Bifunctional chelators for technetium-99m radiopharmaceuticals

A bifunctional chelator, 3,3-bis(thioacetamidomethyl)propanoic acid, was prepared containing a symmetrical bisamido bisthiolate (N2S 2) core for chelation with rhenium or technetium, and a carboxylic acid group for conjugation to amine containing biomolecules. This N2S 2 chelator was shown to chelate rhenium(V) and technetium-99m(V), resulting in a mixture of anti and syn isomers. Epimerization with 0.5 M NaOH converts the mixture to a single isomer, assigned as the anti isomer based on X-ray crystallography and NMR spectroscopy of the rhenium complex.;Bioconjugation of the N2S2 chelator to (S)-1-phenethylarnine was investigated as a model of amine containing pharmaceuticals. This study demonstrated the conjugating ability of the bifunctional chelator, and that chelation readily occurs with both rhenium and technetium-99m. Also, this conjugate forms complexes as a mixture of anti and syn isomers which may be quantitatively converted to the anti isomer.;A second bifunctional chelator, based on a diamino dioxime (N4) chelation core, has also been investigated. Preparation of this compound was impeded by a number of synthetic difficulties.;Bioconjugation of the N2S2 bifiinctional chelator has been explored with bioactive molecules, and the bioconjugates were characterized. Both rhenium and technetium-99m, formed stable metal complexes with these conjugates. Again, epimerization of the mixture of anti and syn isomers to a single isomer occurred when the mixture was exposed to alkaline conditions. The biomolecules radiolabelled with 99mTc are: a cholecystokinin antagonist based on MK-329 as a potential pancreas and gallbladder imaging agent; estrogen receptor antagonist Z-tamoxifen, and agonist E-tamoxifen, as potential breast cancer imaging agents; and lysine derivatives for application in the radiolabelling of peptides, The unique ability of this chelator to form single isomer radiopharmaceuticals may prove useful in the development of receptor-specific radiopharmaceuticals.