New technetium-99m and rhenium compounds for radiopharmaceuticals applications by means of [2+1] transmetallation reaction

Resumo

This thesis can be seen as a continuation of a previous work in our research group based on the development of a transmetallation reaction for the preparation of second generation radiopharmaceuticals. Briefly, the low solubility of the bioconjugated zinc complex allows the straightforward radiolabeling of fac-{99mTc(CO)3}+ core, with this method the final potential radiopharmaceutical with high specific activity. In this work, two new rhenium complexes have been synthetized by means of a reported zinc complexes derivatized with glucosamine and piperazine. Two π-acceptors ligands, triphenylphosphine trisulfonate and tert-butyl isocyanide, have been used to improve the features of the potential radiotracer, and, at the same time, the use of this ligands will test the versatility of the [2+1] transmetallation reaction. On the other hand, since in the last few years folic acid has awakened interest as a biovector, two new zinc complexes have been synthetized to be used in the transmetallation reaction. Afterwards, the corresponding rhenium complex has been synthetized as a model for the final technetium homologue. The proper obtention of the bioconjugated rhenium complexes has paved the way to perform the radiosynthesis with technetium-99m. After some optimizations, we are able to affirm that the [2+1] transmetallation reaction is a very convenient reaction to bioconjugate fac-{99mTc(CO)3}+ because of its simplicity from an experimental point of view. Moreover, the radiotracers bioconjugated with glucosamine and folic acid derivatives have been studied in vivo and in vitro. These studies have shown a clear biological activity for each potential radiopharamaceuticals. Finally, a lipophilic zinc complex has been synthetized and characterized to apply the above-mentioned reaction for liposome radiolabeling. Despite this product is not anchored in the phospholipid bilayer, the corresponding rhenium and technetium-99m products show an amphiphilic behavior. Thus, since amphiphilic molecules can interact with phospholipids, in this work is shown how the [2+1] transmetallation reaction can be useful for liposome radiolabeling.