Preclinical evaluation of Fe-(5-C2H5-EHPG)- as a contrast agent in MR imaging of hepatobiliary system.

Abstract

Iron(III)-N, N'-ethylenebis[2-(2-hydroxy-5-phenyl)glycine] [Fe-(5-C2H5-EHPG)-] is a paramagnetic complex designed for use as a hepatobiliary agent. Test procedures included synthesis, characterization, toxicity evaluation, biodistribution and experiments for animal MR images. The dose of LD50 in acute toxicity test of Fe-(5-C2H5-EHPG)- in mice was 3.49 mmol/kg. 111In-(5-C2H5-EHPG)- biodistribution studies revealed that the activities were (4.78 +/- 0.97, 5.34 +/- 0.91, 4.53 +/- 0.35)%ID and (0.88 +/- 0.18, 0.99 +/- 0.17, 0.84 +/- 0.06)%ID/gm in the liver at time intervals of 10, 30 and 60 minutes after injection; (5.76 +/- 0.15, 5.75 +/- 0.15, 4.00 +/- 0.04)%ID and (0.49 +/- 0.03, 0.49 +/- 0.05, 0.34 +/- 0.01)%ID/gm in the blood; (1.27 +/- 0.91, 1.46 +/- 1.00, 1.52 +/- 0.46) %ID and (0.89 +/- 0.17, 1.02 +/- 0.18, 1.06 +/- 0.08)%ID/gm in the kidneys, respectively. The results of image enhancement correlated well to the biodistribution. Analysis of the MR images showed degrees of maximal parenchymal % increase of signal to noise ratio (S/N) was 42.09 +/- 3.59% for normal liver at 30 minutes postinjection, which exceeded the value of pathologic liver with bile duct obstruction 16 hours 17.26 +/- 6.6 %, 1 week 19.80 +/- 6.46% and 4 weeks 32.20 +/- 9.01%, respectively, and acute hepatitis 16.50% +/- 4.02%. Persistent enhancement plateau was documented up to 60 minutes after injection and normalized to precontrast value within 22 hours. The common duct was opacified at 10-15 minutes after injection of contrast agent. These results indicated that the Fe-(5-C2H5-EHPG)- could be rapidly extracted from the blood stream by the hepatocytes and excreted into the bile duct. The initial evaluation of Fe-(5-C2H5-EHPG)- demonstrated that Fe-(5-C2H5-EHPG)- was well suited for enhancement of normal liver parenchyma and was compromised with deterioration of liver function. However, the increase of the liver intensities in the animal model of the total biliary obstruction group normalized to precontrast value within 22 hours, which indicated that renal clearance as an effective alternative pathway for biliary excretion. In conclusion, these results indicate that Fe-(5-C2H5-EHPG)- has the potential of becoming a safe and reliable magnetopharmaceutical for the hepatobiliary system.