Original contribution
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

https://doi.org/10.1016/j.mri.2005.10.035Get rights and content

Abstract

Purpose

A newly developed contrast material, CH3-DTPA-Gd (NMS60), a trimer containing 3 Gd3+ 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 (R1=1/T1) and the transverse relaxation rate (R2*=1/T2*) of NMS60 and Gd-DTPA were determined at 20°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 T1 and R2* studies (DUCE imaging) were also carried out in two patients.

Results

Regarding the relaxivity per Gd, R1 and R2* of NMS60 were 9.5 and 11.0 (mmol/L·s)−1, respectively, compared to 4.8 and 7.2 (mmol/L·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.

Introduction

Since gadopentetate dimeglumine [Gd-DTPA, Magnevist 0.5 mmol (Gd)/ml; Schering, Berlin, Germany] was introduced in 1988 [1], contrast materials have been used in numerous cases in MRI. These contrast agents do not have organ specificity and distribute into extracellular fluid (ECF) nonspecifically. Gadolinium (Gd), a key atom of the ECF contrast agent, is a paramagnetic substance and its T1-shortening effect is relatively high at low concentrations. However, most contrast agents containing one metal atom like Gd-DTPA show an R1 relaxivity of <4 (mmol/L·s)−1 at 37°C. To improve the relaxivity, compounds containing multiple metals have been investigated [2].

A newly developed contrast material, CH3-DTPA-Gd [NMS60 0.5 mmol (Gd)/ml; Nihon Medi-Physics, Japan], which is a trimer with a molecular weight of 2158 Da, containing 3 Gd3+ atoms per molecule (Fig. 1), has been shown to offer greater enhancement and longer vascular retention than Gd-DTPA (molecular weight, 547 Da) in MR angiography in animals [3], [4], [5]. In a study using a VX2 tumor model in rabbits, NMS60 was reported to show greater enhancement than Gd-DTPA [3]. More recently, NMS60 has been shown to offer significantly greater vascular enhancement for much longer periods of time than Gd-DTPA in dogs [4]. Because of its high relaxivity and extravasation capabilities, NMS60 is expected to provide greater enhancement and clinical usefulness. On the basis of the safety confirmed by a phase I study in healthy patients, an early phase II clinical trial was carried out.

In this article, we report on our results of the early phase II clinical trial of NMS60 in brain tumors together with supplementary investigations. In addition to following the study protocol, we carried out dual (or double-echo) dynamic contrast-enhanced studies (DUCE imaging reported previously [6]) to evaluate the usefulness of NMS60. In this DUCE imaging, contrast-enhanced T1 and R2* studies can be performed in one sequence.

Section snippets

Contrast material

NMS60, a newly developed synthetic oligomeric Gd complex, was supplied by Nihon Medi-Physics (Tokyo, Japan). Gd-DTPA was supplied by Nihon Shering (Osaka, Japan). The molecular mean diameter of NMS60 is 1.1 nm, which is approximately twice as large as that of Gd-DTPA [4]. Thus, the apparent molecular volume of NMS60 is approximately eight times larger than that of Gd-DTPA, although its molecular weight is just four times larger than that of Gd-DTPA [3]. R1 and R2* relaxivities per Gd in water

Contrast material

Table 1 shows the relaxivity per Gd of NMS60 and Gd-DTPA measured for diluted solutions, in comparison with the previously reported data at 37°C [4]. Both the R1 and R2* relaxivities of NMS60 were higher than those of Gd-DTPA.

Patient monitoring

Four patients received the dose of 0.1 mmol (Gd)/kg and six received the 0.2 mmol (Gd)/kg dose. Administration of NMS60 was well tolerated, and no severe adverse reaction was observed in any patient. There was no pain or discomfort at the time of injection. No significant

Discussion

The R1 and R2* relaxivities of NMS60 and Gd-DTPA measured at 37°C have been reported by the group that developed NMS60, but measurement of relaxivities is susceptible to the inhomogeneity within a magnetic field, so we measured the relaxivities at 20°C with our system. The R1 and R2* relaxivities measured in the present study indicated the efficacy of NMS60. It was confirmed that the R1 of NMS60 was 2.0 to 2.7 times higher than that of Gd-DTPA. In addition, the R2* of NMS60 was also higher than

References (23)

  • T. Miyati et al.

    Dual dynamic contrast-enhanced MR imaging

    J Magn Reson Imaging

    (1997)
  • View full text