Hepatobiliary Chelates

Chelates used as hepatobiliary contrast agents consist of a paramagnetic ion bound to an organic ligand, forming a complex that shows affinity for hepatocytes. This type of complex is desirable to increase uptake of the contrast agent by the hepatocytes and to reduce toxicity of the paramagnetic metal ion as is done with gadolinium. Possible chelates for hepatobiliary imaging include Fe-EHPG and derivatives, Gd-HIDA, Cr-HIDA, B-19036, and Mn-DPDP.

Fe-EHPG (Iron(III) ethylenebis-(2-hydroxyphenylglycine)) is a structural analog of the radionuclide 99mTc- iminodiacetate (Tc-IDA) used for hepatobiliary imaging in nuclear medicine. Fe-EHPG is a very stable complex over a large pH range making it likely to be nontoxic. Fe-EHPG has been shown to improve visualization of small and medium-sized, blood-borne liver metastases in mice. To my knowledge no clinical studies with this material have been performed.

Chromium diethyl HIDA meglumine (Cr-HIDA) is another analog of a hepatobiliary radiopharmaceutical that has been tested in rats and rabbits. Excretion was 45%-77% after one hour. The dose required to give significant increased signal in the liver (0.25 mmol/kg) results in a safety ratio in mice of 6:1, compared to 100:1 for Gadolinium-DTPA. This low ratio for Cr-HIDA precludes clinical use.

An octadentate chelate of gadolinium coded B-19036 (Bracco Industria Chimica S.p.A., Milan, Italy) may be used as a hepatobiliary contrast agent. It is a highly stable complex with an LD50 in mice comparable to Gd-DTPA. It has yet to be tested in humans.

Manganese(II)-dipyridoxal diphosphate (Mn-DPDP) is a manganese chelate derived from vitamin B6, pyridoxal-5- phosphate. It shows efficacy in detecting small liver metastases in rabbits and has undergone phase I clinical trials showing it to be safe and effective in enhancing the signal intensity of the liver. It has a safety ratio of 200:1 in rats which is somewhat better than that for Gd-DTPA. Unlike Fe-EHPG and its derivatives whose uptake by hepatocytes depend on their lipophilic attraction to the cell membrane, Mn-DPDP is recognized by a vitamin B6 transport system in the cell membrane.