Chemistry Reference
In-Depth Information
The main limitations of current 13 C based DNP magnetic resonance spectros-
copy imaging (MRSI) are, first, the very short lifetime of the hyperpolarization. For
example, the 13 C-labeled molecules have a typical life time less than 40 s in vivo.
And, second, high concentration of the hyperpolarized molecule is required
because, following dissolution and intravenous injection, the 13 C-labeled molecule
is diluted by about two orders of magnitude before it reaches the tissue of interest
[ 64 ]. However, there are ways to tackle these limitations. For example, the lifetime
can be extended by placing the 13 C label in a position in the molecule where there is
no or only very weak proton coupling [ 65 ]. Accordingly, highly soluble small
metabolites, such as [1- 13 C] pyruvate, [5- 13 C] glutamine, and [1,4- 13 C 2 ] fumarate,
have been designed and they have been effectively applied to obtain greatly
improved MRSI results. Furthermore, these specifically 13 C labeled compounds
have the advantage of significantly different 13 C chemical shifts from the bulk
carbon signal and thus can be readily distinguished in the low resolution spectra
measured in vivo.
A number of papers dealing with metabolic imaging by 13 C-hyperpolarized
pyruvate have appeared in the literature since 2006 [ 66 - 76 ]. Pyruvate is a key
molecule in major metabolic and catabolic pathways in mammalian cells, as it is
converted to alanine, lactate or carbonate to varying extent depending on the status of
the cells. Pyruvic acid naturally forms a glass and has been polarized by up to 40%.
Golman et al . [ 66 ] reported one of the first examples of tumor imaging in vivo by this
technique, which showed the maps of distribution of pyruvate, alanine, and lactate
after a pyruvate injection into a rat with a P22 tumor. The tumor is clearly revealed by
the highest NMR 13 C signal from lactate produced within 30 s [ 66 ]. Recently,
hyperpolarized pyruvate has been utilized as a therapy response marker [ 72 ]. Within
24 h of cytotoxic drug treatment the pyruvate-lactate exchange was substantially
reduced in lymphoma tumors [ 72 ]. It was shown that monitoring changes in
hyperpolarized pyruvate-lactate exchange compares favorably with FEG-PET for
detecting treatment response [ 64 ]. Thus measurement of pyruvate-lactate exchange
may be an alternative to FEG-PET for imaging tumor treatment response in the clinic,
in particular for tumors that are not FDG-avid, such as the prostate tumor.
Many pathological states are associated with changes in tissue acid-base balance,
including inflammation and ischaemia [ 77 - 79 ]. For instance, most tumors have an
acidic extracellular pH compared to normal tissue and this can be correlated with
prognosis and response to treatment [ 80 - 82 ]. Despite the importance of pH and its
relationship to disease, there is currently no clinical tool available to image the
spatial distribution of pH in humans. In principle, tissue pH could be determined
from 13 C-MRSI measurements of endogenous H 13 CO 3 and 13 CO 2 using the
Henderson-Hasselbalch equation, if there was sufficient signal-to-noise:
H 13 CO 3
13 CO 2 Þ
pH
¼
p K a þ
log
ð½
(15)
One study has shown that the extracellular pH in tumors can be imaged in vivo
from the ratio of the signal intensities of H 13 CO 3 and 13 CO 2 following intravenous
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