The sweet spot: FDG and other 2-carbon glucose analogs for multi-modal metabolic imaging of tumor metabolism

Abstract

Multi-modal imaging approaches of tumor metabolism that provide improved specificity, physiological relevance and spatial resolution would improve diagnosing of tumors and evaluation of tumor progression. Currently, the molecular probe FDG, glucose fluorinated with (18)F at the 2-carbon, is the primary metabolic approach for clinical diagnostics with PET imaging. However, PET lacks the resolution necessary to yield intratumoral distributions of deoxyglucose, on the cellular level. Multi-modal imaging could elucidate this problem, but requires the development of new glucose analogs that are better suited for other imaging modalities. Several such analogs have been created and are reviewed here. Also reviewed are several multi-modal imaging studies that have been performed that attempt to shed light on the cellular distribution of glucose analogs within tumors. Some of these studies are performed in vitro, while others are performed in vivo, in an animal model. The results from these studies introduce a visualization gap between the in vitro and in vivo studies that, if solved, could enable the early detection of tumors, the high resolution monitoring of tumors during treatment, and the greater accuracy in assessment of different imaging agents.

Keywords: FDG; FDG-PET; Glucose; deoxyglucose; glucose uptake; multi-modal imaging.

Figure 1

Chemical structures of all the molecules discussed in this review.

Figure 2

Schematic depicting the method of facilitated glucose transport via glucose transport proteins (GLUT), shown in green. Adapted from Pauwels et al. in 1998 [24].

Figure 3

Schematic showing the transport of FDG into the cell and the subsequent metabolism of it into FDG-6P. Like many chemical reactions within the body, this process is reversible, and the variables k₁, k₂, k₃ and k₄ are the kinetic constants that describe the transport of FDG into the cell, its phosphorylation to FDG-6-Phophate, its dephosphorylation back to FDG and its transport out of the cell, respectively.

Figure 4

Schematic of the setup for radioluminescence microscopy as well as some early results showing the fluorescent signal from GFP and the signal from the scintillation of the decay products of FDG. Reprinted with permission from Pratx et al. 2012 [42].

Figure 5

Radioluminescence microscopy results of FDG and 2-NBDG. Reprinted with permission from Pratx et al. 2012 [42]. Scale bar is 100 µm.

Figure 6

Uptake of 2-NBDG in tumorigenic cells (left) and an image of background fluorescence (center) along with fluorescent signal intensities from all cell lines (right). Note the 5-fold increase in 2-NBDG uptake in tumorigenic cells (left two bars in the right panel) versus non-tumorigenic (right bar in the right panel). Reprinted with permission from O’neil et al. 2005 [43].

Figure 7

Figure showing the increased uptake of 2-NBDG in a fasting state (bottom) compared to a fed state (top). Reprinted with permission from Sheth et al. 2009 [44].

Figure 8

Figure showing the FDG-PET volumes (pink in the right panel) overlaid with the fDOT generated 2-DG volumes (blue in the right panel). Also shown are the original FDG-PET images (left), the 3D-optical scans of 2-DG (left center) and their overlay (right center). Reprinted with permission from Garafalakis et al. 2012 [18].