Synthesis and evaluation of 99m Tc/Re-tricarbonyl complexes of the triphenylphosphonium cation for mitochondrial targeting.

INTRODUCTION: Lipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development of99m Tc tumor-targeted imaging agents.

METHODS: Two tridentate ligands containing the triphenylphosphonium cation, L1 (S-cysteinyl) and L2 (N-iminodiacetate) as well as the respective99m Tc/ReL1 and99m Tc/ReL2 tricarbonyl complexes were synthesized. The effect of the ligands and the Re complexes on cell growth in U-87 MG glioblastoma cells was assessed. In vitro stability studies and measurement of logP of the99m Tc tracers was performed. The cellular and mitochondrial uptake of the99m Tc tracers in U-87 MG cells was evaluated. Biodistribution of99m TcL1 and99m TcL2 were performed on SCID mice bearing U-87 MG tumors.

RESULTS: The ligands L1, L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single products99m TcL1 and99m TcL2, >90% stable in rat serum, were obtained. LogP was 0.40±0.14 for99m TcL1 and -0.02±0.07 for99m TcL2. L1, ReL1 and ReL2 caused no notable cytotoxicity and L2 was found to infer 40% inhibition of cellular growth at 10-5 M as well as 80% cell death in culture at 10-4 M. The cell uptake of99m TcL1 and99m TcL2 over 4h was 1.26±0.08% and 0.06±0.01% respectively, of which 13.41±3.63% and 18.61±6.19% was distributed in the mitochondria respectively. The initial tumor uptake in mice was found to be >1% ID/g for both99m Tc tracers.

CONCLUSIONS: In vitro mitochondrial and in vivo tumor targeting was observed, better in99m TcL1, however these properties should be optimized in future studies. Advances in Knowledge and Implications for Patient Care: Continuous efforts in this direction may lead to a suitable mitochondrial-targeted99m Tc imaging agent for tumor detection.