Synthesis, characterization and biological evaluation of [188Re(N)(cys ∼)(PNP)]+/0 mixed-ligand complexes as prototypes for the development of 188Re(N)-based target-specific radiopharmaceuticals.

We report on an efficient procedure for the preparation of [(188)Re(N)(PNP)]-based complexes (where PNP is diphosphinoamine) useful in the development of target-specific radiopharmaceuticals. The radiochemical yield of the compounds was optimized considering such reaction parameters as nature of the nitrido nitrogen donor, reaction times and pH level. The chemical identity of the (188)Re agents was determined by high-performance liquid chromatography comparison with the corresponding well-characterized cold Re compounds. (188)Re(N) mixed compounds have been evaluated with regard to stability toward transchelation with GSH and degradation by serum enzymes. The clearance of selected radiocompounds from normal tissues and their in vivo stability were evaluated in rats by biodistribution and imaging studies. (188)Re(N)(cys ∼)(PNP) mixed-ligand compounds were efficiently prepared in aqueous solution from perrhenate using a multistep procedure based on the preliminary formation of the labile (188)Re(III)-EDTA species, which easily undergo oxidation/ligand exchange reaction to afford the (188)Re(V) ≡ N core in the presence of dithiocarbazate. The final mixed-ligand compounds were obtained, at 100 °C, by adding the two bidentate ligands to the buffered (188)Re(V) ≡ N solution (pH 3.2-3.6). However, a relatively high amount of cys ∼ ligand was required to obtain a quantitative radiochemical yield. The complexes were stable toward reoxidation to perrhenate and ligand exchange reactions. In vivo studies showed rapid distribution and elimination of the complexes from the body. No specific uptakes in sensitive tissues/organs were detected. A positive correlation of the distribution of the complexes estimated with biodistribution studies (%ID) and with micro-SPECT semiquantification imaging analysis (standard uptake values) was observed. These results support the possibility of applying [(188)Re(N)(PNP)] technology to the preparation of target-specific agents.