in the worst case. In the current study, the T ₁ contrast media, Dotarem, was diluted to various molarities to measure the signal intensity of T ₁-weighted images as a function of the molarity. The molarity that showed the maximum measurement value of the signal intensity was examined to determine the proper amount of contrast media injected for the MRI scan. The change in the intensity of the signal from the tumor tissue was determined based on the passage of time after injection. The distribution of the maximum signal intensities depending on the time to repeat showed that the signal distribution had >95% of the maximum values when the dilution concentration was in the range of 0.00095–0.00135 mmol/ml. Thus, it is most desirable when 0.084 mmol/kg (patient weight) of contrast media is injected. In experiments involving tumors 0.084, 0.1, and 0.15 mmol/kg were injected to measure the average signal intensity for each molarity. Compared to the signal intensity at a molarity of 0.084 mmol/kg, the three patient’s signal intensities were measured to increase by 6.2, 7.6, and 5.7% at a molarity of 0.1 mmol/kg, and by 21.4, 18.8, and 17.7% at a molarity of 0.15 mmol/kg. However, according to the correlation between the contract media injection amount and the signal intensity increase, the contrast effect was not improved much despite the increase in the injection amount by 19.04 and 78.5%. This study revealed that the optimal level of contrast media of 0.084 mmol/kg body weight should be administered by considering the body weight of patients and the effects of media to reduce side effects of a high dose of contrast media and to prevent environmental pollution.     

Gd-DTPA adrenal gland enhancement at 1.5 T

The change in relative signal intensity of normal adrenal glands in 31 patients was evaluated following bolus administration of 0.1 mmol/kg of gadolinium diethylenetriamine pentacetic acid (Gd-DTPA). A marked increase in relative intensity of greater than 300% was observed within 2.5 min following contrast administration upon comparison of pre- and postcontrast T1-weighted gradient-echo images (TR = 47 msec, TE = 13 msec, pulse angle 80 degrees). Significantly elevated relative intensities of 55% and 44% persisted on postcontrast T1-weighted spin-echo images obtained at further delay times averaging 8 and 20 min, respectively, when compared to the identical precontrast sequence.     

MRI contrast-dose relationship of manganese(III)tetra(4-sulfonatophenyl) porphyrin with human xenograft tumors in nude mice at 2.0 T

Previously we reported that Mn(III)tetra(4-sulfonatophenyl) porphyrin, MnTPPS₄, is a contrast agent which can effectively enhance tumor detection by MRI. By imaging 30 additional athymic nude mice bearing subcutaneous MCF-7 WT human breast carcinoma xenografts, we have extended dose-contrast relationships over a wide range of intraperitoneal (IP) doses ranging from 0.025 to 0.50 mmol/kg. The benefits of IP injection are higher possible doses on a volume basis and a reduction in toxicity versus IV administration. Full coronal cross-section images have been obtained on a 2-T spectrometer. Although individual tumor masses displayed different distribution patterns, reflective of their internal morphology, single doses of 0.10 mmol/kg or greater were necessary to produce a detectable effect. At a dose of 0.50 mmol/kg, marked enhancement was produced. Multiple small dosages administered over the course of several days before imaging did not produce increased enhancement. Preliminary results on the new porphyrin derivative, MnTPPS₃, indicate that the ratio of the toxic dose to the effective dose may be adjustable to render this class of agents clinically useful.     

MR imaging of the arthritic rabbit knee joint using albumin-(Gd-DTPA)30 with correlation to histopathology

