Synthesis and Characterization of Novel Radiolabelled Substrates for Imaging of GLUT5 Expression in Human Breast Cancer Using Positron Emission Tomography

• Author / Creator

  Trayner, Brendan J

• Overactive glucose transport and metabolism has been widely recognized as one of the fundamental hallmarks of cancer and its progression. The facilitative glucose transporter GLUT1 is widely overexpressed in many tumor types compared to their untransformed counterparts. Due to this, the glucose analogue, 2-deoxy-2-[18F]fluoro-D-glucose (FDG) has been used widely for the imaging of malignant neoplastic tissue through a non-invasive technique, positron emission tomography (PET). PET scans have been very successful in the imaging of many breast cancers expressing high levels of GLUT1, but unfortunately, many breast tumors do not express GLUT1 at high levels, if at all. Clinically, this lack of GLUT1 expression in tumors has led to false-negatives in patients’ PET scans. Interestingly, in 1996 it was first identified that the fructose transporting facilitative hexose transporter GLUT5 is highly expressed in transformed breast tissue compared to the untransformed surrounding tissue. This finding has led to the suggestion that radiolabeled substrates for GLUT5 may be effective in imaging GLUT1 negative, GLUT5 positive tumors. We have rationally designed and synthesized several compounds based around previously performed structural studies and analyzed their behaviour both in vitro and in vivo. The C-6 labelled fructose analogue 6-deoxy-6-[18F]fluoro-D-fructose (6-FDF) has shown favourable in vitro and in vivo characteristics for the imaging of GLUT5 expressing breast tumors. Additionally, its dosimetry and excretory profile suggest the viability of the compound for a clinical trial. Other substrates based
  on the C2 symmetric fructose mimic 2,5-anhydro-D-mannitol (2,5-AM) have also been examined for their behaviour in vitro and in vivo. Further work will be spent on further characterizing additional fructose and 2,5-AM analogues that will shed more light on the structural requirements of GLUT5 and perhaps lead to other tracers that will show utility in the imaging of GLUT5 expressing breast cancer with PET.

• Subjects / Keywords

  • Fructose
  • Positron Emission Tomography
  • Hexose Transport
  • Breast Cancer
  • GLUTs
  • GLUT5
  • Cancer

• Graduation date

  Fall 2012

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3SN01F75

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.