Phenolic Aminocarboxylic Acids as Gallium-Binding Radiopharmaceuticals^[*]

Summary

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.

Zusammenfassung

Die Phenol-Aminocarbonsäure Ethylendiamin-di(o-Hydroxyphenyl-Essigsäure) (EDDHA) und N, N’-bis-(2-Hydroxybenzyl - Ethylendiamine - N, N’-di-Essigsäure (HBED) bilden Galliumkomplexe, die eine hohe Stabilitätskonstante haben, was ihnen ermöglicht, den Austausch des Galliums mit Plasmatransferrin zu verhindern. ⁶⁷Ga-Komplexe mit diesen Liganden wurden durch Einführung von Substitutionsgruppen in den phenolischen Ring synthetisiert, um die Ausscheidung über den renalen oder hepatobiliären Weg zu lenken. Die Menge des ⁶⁷Ga-Br-EDDHA, welches über den hepatobiliären Weg ausgeschieden wurde, war mit dem von einigen ^99mTc-Verbindungen vergleichbar. Die ⁶⁷Ga-Br-HBED-Ausscheidung war annähernd gleich, jedoch mit verzögerter Transitzeit aus der Leber. ⁶⁷Ga-COOH-EDDHA wurde ausschließlich über die Niere ausgeschieden. Diese Befunde bilden die Grundlage zur Entwicklung neuer ⁶⁷Ga oder ⁶⁸Ga-Radiopharmazeutika, letztere zur Anwendung in der Positron-Emissions-Tomographie, unter Verwendung dieser phenolischen Aminocarboxylate.

^* Presented in part at the Third International Symposium on Radiopharmacology, Freiburg i. Br., West Germany, September 21-25, 1983.

^** Also known as N,N’-ethylene bis-[2-(o-hydroxyphenyl)]-glycine (EHPG)

• References

• 1 Davis B., Saltman P., Benson S. The stability constants of the iron transferrin complex. Biochem. Biophys. Res. Commun. 1962; 08: 56-60.
• 2 Dexter M., Cranston R. J. Preparation of phenolic ethylenediamine-polycarboxylic acids. U. S. Patent 2. 1958; 824: 128.
• 3 Frost A. E., Freedman H. F.I., Westbach S. J., Martell A. E. Chelating tendencies of N,N’-ethylene bis-[2-(o-hydroxyphenyl)]-glycine. J. Am. chem. Soc. 1958; 80: 530-6.
• 4 Geigy A-G. Improvements relating to alkylene or cycloalkylene diamine diacetic acids, their heavy metal complexes and their use. Brit. Patent. 1960; 843: 003.
• 5 Harris W. R., Martell A. E. Aqueous complexes of gallium (III). Inorg. Chem. 1976; 15: 713-9.
• 6 Harris W. R., Pecoraro V. Thermodynamic binding constants for gallium transferrin. Biochem. 1983; 22: 292-9.
• 7 Harris W. R., Weitl F. L., Raymond K. N. Synthesis and evaluation of an enterobactin model compound. 1,3,5-tris- (2,3-dihydroxybenzoylaminomethyl) benzene and its iron (III) complex. J. chem. Soc. (London) Chem. Commun. 1979; 177-8.
• 8 Hunt F. C., Maddalena D. J. Phenolic aminocarboxylic acids. New chelating agents for modifying gallium-67 biodistribution. J. labelled Compd. Radiopharm. 1982; 19: 1408-9.
• 9 Hunt F. C., Wilson J. G., Maddalena D. J. et al.: Technetium-99m chelates of phenolic aminocarboxylic acids for hepatobiliary scintigraphy. Proc. 1st Asia and Oceania Congr. on Nucl. Med. 149-153 Sydney: 1976.
• 10 L’Eplattenier F. L., Murase J., Martell A. E. New multidentate ligands. VI. Chelating tendencies of N,N’ – di (2-hydroxybenzyl) ethylenediamine – N,N’ diacetic acid. J. Am. chem. Soc. 1967; 89: 837-43.
• 11 Moerlein S. M., Welch M. J. The chemistry of gallium and indium as related to radiopharmaceutical production. Int. J. nucl. Med. Biol. 1981; 08: 277-87.
• 12 Moerlein S. M., Welch M. J., Raymond K. N. Use of tricatecholamide ligands to alter the biodistribution of gallium-67. J. nucl. Med. 1982; 23: 502-6.
• 13 Moerlein S. M., Welch M. J., Raymond K. N., Weitl F. L. Tricatecholamide analogs of enterobactin as galliumand indium-binding radiopharmaceuticals. J. nucl. Med. 1981; 22: 710-9.
• 14 Pitt C. G., Martell A. E. The design of chelating agents for the treatment of iron overload. Am. Chem. Soc. Symposium No. 140. Inorganic Chemistry in Biology and Medicine. Martell A. E. Ed. 280-312 1980;
• 15 Schumacher J., Matys R., Hauser H. et al. A ⁶⁸Ga-labelled tetrabromophthalein (⁶⁸Ga BP-IDA) for positron imaging of hepatobiliary function. J. nucl. Med. 1983; 24: 593-602.