Evaluation of [Gd(Bz‐TTDA)]^2– as a potential contrast agent in MR imaging of the hepatobiliary system: An animal study

Abstract

Purpose:To evaluate the potential of a new lipophilic paramagnetic complex [Gd(Bz-TTDA)] 2-[(4s)-4-benzyl-3,6,10-tri(carboxymethyl)-3,6,10-triazadodecandioic acid] 2-designed for use as a hepatobiliary MR contrast agent. Materials and Methods:MR imaging studies for normal and hepatocellular carcinoma (HCC) rat models were performed using a 1.5-T scanner. Sequential multislice T1-weighted turbo field echo (TFE) (TR/TE/flip angle: 15 msec/6.1 msec/25°) coronal images of normal rats were obtained before and after intravenous injections of 0.1 mmol/kg [Gd(Bz-TTDA)] 2-in study groups (N ϭ 12) or 0.1 mmol/kg gadopentate dimeglumine (Gd-DTPA) 2-in control groups (N ϭ 12). Similar protocols of MR imaging with additional T2-weighted images were used for the rats with implanted HCC in both study and control groups (N ϭ 12, in each group). MR images were analyzed to evaluate the time-enhancement change (% increase of signal-to-noise ratio [SI/N]) in normal liver, renal cortex, renal medulla, and tumors. The liver-lesion contrast-to-noise ratios (CNR) were also evaluated in study and control groups. The rats were killed immediately after the last MR scan to undergo autopsy and histopathologic observation. The acute toxicity test (medial lethal dose, LD50) in mice was also done. Results:The liver enhancement in normal rats reached a plateau 5-50 minutes after injection of [Gd(Bz-TTDA)] 2-, maintained for three hours, then gradually declined. Intensity of enhancement in liver, renal cortex, and medulla after injection of [Gd(Bz-TTDA)] 2-was significantly higher than with Gd-DTPA. The efficacy of tumor characterization with injection of [Gd(Bz-TTDA)]2-was similar to that of Gd-DTPA at the early dynamic phase of the contrast study. However, the liver-lesion CNRs were significantly higher in the study group in the later phase, when tumor enhancement decreased and liver enhancement persisted. The dose of LD50 in acute toxicity test of [Gd(Bz-TTDA)] 2-in mice was 7.5 mmol/kg. Conclusion:The preliminary results in this animal study indicated that [Gd(Bz-TTDA)] 2-has the potential of becoming a reliable liver MR contrast agent.

Comparison of Gd‐Bz‐TTDA, Gd‐EOB‐DTPA, and Gd‐BOPTA for dynamic MR imaging of the liver in rat models

“…After 60 minutes, liver enhancement due to these the two commercial agents was below 50% while that of Gd-Bz-TTDA still remained above 110%. Our previous report showed that at 3 hours after injection of Gd-Bz-TTDA, approximately 95% of enhancement was preserved, which gradually declined to 15% at 24 hours [10]. This prolonged liver enhancement, which was still apparent up to 24 hours after injection, might be of little clinical benefit even though our preliminary subacute toxicity study in rats showed no evidence of changes to the liver [10].…”

“…Nevertheless, the liver-lesion CNRs were higher in rats injected with Gd-Bz-TTDA than the other two groups due to more intense and prolonged liver enhancement. A previous toxicity study on Gd-Bz-TTDA revealed no changes in liver or kidney tissues when the animals were sacrificed at 14 days postinjection [10]. The LD50 (Lethal Dose, 50%) of Gd-Bz-TTDA in mice is 7.5 mmol/kg [10].…”

“…A previous toxicity study on Gd-Bz-TTDA revealed no changes in liver or kidney tissues when the animals were sacrificed at 14 days postinjection [10]. The LD50 (Lethal Dose, 50%) of Gd-Bz-TTDA in mice is 7.5 mmol/kg [10]. This value is comparable with the LD50 of Gd-EOB-DTPA, which ranges from 7.5e10 mmol/kg, and that of Gd-BOPTA, which ranges from 5.7e7.9 mmol/kg [25,29,30].…”

“…Gd-Bz-TTDA can also improve tumor conspicuity in late phase images by providing intense liver enhancement [10]. A toxicity study was also conducted that shows that it is safe for these purposes [10]. The R1 relaxivity of Gd-Bz-TTDA is superior to Gd-BOPTA.…”

“…The preliminary results of our previous study showed intense liver enhancement in normal rats lasting from 5 minutes to 3 hours. Gd-Bz-TTDA can also improve tumor conspicuity in late phase images by providing intense liver enhancement [10]. A toxicity study was also conducted that shows that it is safe for these purposes [10].…”