Effect of the triphenylphosphonium cation on the biological properties of new rhenium and technetium-99m fac-[M(CO)3(NSN)]±-type complexes: Synthesis, structural characterization, in vitro and in vivo studies

Abstract

Triphenylphosphonium (TPP) cations have been used for the development of tumor or myocardial diagnostic radiopharmaceuticals. In this work, the development of new [99mTc][Tc(CO)3(N,S,N)]+ complexes of the (N,S,N) tridentate chelator benzimidazol-2-yl-methylthioethylamine (L), and its triphenylphosphonium (TPP) cation derivative L-TPP is described. The TPP-moiety was conjugated at the Nτ-benzimidazol position of L. The reaction of the chelators L and L-TPP with a suitable precursor [Re(sol)3(CO)3]+ yielded single products of ReL+ and ReL-TPP2+. The complexes were characterized by spectroscopic methods and furthermore the structure of ReL was elucidated by X-ray crystallography. The respective 99mTc-radiotracers were synthesized in high yield, their lipophilicity was measured and both exhibited high stability in cysteine, histidine solutions as well as in rat plasma. The in vitro cell studies in human erythroleukemia K-562 and glioblastoma U-87MG tumor cells showed that the tracer 99mTcL+ exhibited significantly higher cellular uptake, while 99mTcL-TPP2+ exhibited significantly higher mitochondrial accumulation. The tracers 99mTcL+ and 99mTcL-TPP2+ exhibited fast blood elimination and excretion via the hepatobiliary and the renal routes after intravenous administration in healthy mice. Tracer 99mTcL+ exhibited higher myocardial uptake and renal excretion, while 99mTcL-TPP2+ exhibited primarily hepatobiliary excretion. These data confirm the high mitochondrial accumulation of 99mTcL-TPP2+ in vitro and show its potential as a candidate for tumor imaging.