European Journal of Radiology 79 (2011) 369–374

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European Journal of Radiology

journal homepage: www.elsevier.com/locate/ejrad

The synthesis of a d-glucosamine contrast agent, Gd-DTPA-DG, and its

application in cancer molecular imaging with MRI
Wei Zhang a , Yue Chen a,∗ , Da Jing Guo b , Zhan Wen Huang a , Liang Cai a , Ling He c
a
Department of Nuclear Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, PR China
b
Department of Radiology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, PR China
c
West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The purpose of this study is to describe the synthesis of Gadolinium-diethylenetriamine pen-
Received 11 July 2010 taacetic acid-deoxyglucosamine (Gd-DTPA-DG) which is a d-glucosamine metabolic MR imaging contrast
Accepted 20 October 2010 agent. We will also discuss its use in a pilot MRI study using a xenograft mouse model of human adeno-
carcinoma.
Keywords: Methods: This novel contrast agent was specifically studied because of its ability to “target” metabolically
Gd-DTPA
active tumor tissues. In this study Gd-DTPA-DG is used to investigate how tumor tissues would react to
Magnetic resonance imaging (MRI)
a dose of 0.2 mmol Gd/kg over a 120 min exposure in a xenograft mouse model. These experiments used
d-Glucosamine
Molecular imaging
athymic mice implanted with human pulmonary adenocarcinoma (A549) as demonstrated by dynamic
Tumor targeting MRI. Alternately, another contrast agent that is not specific for targeting, Gd-DTPA, was used as the
control at a similar dose of gadolinium. Efficacy of the targeted contrast agent was assessed by measuring
relaxation rate in vitro and signal intensity (SI) in vivo. Statistical differences were calculated using one-
way analysis of variance.
Results: The synthesized Gd-DTPA-DG was shown to improve the contrast of tumor tissue in this model.
Gd-DTPA-DG was also shown to have a similar pharmacokinetic rate but generated a higher relaxation
rate in tumor tissues relative to the control contrast Gd-DTPA. In comparison to the pre-contrast imaging,
the SI of tumor tissue in the experimental group was shown to be significantly increased at 15 min after
injection of Gd-DTPA-DG (p < 0.001). The enhanced signal intensity spread from the edge of the tumor to
the center and seemed to strengthen the idea that MRI performance would be useful in different tumor
tissues.
Conclusion: This preliminary study shows that this new chelated contrast agent, Gd-DTPA-DG, can be
specifically targeted to accumulation in tumor tissue as compared to normal tissues. This targeted para-
magnetic contrast agent has potential for specific cancer molecular imaging with MRI.
© 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction trol contrast delivery to specific areas of interest using relevant

The goal of molecular imaging is to noninvasively detect and
characterize nascent pathology based upon a unique presentation
of biomarkers. These biomarkers should help differentiate abnor-
mal cells from their normal cell counterparts. MRI is known to
have excellent spatial resolution, is reasonably noninvasive, and
is a sequentially repeatable process to help track disease changes
due to its lack of ionizing radiation [1]. However, MRI that is
augmented by the use of contrast agents for imaging, can help
further highlight differences between tumor and normal tissues.
Contrast agents can be biologically encapsulated in order to con-
∗ Corresponding author. Tel.: +86 830 3165722; fax: +86 830 3165720.
E-mail address: chenyue5523@126.com (Y. Chen).
targeting capabilities [2]. In this emerging field of molecular imag-
ing, Gadolinium-diethylenetriamine pentaacetic acid is shown to
be a beneficial MR contrast agent. This agent has a long history of
use in MRI. Additionally, several groups have created gadolinium-
containing micelles, microspheres, nanoparticles, and liposomes
for the purposes of specified target delivery or for modification of
biodistribution. These gadolinium-containing particles have been
used to increase the site-specific concentration of gadolinium, as
compared to using aqueous gadolinium or gadolinium-conjugated
to targeting molecules [3–5]. We have previously reported a
specifically sensitive nuclear detection agent, technetium-99m
diethylenetriamine pentaacetic acid-d-glucosamine (99m Tc-DTPA-
DG), which showed excellent tumor targeting. These agents
are promising imaging agents for clinical tumor targeting and
imaging. In this study, we explore a mechanism of combining

0720-048X/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejrad.2010.10.021
370 W. Zhang et al. / European Journal of Radiology 79 (2011) 369–374
Fig. 1. The synthesis of Gd-DTPA-DG.
