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