Nucleoside transporters in PET imaging of proliferating cancer cells using 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine

Abstract

The movement of physiologic nucleosides and nucleoside analogue drugs across biological membranes is mediated by nucleoside transport proteins. In cancer, nucleoside transporters have an important role in maintaining the hyperproliferative state of tumours and are important targets for diagnostic and therapeutic agents in the detection, treatment and monitoring of cancers. The nucleoside-based probe 3ꞌ-deoxy-3ꞌ-[18F]fluoro-L-thymidine ([18F]FLT) has been developed for PET imaging of proliferating cancer cells, which is less prone than 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) to non-specific effects. [18F]FLT enters proliferating cells through nucleoside transporters, then becomes phosphorylated and blocks DNA synthesis, whilst also becoming trapped inside the cell. Practicable and automated chemical syntheses of [18F]FLT have been developed, for which the most widely used radiolabelling precursor is the thymidine derivative 3-N-boc-5ꞌ-O-dimethoxytrityl-3ꞌ-O-nosyl-thymidine. [18F]FLT PET imaging has undergone feasibility studies and has been assessed in pre-clinical and clinical studies for the detection and diagnosis of cancers and in monitoring their response to treatments. The roles of nucleoside transporters, especially ENT1, in the cellular uptake of [18F]FLT have been investigated.