TY - JOUR
T1 - Synthesis and evaluation of 99mTc/Re-tricarbonyl complexes of the triphenylphosphonium cation for mitochondrial targeting
AU - Paparidis, Georgios
AU - Akrivou, Melpomeni
AU - Tsachouridou, Vicky
AU - Shegani, Antonio
AU - Vizirianakis, Ioannis S.
AU - Pirmettis, Ioannis
AU - Papadopoulos, Minas S.
AU - Papagiannopoulou, Dionysia
PY - 2018/2
Y1 - 2018/2
N2 - 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 of 99mTc tumor-targeted imaging agents. Methods Two 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. Results The 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− 5 M as well as 80% cell death in culture at 10− 4 M. The cell uptake of 99mTcL1 and 99mTcL2 over 4 h 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. Conclusions In 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.
AB - 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 of 99mTc tumor-targeted imaging agents. Methods Two 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. Results The 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− 5 M as well as 80% cell death in culture at 10− 4 M. The cell uptake of 99mTcL1 and 99mTcL2 over 4 h 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. Conclusions In 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.
KW - Mitochondrial targeting
KW - Technetium
KW - Tricarbonyl complexes
KW - Triphenylphosphonium
KW - Tumor imaging agents
UR - http://www.scopus.com/inward/record.url?scp=85037642286&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2017.11.003
DO - 10.1016/j.nucmedbio.2017.11.003
M3 - Article
C2 - 29227814
AN - SCOPUS:85037642286
SN - 0969-8051
VL - 57
SP - 34
EP - 41
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
ER -