Synthesis of tricarbonyl rhenium and technetium complexes of a 5′-carboxamide 5-ethyl-2′-deoxyuridine for selective inhibition of herpes simplex virus thymidine kinase 1

Herpes simplex virus thymidine kinase type 1 (HSV1-TK) is frequently used as reporter protein in gene therapy. Our aim is to produce single photon emitting reporter probe based on technetium-99m. The synthesis of organometallic technetium and rhenium complexes of a 5′-carboxamide 5-ethyl-2′-deoxyuridine derivative able to selectively inhibit HSV1-TK is presented. The 5-ethyl-2′-deoxyuridine functionalized with a suitable tridentate chelating system at position 5′ was synthesized from commercial 2′-deoxyuridine in seven steps. The 5-ethyl-2′-deoxyuridine derivative was labeled with the fac-M(CO)3-core (M = Tc, Re). The resulting rhenium complex was found to be a selective competitive inhibitor of HSV1-TK (Ki = 4.56 μM). Inhibition of the human cytosolic thymidine kinase (hTK1) previously reported with organometallic rhenium and technetium complexes of 5′-carboxamide thymidine derivative was not observed. The uptake of the technetium-99m complex in transfected cells expressing HSV1-TK has been evaluated to assess its possible use as reporter.

Graphical abstractThe first organo-technetium and organo-rhenium complex of 5-ethyl-2′-deoxyuridine has been prepared. The selectively inhibit the viral HSV1-TK in a competitive manner but do not display any activity against human TK 1. The potency of inhibition is significantly improved compared to the isostructural thymidine derivative by virtue of exchange of the methyl group by an ethyl group at position 5 of the base functionality. In vitro cell experiments revealed a low uptake of the radioactive complex in HSV1 TK-positive cells.Figure optionsDownload full-size imageDownload as PowerPoint slide