Synthesis, in vitro and in silico assessment of organometallic Rhenium(I) and Technetium(I) thymidine complexes

Thymidine kinases have been identified as suitable targets for non-invasive imaging of gene therapy and cancer. Thus, there is a high interest in new, reliable and inexpensive radiolabeled thymidine analogues for these applications. In this study we present the synthesis and in vitro evaluation of M(CO)(3)-complexes of thymidine (M = Tc-99m, Re) for potential use in SPECT tumor imaging. 5'-amino-5'-deoxythymidine was derivatized at position C5' with spacers of various lengths (similar to 0-30 angstrom) carrying tridentate metal chelating entities such as iminodiacetic acid and picolylamine-N-monoacetic acid. The nucleoside derivatives were reacted with the precursors [ReBr3(CO)(3)](2-) and [Tc-99m(OH2)(3)(CO)(3)](+), respectively. The organometallic thymidine complexes have been fully characterized by means of IR, NMR and mass spectrometry. Enzyme kinetic studies revealed mixed inhibition of the human cytosolic thymidine kinase with K-i values ranging from 4.4 to 334 mu M for all thymidine complexes. Competitive inhibition of herpes simplex virus type 1 thymidine kinase was only achieved when thymidine and the metal core were separated by a spacer of approximately 30 angstrom length. These findings were supported by in silico molecular docking and molecular dynamic experiments. (C) 2006 Elsevier B.V. All rights reserved.