gadolinium with DTPA-DG to make a new specific MR contrast
agent.
2. Materials and methods
2.1. Materials
Chemicals were used without further purification unless stated.
DTPA was purchased from Sigma–Aldrich (Shanghai, China), Gd2 O3
was obtained from Rare-Chem. Hi-Tech Co., Ltd. (Huizhou, China).
Human adenocarcinoma (A549) cells were purchased from the Key
Laboratory of Biotherapy of Human Disease of the Ministry of Edu-
cation, West China Hospital, Sichuan University (Chengdu, Sichuan,
China). RPMI-1640 culture solution, 10% fetal calf serum, paren-
zyme and penicillin-streptomycin were purchased from GIBCO/BRL
Corporation (GIBCO Grand Island, NY). Nude mice were purchased
from the Animal Experimental Center of Sichuan University. Gd-
DTPA (Magnevist) was purchased from Schering Plough Corp.
(Schering-Plough Corp., Guangzhou, China).
2.2. Methods
2.2.1. Tumor model
Human pulmonary adenocarcinoma cells were harvested from
patients with trypsin/EDTA, washed, and suspended in normal
saline at a concentration of 1 × 107 cells/ml. A 0.1 ml dose of sus-
pended cells (1 × 106 cells) were injected subcutaneously in the
right dorsal scapular region of mice using a 25-gauge needle. Ani-
mals were visually inspected every other day for changes in general
appearance, behavior, and tumor growth. MRI studies were con-
ducted when the tumor volume reached 10 mm × 10 mm × 10 mm,
as measured by caliper.
2.2.2. Preparation of Gd-DTPA-DG
2.2.2.1. The synthesis of DTPA-bis(anhydride). A mixture of DTPA
(7.8 g, 0.02 mol) was added to a 50 ml flask, acetic anhydride (7.6 ml,
0.08 mol) and dry pyridine (10 ml, 0.12 mmol) were added and
heated at 65 ◦ C for 24 h. After cooling to room temperature, the
resulting mixture was filtered and the solid portion was washed
with diethyl ether. After drying 15 min under a vacuum, the residue
(6.5 g) was used for the next step in the reaction without extra
purification.
2.2.2.2. The synthesis of DTPA-DG. To prepare monosubstituted
derivatives, DTPA-bis (anhydride) (3.57 g, 10 mmol) was dissolved
in 80 ml DMSO by heating at 80 ◦ C. Once dissolved, water (0.18 ml,
10 mmol) was added to the solution and kept at 80 ◦ C. After
stirring for 2 h, the solution was cooled to room temperature. d-
Glucosamine hydrochloride (2.13 g, 10 mmol) and triethylamine
(1.01 g, 10 mmol) was added and the resulting mixture was
stirred for 24 h at room temperature. 80 ml CH2 Cl2 was added
to the reaction mixture to initiate separation, the supernatant
was then decanted. This pellet crude product was washed with
dichloromethane (50 ml, 3 times) to remove the remaining DMSO.
This product was then purified by running over a sephadex G-15
column and the white solid (2.3 g) was obtained. This monosub-
stituted derivative will be used for the next step in the synthesis
reaction.
