title: New fluorinated fructose analogs as selective probes of the hexose transporter protein GLUT5.
abstract: Facilitated hexose transporters (GLUTs) mediate the transport of hexoses and other substrates across the membranes of numerous cell types, and while some are expressed ubiquitously (e.g., GLUT1), others are more tissue specific (e.g., GLUT5). These properties have been exploited for the imaging of cancer cells by the use of hexose based probes, including fluorinated hexose derivatives for use with positron emission tomography (PET). However, design of new probes has been hampered by a limited understanding of how GLUT transporters interact with their substrates at the molecular level. Two fluorinated fructose surrogates designed for uptake by the GLUT5 transporter are described here: 3-deoxy-3-fluoro-D-fructose (3-FDF) and 1-deoxy-1-fluoro-2,5-anhydromannitol (1-FDAM). Synthesis (both cold and radiolabeled) and in vitro analysis of their transport characteristics in two breast cancer cell lines (EMT-6 and MCF-7) expressing GLUT5 are detailed. Both analogues are readily taken up into both cancer cell lines, with uptake mediated primarily by GLUT5. They also have low IC50 values, indicating a high affinity for the transporter, suggesting that the uptake of these probes would be unaffected by endogenously circulating fructose. Selective uptake by GLUT5 was also demonstrated in Xenopus oocytes. Finally, these results are the first demonstration that a hexose existing predominantly in the pyranose ring structure (3-FDF) is transported by GLUT5, strongly suggesting that this transporter can handle both furanose and pyranose forms of fructose.
authors.affiliation: Department of Chemistry, 11227 Saskatchewan Drive University of Alberta, Edmonton, AB, Canada T6G 2G2. frederick.west@ualberta.ca.
authors.forename: Olivier-Mohamad
authors.initials: OM
authors.lastname: Soueidan
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Trayner
authors.forename: Tina N
authors.initials: TN
authors.lastname: Grant
authors.forename: Jeff R
authors.initials: JR
authors.lastname: Henderson
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
authors.forename: F G
authors.initials: FG
authors.lastname: West
authors.forename: Chris I
authors.initials: CI
authors.lastname: Cheeseman
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D003571:Cytochalasin B / Q000494:pharmacology; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051296:Glucose Transporter Type 5 / Q000032:analysis* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells / Q000187:drug effects / Q000378:metabolism; D015336:Molecular Probe Techniques; D015335:Molecular Probes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D014981:Xenopus
chemical_list: D002250:Carbon Radioisotopes; D051296:Glucose Transporter Type 5; D015335:Molecular Probes; C495726:SLC2A5 protein, human; C085580:3-deoxy-3-fluorofructose; D005632:Fructose; D003571:Cytochalasin B