The chemistry of gallium and indium as related to radiopharmaceutical production

There is great interest in the medical application of the radioactive isotopes of the group IIIB elements gallium and indium. The design of radiopharmaceuticals labeled with gallium and indium is complicated by the fact that both metals form strong chelates with the plasma protein transferrin. Due to the large stability constants of these chelates, a gallium or indium radiopharmaceutical will exchange its metal to transferrin unless the metal is bound with a stability constant greater than 10²⁰. To date, very few compounds of gallium or indium have been described which are thermodynamically stable with respect to exchange to transferrin. However, the rate at which equilibrium is reached is often slow compared to the biological event. As an example of this, the fast glomerular filtration rate of gallium- and indium-DTPA is much faster than the rate of exchange with transferrin. There have been two major efforts in the development of gallium and indium radiopharmaceuticals. The first of these efforts has been to develop a bifunctional chelate such as 1-(p-benzenediazonium)-ethylenediamine-N,N,N′,N′-tetraacetic acid, which was developed by SUNDBERG et al., to form a bridge between the metal-EDTA complex and a protein or peptide by means of the azide group. Similar compounds have been developed by other workers to attach DTPA to various proteins. Tricatecholamide analogs of enterobactin, which have been investigated for their potential for binding gallium and indium, will be discussed in terms of the ultimate aim of using these molecules to attach indium and gallium to biomolecules. The second approach to the design of gallium and indium radiopharmaceuticals is to develop a labeled species to which transferrin has no access. This has been utilized to great advantage in the labeling of blood components with both indium- and gallium-8-hydroxyquinolate as lipophilic agents to passively diffuse into cells.