Synthesis, in vitro, and in silico evaluation of organometallic technetium and rhenium thymidine complexes with retained substrate activity toward human thymidine kinase type 1.
Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for noninvasive imaging of cancer cell proliferation using radiolabeled substrates such as [ (18)F]fluorothymidine ([ (18)F]FLT). However, a thymidine tracer useful for single photon emission tomography (SPECT) based on the inexpensive radionuclide technetium-99m would be of significant interest. In this work, a series of thymidine derivatives labeled with the organometallic [M(CO) 3] (+) core (M = (99m)Tc, Re) were synthesized. Neutral, cationic, and anionic complexes were readily formed in aqueous media, and all were substrates of recombinant hTK1 when incubated with ATP. The neutral complexes were phosphorylated to a greater extent than the charged complexes. The extent of phosphorylation was further improved by increasing the spacer length separating thymidine and the organometallic core. A molecular dynamics simulation study performed with a modified hTK1 structure supported the experimental findings. In vitro cell internalization experiments performed in a human neuroblastoma cell line (SKNMC) showed low uptake of the charged complexes but significant uptake for the neutral, lipophilic complexes with a log P value >1.
Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
Dominique
D
Desbouis
Harriet
H
Struthers
Vojtech
V
Spiwok
Tatiana
T
Küster
Roger
R
Schibli
D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D019295:Computational Biology; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D012211:Rhenium / Q000737:chemistry*; D013379:Substrate Specificity; D013936:Thymidine / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013937:Thymidine Kinase / Q000737:chemistry / Q000378:metabolism*
D002614:Chelating Agents; D008024:Ligands; D015609:Organotechnetium Compounds; D012211:Rhenium; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine