For decades, fluorodeoxyglucose (18F-FDG) has been the “gold standard” tracer for Positron Emission Tomography (PET) imaging of cancer as it reports a regional disease-linked increase in glucose demand. Nevertheless, false positive results are common, as increased glucose metabolism is also observed if infectious/inflammatory conditions are present. It leads to the accumulation of 18F-FDG in these regions through the ubiquitously present in all tissues facilitative sugar transporters (GLUTs). Diagnosis and staging of some cancers are also difficult due to the false-negative results since not all cancers rely on glucose for development and progression. Hence, targeting pathways specific to cancer is desired for developing novel PET imaging agents to be diagnostically beneficial. Since many cancers significantly rely on fructose upon development, growth, and progression, fructose-transporting GLUTs are seen as diagnostic targets. Among these GLUTs, fructose-specific GLUT5 transporter is a unique target for the development of PET imaging agents. Here we report a fluoride-functionalized probe that specifically targets GLUT5 in the presence of sugar nutrients. The use of a late-stage functionalization strategy enabled by the click chemistry approach in the synthesis of the probe supports the extension of the current synthetic methodology to obtaining 18F-analogs for future GLUT5-specific in vivo cancer imaging probes. To access ManCou-F1, the glycoconjugate of coumarin and fructose-targeting sugar mimic (2,5-anhydro-D-mannitol, 2,5-AM) was used as a starting material for the late-stage click chemistry functionalization. The uptake of the new ManCou-F1 probe was investigated using a GLUT5-positive breast adenocarcinoma MCF7 cell line (early stage of cancer). Through multiple inhibition studies, it was established that the ManCou-F1 probe enables specific direct analysis of GLUT5 activity in cells in complete nutrient media. Data on the probe’s cancer selectivity, GLUT5 specificity, cytotoxicity, and uptake efficiency will be presented. In summary, a non-radiolabeled fluoride 2,5-AM–coumarin-based probe (ManCou-F1) compatible with late-stage functionalization has the potential to serve as a PET imaging agent for fructose-dependent diseases.

Click chemistry approach provides GLUT5-targeting glycoconjugates as potential more specific PET imaging probes

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