2.2.2.3. The synthesis of Gd-DTPA-DG. The above mentioned mono-
substituted derivatives (0.554 g, 1 mmol) were dissolved in 8 ml
water and Gd2 O3 (0.363 g, 1 mmol) was added. After stirring for 6 h
at 80 ◦ C, the mixture was filtered to remove excess Gd2 O3 . Acetone
(25 ml) was added to the filtrate and the suspension was filtered to
leave a white product. The crude product was washed with acetone
and diethyl ether and after washing yielded 0.612 g of product. A
diagram of the synthesis of Gd-DTPA-DG is shown in Fig. 1.
2.2.3. In vitro MRI studies
Consideration of the role of paramagnetically chelated Gd-DTPA
was calculated for only T1 , because the T2 values were not statis-
tically different at the tested Gd-DTPA particle concentrations, as
was expected. We therefore only determined T1 relaxivities in vitro.
Gd-DTPA and Gd-DTPA-DG were dissolved in distilled water and
samples were read using a 1.5-T scanner (Excite-II, Echospeed;
GE medical system) accompanied by an 8-channel neurovascu-
lar array coil. Suspended particles containing Gd-DTPA from 0
to 0.5 mM were scanned and compared to the same concentra-
tions of unencapsulated Gd-DTPA. For T1 measurements, a fast spin
echo sequence inversion recovery (FSE IR) sequence was used with
the following imaging parameters: repetition time (TR): 3000 ms;
echo time (TE): 7.8 ms; TI: 50, 75, 100,150, 200, 250, 300, 400,
500, 600, 700, 800, 900 and 1000 ms; band width: 15.6 kHz; FOV:
180 mm × 90 mm; slice thickness: 3.0 mm; matrix: 256 × 128; flip
angle: 90◦ ; and NEX: 1.
2.2.4. In vivo MRI studies
Twenty, Specific Pathogen Free (SPF) female athymic nude mice
(5–6 weeks old, 20–25 g) were randomly assigned to two groups:
the experimental group (n = 10) and the control group (n = 10).
Mice were given vena caudalis injections, where Gd-DTPA-DG was
injected in the experimental group and Gd-DTPA was used in the
 W. Zhang et al. / European Journal of Radiology 79 (2011) 369–374
control group (0.2 mmol/kg for both groups). The tumor-bearing
mice were anesthetized by intramuscular (im) administration of
a 1:1 mixture of ketamine and midazolam (0.04 ml per mouse),
with 0.8–1.0 l/min O2 sevoflurane as the inhalation anesthetic.
Axial and coronal MR images of the mice were acquired on a
1.5-T scanner (GE Healthcare) using a FSE T1 WI pulse sequence
with a 3 inch surface coil, before injection, and at 15 min, 30 min,
60 min, 90 min, and 120 min after injection of the contrast agent.
Plain and enhanced imaging parameters were as follows: repeti-
tion time (TR): 400 ms; echo time (TE): 14.9 ms; NA: 1; flip angle
(˛): 90◦ ; Matrix: 192 × 128; FOV: 14 mm × 14 mm; slice thickness:
2 mm;and BW: 10 kHz. All data were analyzed using the free soft-
ware package OsiriX (OsiriX Foundation, Switzerland). Regions of
interest (ROIs) were designated in the right dorsal scapular region
in each mouse. Signal intensities (SI) in these ROIs (≥10 mm2 ) were
measured at different time points and intensity measurements
were acquired. The tumor periphery was defined as the outer 2 mm
rim of the measured tumor.
2.2.5. Statistical analysis
All T1 values and SI values were measured in the experimen-
tal and control groups. All data were analyzed using the Statistical
Package for Social Sciences (SPSS for Windows, Version 14.0, SPSS,
Chicago, IL, USA). Results are expressed as mean ± standard devia-
tion (SD). Statistical differences between groups or within groups
of subjects were calculated using repeated-measures or one way
ANOVAs where p < 0.05 is the level of significance.
