Influence of the Denticity of Ligand Systems on the in Vitro and in Vivo Behavior of 99mTc(I)−Tricarbonyl Complexes: A Hint for the Future Functionalization of Biomolecules

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Abstract
Functionalization of biologically relevant molecules for the labeling with the novel fac-[99mTc(OH2)3(CO)3]+ precursor has gained considerable attention recently. Therefore, we tested seven different tridentate (histidine L 1, iminodiacetic acid L 2, N-2-picolylamineacetic acid L 3, N,N-2-picolylaminediacetic acid L 4) and bidentate (histamine L 5, 2-picolinic acid L 6, 2,4-dipicolinic acid L 7) ligand systems, with the potential to be bifunctionalized and attached to a biomolecule. The ligands allowed mild radiolabeling conditions with fac-[99mTc(OH2)3(CO)3]+ (30 min, 75 °C). The ligand concentrations necessary to obtain yields of >95% of the corresponding organometallic complexes 1-7 ranged from 10-6 to 10-4 M. Complexes of the general formula “fac-[99mTcL(CO)3]” (L = tridentate ligand) and “fac-[99mTc(OH2)L‘(CO)3]” (L‘ = bidentate ligand), respectively, were produced. Challenge studies with cysteine and histidine revealed significant displacement of the ligands in complexes 5−7 but only little exchange with complexes 1−4 after 24 h at 37 °C in PBS buffer. However, no decomposition to 99mTcO4- was observed under these conditions. All complexes showed a hydrophilic character (log Po/w values ranging from −2.12 to 0.32). Time-dependent FPLC analyses of compounds 1−7 incubated in human plasma at 37 °C showed again no decomposition to 99mTcO4- after 24 h at 37 °C. However, the complexes with bidentate ligands (5−7) became almost completely protein bound after 60 min, whereas the complexes with tridentate coordinated ligands (1−4) showed no reaction with serum proteins. The compounds were tested for their in vivo stability and the biodistribution characteristics in BALB/c mice. The complexes with tridentate coordinated ligand systems (1−4) revealed generally a good and fast clearance from all organs and tissues. On the other hand, the complexes with only bidentate coordinated ligands (5−7) showed a significantly higher retention of activity in the liver, the kidneys, and the blood pool. Detailed radiometric analyses of murine plasma samples, 30 min p.i. of complex fac-[99mTcL1(CO)3], 1, revealed almost no reaction of the radioactive complex with the plasma proteins. By contrast, in plasma samples of mice, which were injected with complex fac-[99mTc(OH2)L5(CO)3]+, 5, the entire radioactivity coeluded with the proteins. On the basis of these in vitro and in vivo experiments, it appears that functionalization of biomolecules with tridentate-chelating ligand systems is preferable for the labeling with fac-[99mTc(OH2)3(CO)3]+, since this will presumably result in radioactive bioconjugates with better pharmacokinetic profiles.

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