Potential radiopharmaceuticals for the diagnosis of biliary atresia and neonatal hepatitis: EHPG and HBED chelates of 67Ga and 111In.

Radiopharmaceuticals suitable for use in cases where delayed excretion of hepatobiliary tracer can occur, were formulated from indium-111 and gallium-67 and the chelating agents N,N'-ethylene-bis-[o-hydroxy-phenylglycine], (EHPG) and N,N'-bis-[2-hydroxybenzyl] ethylenediamine-N,N'-diacetic acid, (HBED). The hepatobiliary excretion of these 67Ga and 111In chelates was optimised by using chelators which had substituents in the phenolic ring; halogen substituents imparted the most favourable characteristics.

Chelator-induced enhancement of 67Ga tumour imaging: comparison of desferrioxamine with N,N'-ethylene-bis[2-hydroxy-5-carboxyphenylglycine].

Intravenous injection of the gallium chelating agents, N,N'-ethylene bis[2-hydroxy-5-carboxyphenyl-glycine], (COOH-EHPG), or desferrioxamine (DFO) after gallium-67 (67Ga) injection, improved tumour/non-tumour tissue uptake ratios in mice bearing the EMT-6 sarcoma. Six hours post injection of gallium and 2 h post chelator, COOH-EHPG enhanced the tumour/blood ratios by an order of magnitude compared to untreated controls, whereas DFO increased the ratios three-fold. Twenty two hours post gallium and 2 h post chelator, the increases in ratios compared to controls were seven-fold for COOH-EHPG and two-fold for DFO. The study thus demonstrated the superior ability of COOH-EHPG for the enhancement of 67Ga tumour/blood ratios compared with DFO.

Phenolic aminocarboxylate chelates of 99mTc as hepatobiliary agents.

A series of alkyl- and halogen-substituted derivatives of ethylenediamine di[o-hydroxyphenylacetic acid] (EDDHA) and N,N'-bis[2-hydroxybenzyl] ethylenediamine N,N'-diacetic acid (HBED) were complexed with 99mTc and their biodistribution was determined in rats. All complexes displayed substantial hepatobiliary excretion; of each series, 99mTc-Br-EDDHA and 99mTc-di-Cl-HBED had the maximum amount in the gastrointestinal tract. Scintigraphic studies of 99mTc-Cl-EDDHA in dogs revealed prompt imaging of the liver followed by imaging of the gall bladder as the complex was excreted into the bile.

Phenolic aminocarboxylic acids as gallium-binding radiopharmaceuticals.

The phenolic aminocarboxylic acids ethylenediamine di [o-hydroxyphenylacetic acid] (EDDHA) and N,N'-bis [2-hydroxybenzyl] ethylenediamine N,N'-diacetic acid (HBED) form gallium complexes having high stability constants which enable them to resist exchange of gallium with plasma transferrin. 67Ga complexes were synthesized with these ligands, placing substituent groups in the phenolic ring to direct excretion via the renal or hepatobiliary route. The amount of 67Ga-Br-EDDHA excreted via the hepatobiliary route was comparable with that of some of the 99mTc agents. Excretion of 67Ga-Br-HBED was similar but with delayed transit from the liver. 67Ga COOH-EDDHA was excreted exclusively via the renal route. These findings provide a basis for developing new 67Ga or 68Ga radiopharmaceuticals, the latter for use in positron emission tomography, using these phenolic aminocarboxylates.

Technetium-99m benzimidazolyl iminodiacetic acid hepatobiliary radiopharmaceuticals: structure biodistribution studies.

The biodistribution of fifteen structural variants of the hepatobiliary radiopharmaceutical, technetium-99m benzimidazolyl iminodiacetic acid (BIMIDA) were determined 1 h after i.v. injection into rats. The best compounds with respect to hepatobiliary excretion were those with halogen substituents in the benzene ring of the BIMIDA ligand. The cholescintigraphic properties of the BIMIDA compounds compared favourably with those of technetium-99m acetanilido iminodiacetic acid (HIDA) radiopharmaceuticals.