The purpose of this study was to demonstrate a technique, in a pilot study, for measuring abnormal capillary permeability in synovial tissue of rabbit arthritic knees using dynamic MRI with a gadolinium-based blood pool agent. Arthritis, simulating rheumatoid arthritis, was induced in knees of 8 rabbits by intra-articular injection of carrageenan (n = 4) or ovalbumin (n = 4). Sequential fat presaturated T1-weighted Spoiled Grass images were obtained before and up to 30 min after intravenous administration of albumin-(Gd-DTPA)30. Estimates of synovial tissue plasma-volume (PV), fractional-leak-rate (FLR), and permeability-surface-area-product (PS) were computed. Histologic correlation was obtained in the corresponding regions. Dynamic MRI showed extravasation of albumin-(Gd-DTPA)30 into hypertrophic synovium in six of the eight arthritic knees. Histologic examination of these six knees showed markedly inflamed synovium. The two knees that did not show abnormal vascular permeability contained non-hypertrophic synovium. None of the rabbits showed abnormal permeability in muscle. MRI derived microvascular characteristics (PV, FLR and PS) correlated positively (r2 = 0.51, 0.97 and 0.86) with the histology. Factors involving the structural and functional microvascular characteristics of synovial tissue can be estimated non-invasively using albumin-(Gd-DTPA)30. This technique may be useful for monitoring disease progression and treatment response in rheumatoid arthritis.     

3D spin-lock imaging of human gliomas

We investigated whether the simultaneous use of paramagnetic contrast medium and 3D on-resonance spin lock (SL) imaging could improve the contrast of enhancing brain tumors at 0.1 T. A phantom containing serial concentrations of gadopentetate dimeglumine (Gd-DTPA) in cross-linked bovine serum albumin (BSA) was imaged. Eleven patients with histologically verified glioma were also studied. T₁-weighted 3D gradient echo images with and without SL pulse were acquired before and after a Gd-DTPA injection. SL effect, contrast, and contrast-to-noise ratio (CNR) were calculated for each patient. In the glioma patients, the SL effect was significantly smaller in the tumor than in the white and gray matter both before (p = 0.001, p = 0.025, respectively), and after contrast medium injection (p < 0.001, p < 0.001, respectively). On post-contrast images, SL imaging significantly improved tumor contrast (p = 0.001) whereas tumor CNR decreased slightly (p = 0.024). The combined use of SL imaging and paramagnetic Gd-DTPA contrast agent offers a modality for improving tumor contrast in magnetic resonance imaging (MRI) of enhancing brain tumors. 3D gradient echo SL imaging has also shown potential to increase tissue characterization properties of MR imaging of human gliomas.     

Evaluation of CH3-DTPA-Gd (NMS60) as a new MR contrast agent: early phase II study in brain tumors and dual dynamic contrast-enhanced imaging

PURPOSE: A newly developed contrast material, CH3-DTPA-Gd (NMS60), a trimer containing 3 Gd(3+) atoms per molecule, has been shown to offer greater enhancement and longer vascular retention than gadopentetate dimeglumine (Gd-DTPA) in animals. We report on our early phase II study on NMS60 in brain tumor patients together with supplementary investigations. METHODS AND MATERIALS: The longitudinal relaxation rate (R(1)=1/T(1)) and the transverse relaxation rate (R(2)*=1/T(2)*) of NMS60 and Gd-DTPA were determined at 20 degrees C in water at 1.5 T. An NMS60 dose of 0.1 or 0.2 mmol (Gd)/kg was randomly assigned and administered to 10 patients (five women, five men; mean age: 49 years) with brain tumors. Safety and contrast-enhancing ability of NMS60 were evaluated. Dual dynamic contrast-enhanced T(1) and R(2)* studies (DUCE imaging) were also carried out in two patients. RESULTS: Regarding the relaxivity per Gd, R(1) and R(2)* of NMS60 were 9.5 and 11.0 (mmol/L x s)(-1), respectively, compared to 4.8 and 7.2 (mmol/L x s)(-1) for Gd-DTPA. Although a transient slight increase of alanine aminotransferase was observed in one case, no other adverse reactions were observed after administration of NMS60. Contrast enhancement by NMS60 was excellent at both concentrations, and when tumor detectability was assessed with a five-point scale, the diagnostic usefulness was 4 or higher in all cases. In DUCE imaging, NMS60 appeared to show high signal intensity, when compared with the data obtained separately for Gd-DTPA. CONCLUSION: NMS60 had a high contrasting effect and little toxicity, and is expected to be clinically useful.