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

Abstract

IntroductionLipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development of 99mTc tumor-targeted imaging agents. MethodsTwo tridentate ligands containing the triphenylphosphonium cation, L1 (S-cysteinyl) and L2 (N-iminodiacetate) as well as the respective 99mTc/ReL1 and 99mTc/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 the 99mTc tracers was performed. The cellular and mitochondrial uptake of the 99mTc tracers in U-87 MG cells was evaluated. Biodistribution of 99mTcL1 and 99mTcL2 were performed on SCID mice bearing U-87 MG tumors. ResultsThe ligands L1, L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single products 99mTcL1 and 99mTcL2, >90% stable in rat serum, were obtained. LogP was 0.40±0.14 for 99mTcL1 and −0.02±0.07 for 99mTcL2. L1, ReL1 and ReL2 caused no notable cytotoxicity and L2 was found to infer 40% inhibition of cellular growth at 10−5M as well as 80% cell death in culture at 10−4M. The cell uptake of 99mTcL1 and 99mTcL2 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 both 99mTc tracers. ConclusionsIn vitro mitochondrial and in vivo tumor targeting was observed, better in 99mTcL1, 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-targeted 99mTc imaging agent for tumor detection.