Tracer Development for the Molecular Imaging of Breast Cancer: Synthesis and Biological Evaluation of C-3 Modified 2,5-Anhydro-D-mannitol Derivatives as Potential Tracer Molecules

  • Author / Creator
    Kondapi, Venkata Pavan Kumar
  • Mammography is the most frequently used imaging method for the detection of breast cancer. Despite the key role of mammography in the breast cancer detection, false-negative diagnosis by mammograms ranges from 4 to 34%. Positron emission tomography (PET), a tracer based molecular imaging method is an alternative to mammography for the detection of breast cancer. The most commonly used PET tracer [18F]-2-fluoro-2-deoxy-D-glucose ([18F]-FDG) also provides false-positive and false-negative diagnosis of breast cancer. Mammalian hexose transporters (GLUTs) facilitate the transport of hexoses from the extracellular spacer to intracellular space and vice versa. To date, 14 different types of GLUTs, which exhibit difference in substrate specificity, are known. The ubiquitously expressed transporter protein GLUT1 transports [18F]-FDG. Enzymatic phosphorylation of [18F]-FDG with hexokinase prevents the back-transport of [18F]-FDG by GLUT1. Due to minimal or complete lack of expression of GLUT1 in some breast cancer cells and ubiquitous expression of GLUT1 in some normal cells, relatively lower accumulation of [18F]-FDG was observed in breast cancer cells over normal cells. After the discovery of GLUT5 in many breast cancer cells, tracers targeting this transporter were developed for the imaging of breast cancer. Unfortunately, these tracers were back transported from the breast cancer cells due to their inability to undergo enzymatic phosphorylation by hexokinase. Tracers that target the GLUT5 transporter protein and undergo enzymatic phosphorylation in the presence of hexokinase could significantly improve the efficiency of PET or optical imaging in the detection of certain types of breast cancers. This thesis comprises our studies of synthesis and biological evaluations of novel 2,5-anhydro-D-mannitol (2,5-AM)-based scaffolds, to examine their ability to serve as tracers in the molecular imaging of early stage breast cancer. Chapter 1 of this thesis provides a broad introduction to the hexose-based tracer development for the molecular imaging of breast cancer. Structural requirement of hexoses for the efficient GLUT-substrate binding is also overviewed in this Chapter. In Chapter 2, modification of the C-3 position of 2,5-AM via diastereoselective epoxide ring-opening of 2,5:3,4-dianhydro-D-allitol is described. Chapter 2 also discusses the solvent polarity effects on this epoxide ring-opening process. Chapter 3 presents the biological evaluation of 3-fluoro-3-deoxy-2,5-anhydro-D-mannitol whose 18F-labeled version could potentially be used as a PET tracer for the detection of breast cancer. In addition, Chapter 3 also deals with the structure-activity relationship between GLUT5 and the C-3 modified 2,5-AM derivatives. D-Fructose and D-glucose transport inhibition into EMT-6 cells by C-3 modified 2,5-AM derivatives, followed by control experiments are used to determine the structural requirement of the C-3 modified 2,5-AM derivatives for GLUT recognition. In Chapter 4, synthesis and biological evaluations of a new probe 3-(N-(4-nitro-2,1,3-benzoxadiazol-7-yl))amino-2,5-anhydro-D-mannitol are described, along with docking studies performed by collaborators. Our studies demonstrate that this is the first GLUT5 targeting probe that exhibits low efflux from the murine breast tumor cells. Chapter 5 comprises the synthesis and biological evaluation of C-3 modified 2,5-AM bearing near-infrared emitting dyes as probes for the optical imaging of breast cancer.

  • Subjects / Keywords
  • Graduation date
    Spring 2016
  • Type of Item
  • Degree
    Doctor of Philosophy
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  • 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.
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  • Citation for previous publication
    • “Efficient and Easy Access to Optically Pure Tetrasubstituted Tetra¬hydrofurans via Stereoselective Opening of C2-Symmetric Epoxide and Aziridine Rings”, European Journal of Organic Chemistry, 2016, 1367-1379.
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)