New bioconjugated technetium and rhenium folates synthesized by transmetallation reaction with zinc derivatives

The zinc dithiocarbamates functionalized with folic acid 2(Zn) and 3(Zn) were synthesized with a simple straightforward method, using an appropriated folic acid derivative and a functionalized zinc dithiocarbamate (1(Zn)). Zinc complexes 2(Zn) and 3(Zn) show very low solubilities in water, making them useful for preparing Tc-99m radiopharmaceuticals with a potentially high molar activity. Thus, the transmetallation reaction in water medium between the zinc complexes 2(Zn) or 3(Zn) and the cation fac-[Tc-99m(H2O)(3)(CO)(3)](+), in the presence of the monodentate ligand TPPTS, leads to the formation of the 2 + 1 complexes fac-[Tc-99m(CO)(3)(SS)(P)] bioconjugated to folic acid (2(Tc) and 3(Tc)). In spite of the low solubility of 2(Zn) and 3(Zn) in water, the reaction yield is higher than 95%, and the excess zinc reagent is easily removed by centrifugation. The Tc-99m complexes were characterized by comparing their HPLC with those of the homologous rhenium complexes (2(Re) and 3(Re)) previously synthesized and characterized by standard methods. Preliminary in vivo studies with 2(Tc) and 3(Tc) indicate low specific binding to folate receptors. In summary, Tc-99m folates 2(Tc) and 3(Tc) were prepared in high yields, using a one-pot transmetallation reaction with low soluble zinc dithiocarbamates (>1 ppm), at moderate temperature, without needing a subsequent purification step.