Liver imaging agents

The Schiff bases derived from pyridoxal and amino acids having the general structure (40) have also been investigated as potential liver imaging agents for use with 553,683-685 com-... 

The use of LDL and other lipoproteins in drug targeting has been reviewed [170,172], Damle et al. [173] have shown that radiopharmaceuticals, such as iopanoic acid, a cholecystographic agent, could be incorporated in chylomicron remnants by esterification with cholesterol and used for liver imaging. About 87% of the chylomicron remnant-loaded iopanoic acid accumulated in the liver within 0.5 hour after administration, compared with 31% accumulated using a... 

Fig. 13. X-ray crystal structure of complex Gd(III)-76, Na2[Gd(B0PTA)(H20)], an MRI contrast agent on clinical trial for liver imaging. Adapted from (321).

These different approaches in the search for MRI liver contrast agents have also been tried for X-ray imaging. In the following chapters, the literature will be reviewed for compounds with potential as X-ray liver contrast agents. 

The use of the reticulo-endothelial system (RES) was the first approach to liver contrast agents. As an adjunct, spleen imaging would also be possible with a contrast agent that is taken up by the RES. The Kupffer cells of the liver, which represent 10% of all hepatic cells, constitute the major portion (80-90%) of all fixed macrophages and they are extremely effective in the phagocytosis of all types of particles. The downside of the use of this mechanism, however, is the concomitant release of toxic mediators that might and - as a matter of fact - often has made this approach non-feasible. Adverse events provoked by the mediators are changes in blood pressure (most often hypotension) and fever. 

Intestinal absorption studies of Mn-MP were undertaken in an effort to assess the viability of the metalloporphyrin as an oral hepatobiliary agent [101, 102]. Mixed micelles of Mn-MP complexed with monoolein and taurocholate were administered to rats, resulting in liver image enhancement 68% above baseline levels six hours after administration [101]. In pigs, the mixed micelle preparation showed variable enhancement over 24 hours. Observation that Mn-MP interacts with oleic acid vesicles [103] led to investigations of the effect of oleic acid on the absorption rate of Mn-MP from the small bowel into the circulatory system [102,104]. The increase in absorption of the complex was mediated by a decrease in the relaxivity of the metalloporphyrin resulting from the interaction with the lipid vesicles. 

The iron(III) tris-complex of Tiron (Fig. 13) has an R, value of 3.15 mM"1 s 1 at 60 MHz and 25 °C [163]. This value is higher than that reported for any other low-molecular weight iron(III) complex [10]. Injection of 0.15 mmol kg-1 into rats demonstrated maximum increases in the kidney and liver image signals of 137% and 73 %, respectively. No toxic effects were seen at this concentration, but all animals injected with 0.3 mmol kg1 of contrast agent died. 

---