Charge Dependent Substrate Activity of C3′ and N3 Functionalized, Organometallic Technetium and Rhenium-Labeled Thymidine Derivatives toward Human Thymidine Kinase 1

Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as [18F]3′-fluoro-3′-deoxythymidine ([18F]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3′ and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide−alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3′ or N3 position with chelating systems suitable for the M(CO)3 core (M = 99mTc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substr...