Hyperpolarized [2-13C]-fructose: a hemiketal DNP substrate for in vivo metabolic imaging - PubMed (original) (raw)
Hyperpolarized [2-13C]-fructose: a hemiketal DNP substrate for in vivo metabolic imaging
Kayvan R Keshari et al. J Am Chem Soc. 2009.
Abstract
Hyperpolarized (13)C labeled molecular probes have been used to investigate metabolic pathways of interest as well as facilitate in vivo spectroscopic imaging by taking advantage of the dramatic signal enhancement provided by DNP. Due to the limited lifetime of the hyperpolarized nucleus, with signal decay dependent on T(1) relaxation, carboxylate carbons have been the primary targets for development of hyperpolarized metabolic probes. The use of these carbon nuclei makes it difficult to investigate upstream glycolytic processes, which have been related to both cancer metabolism as well as other metabolic abnormalities, such as fatty liver disease and diabetes. Glucose carbons have very short T(1)s (<1 s) and therefore cannot be used as an in vivo hyperpolarized metabolic probe of glycolysis. However, the pentose analogue fructose can also enter glycolysis through its phosphorylation by hexokinase and yield complementary information. The C(2) of fructose is a hemiketal that has a relatively longer relaxation time (approximately 16 s at 37 degrees C) and high solution state polarization (approximately 12%). Hyperpolarized [2-(13)C]-fructose was also injected into a transgenic model of prostate cancer (TRAMP) and demonstrated difference in uptake and metabolism in regions of tumor relative to surrounding tissue. Thus, this study demonstrates the first hyperpolarization of a carbohydrate carbon with a sufficient T(1) and solution state polarization for ex vivo spectroscopy and in vivo spectroscopic imaging studies.
Figures
Figure 1
The mechanism for transport by GLUT5 and the first step of metabolism of fructose to fructofuranose-6-phosphate by hexokinase.
Figure 2
The natural abundance spectrum of fructose (a) and DNP spectrum of [2-13C]-fructose (b). The linear form is present in the DNP spectrum, but at a very low level analogous to the thermal spectrum. (Top) Structures of each of the isomers are shown with their analogous resonance.
Figure 3
(a) Spectrum of fructose reacted with 400U of hexokinase, the zoomed in region demonstrates the resonances corresponding to the fructose and fructose-6-phosphate. (b) The dynamic spectrum after 5 secs of reaction with hexokinase. (c) The thermal spectrum of same solution with hexokinase averaged 85 min post DNP.
Figure 4
(a) T2-weighted image of a moderate to late stage TRAMP mouse prostate tumor. Metabolite image overlays of the resonances corresponding to total hyperpolarized fructose (b) and composite β-fructofuranose-6-phosphate and β-fructofuranose (c) obtained after injection of 80mM [2-13C] fructose demonstrate spatial differences in total fructose versus the composite β-fructofuranose-6-phosphate resonance. Spectra corresponding to the two red voxels (d) in the tumor demonstrate the resonances corresponding to β-fructopyranose and the composite β-fructofuranose-6-phosphate and β-fructofuranose. Pyruvate and lactate resonances are shown from the same locations (e) obtained after an injection of 80mM hyperpolarized pyruvate in the same mouse.
Figure 5
(a) T2-weighted image of a TRAMP mouse with tumor only on the right side of the prostate. Metabolic images of total hyperpolarized [2-13C] fructose resonances (b) and the composite β-fructofuranose-6-phosphate and β-fructofuranose (c) are shown overlaid on the T2 weighted image. Resonances corresponding to the β-fructopyranose and composite β-fructofuranose-6-phosphate and β-fructofuranose are shown in the corresponding spectral array (d). The yellow area demonstrates a region of tumor, compared to a region of benign prostate tissue in red. An unassigned spurious, low signal-to-noise resonance appears at 115 ppm.
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