Radioiodinated and astatinated NHC rhodium complexes: synthesis

The clinical development of radioimmunotherapy with astatine-211 is limited by the lack of a stable radiolabeling method for antibody fragments. An astatinated N-heterocyclic carbene (NHC) Rhodium complex was assessed for the improvement of radiolabeling methodologies with astatine.

Wet harvested astatine-211 in diisopropyl ether was used. Astatine was first reduced with cysteine then was reacted with a chlorinated Rh-NHC precursor to allow the formation of the astatinated analogue. Reaction conditions have been optimized. Astatine and iodine reactivity were also compared. Serum stability of the astatinated complex has been evaluated.

Quantitative formation of astatide was observed when cysteine amounts higher than 46.2 nmol/μl of astatine solution were added. Nucleophilic substitution kinetics showed that high radiolabeling yields were obtained within 15 min at 60°C (88%) or within 5 min at 100°C (95%). Chromatographic characteristics of this new astatinated compound have been correlated with the cold iodinated analog ones. The radioiodinated complex was also synthesized from the same precursor (5 min. at 100°C, up to 85%) using [(125)I]NaI as a radiotracer. In vitro stability of the astatinated complex was controlled after 15 h incubation in human serum at 4°C and 37°C. No degradation was observed, indicating the good chemical and enzymatic stability.

The astatinated complex was obtained in good yield and exhibited good chemical and enzymatic stability. These preliminary results demonstrate the interest of this new radiolabeling methodology, and further functionalizations should open new possibilities in astatine chemistry.

Although there are many steps and pitfalls before clinical use for a new prosthetic group from the family of NHC complexes, this work may open a new path for astatine-211 targeting.