Stability and in vivo behavior of Rh[16aneS4-diol]211 at complex: a potential precursor for astatine radiopharmaceuticals

Abstract

Introduction: The heavy halogen (211)At is of great interest for targeted radiotherapy because it decays by the emission of short-range, high-energy α-particles. However, many astatine compounds that have been synthesized are unstable in vivo, providing motivation for seeking other (211)At labeling strategies. One relatively unexplored approach is to utilize prosthetic groups based on astatinated rhodium (III) complex stabilized with a tetrathioether macrocyclic ligand - Rh[16aneS(4)-diol](211)At. The purpose of the current study was to evaluate the in vitro and in vivo stability of this complex in comparison to its iodine analog - Rh[16aneS(4)-diol](131)I.

Methods: Rh[16aneS(4)-diol](211)At and Rh[16aneS(4)-diol](131)I complexes were synthesized and purified by HPLC. The stability of both complexes was evaluated in vitro by incubation in phosphate-buffered saline (PBS) and human serum at different temperatures. The in vivo behavior of the two radiohalogenated complexes was assessed by a paired-label biodistribution study in normal Balb/c mice.

Results: Both complexes were synthesized in high yield and purity. Almost no degradation was observed for Rh[16aneS(4)-diol](131)I in PBS over a 72 h incubation. The astatinated analog exhibited good stability in PBS over 14 h. A slow decline in the percentage of intact complex was observed for both tracers in human serum. In the biodistribution study, retention of (211)At in most tissues was higher than that of (131)I at all time points, especially in spleen and lungs. Renal clearance of Rh[16aneS(4)-diol](211)At and Rh[16aneS(4)-diol](131)I predominated, with 84.1 ± 2.3% and 94.6 ± 0.9% of injected dose excreted via the urine at 4 h.

Conclusions: The Rh[16aneS(4)-diol](211)At complex might be useful for constructing prosthetic groups for the astatination of biomolecules and further studies are planned to evaluate this possibility.

Keywords: Astatine-211; Macrocyclic thioether; Prosthetic groups; Radioiodination; Rhodium complexes.

Fig. 1

Stability of Rh[16aneS₄-diol]¹³¹I complex over time at different temperatures in: (A) phosphate buffered-saline (PBS); (B) human serum.

Fig. 2

Stability of Rh[16aneS₄-diol]²¹¹At complex over time at different temperatures in: (A) phosphate buffered-saline (PBS); (B) human serum.

Fig. 3

Uptake of ²¹¹At and ¹³¹I activity in mouse thyroid after administration of Rh[16aneS₄-diol]²¹¹At (filled bars) and Rh[16aneS₄-diol]¹³¹I (open bars) in normal Balb/c mice.