3. Results
3.1. Chemistry
The synthesis of Gd-DTPA-DG generates a white solid powder,
high-resolution mass spectrometry (HRMS) and NMR data were
generated where m/z (%) for C20 H32 GdN4 O14 [M+H]+ was calcu-
lated at 710.1151. Mass peaks were found at 710.1154. DTPA has
five carboxylate groups (–COOH) and d-glucosamine has an amine
group (–NH2 ). These two particles (DTPA and d-glucosamine) were
then coated over these two kinds of functional groups leading
Gadolinium to be directly conjugated to the remaining carboxyl
group.
3.2. In vitro MRI studies
In this study, the Gd-DTPA-DG caused a change in contrast on
MR images as characterized by their longitudinal relaxation time
(T1 ) as evaluated by using the 1.5-T scanner. Increased Gd-DTPA-DG
concentration led to a decrease in T1 . Gd-DTPA-DG demonstrated a
shorter T1 than Gd-DTPA at the same concentration, but Gd-DTPA-
DG and Gd-DTPA had little to no effect on T2 , as was expected at
this concentration. The highest concentration of Gd-DTPA-DG used
in this study was approximately 0.28 mmol/l, T1 value at this con-
centration was found to be 286.30 ± 0.74 ms, while the T1 value for
the control group (Gd-DTPA) was found to be 335.20 ± 61.57 ms.
These T1 values were not significantly different (p = 0.30) from
each other. At the 0.03–0.07 mmol/l concentration range of the two
particles, T1 values of Gd-DTPA-DG were significantly different as
compared to values for Gd-DTPA (p < 0.001). The smallest concen-
tration of Gd-DTPA-DG that was used was 0.002 mmol/l, T1 value
for this concentration was measured at 1448.93 ± 2.20 ms, which
showed a significant difference as compared to distilled water con-
trol (p < 0.05). The particle-specific T1 values are shown in Fig. 2.
371
Fig. 2. (A) Representative MR images of Gd-DTPA and Gd-DTPA-DG were visualized
using test tubes placed in a water bath. These samples show comparisons between
Gd-DTPA and Gd-DTPA-DG with increasing concentrations of Gd and demonstrates
SI. (B) Curves are shown demonstrating the Gd-DTPA and Gd DTPA-DG T1 values for
samples in 1.5 ml of distilled water. The graph displays the T1 values for concen-
trations of Gd-DTPA and Gd-DTPA-DG which were measured with a fast field-echo
echo-planar inversion recovery MR sequence.
3.3. In vivo MRI studies
Significant visualization of tumor tissues was observed after the
injection of both Gd-DTPA-DG and Gd-DTPA. Axial T1 -weighted
images of the tumor enhanced by the Gd-DTPA-DG and Gd-DTPA
are shown in Figs. 3 and 4, respectively. In the control group, the
tumor immediately showed a clear border with uniform visual
enhancement. SI of tumor tissues increased over time and reached
a maximum at 15 min. After this point the SI gradually decreased,
and reached baseline after 2 h (p = 0.68). The experimental group
showed enhanced intensity in the peripheral region from the begin-
ning and after 15 min the signal gradually increased. The visual
enhancement spread to the tumor center and lasted for 30 min.
The signal from the central region of the tumor was significantly
increased (p < .001) as compared to the pre-contrast image. The
visual enhancement subsequently decreased, but still remained
higher than that of the Gd-DTPA control group at 2 h (p < 0.05).
SI’s of the tumor were measured in both experimental and con-
trol groups at the baseline and at the subsequent time points, this
graph is shown in Fig. 5.
4. Discussion
Gadolinium-diethylenetriamine pentaacetic acid is a positive
MRI contrast agent. This agent has a long history of use in MRI exam-
inations, has been FDA-approved for nearly two decades, and is a
well characterized stable chelate. Gd(III) is shown to have a strong
paramagnetic effect; among all the elements, it has the greatest
impact on the relaxation time of the hydrogen proton. Although
Gd(III) has some serious and toxic side effects, after chelation with
DTPA (diethylenetriamine pentaacetic acid), the complexed ions
have only a minor impact on in vivo metabolism of certain enzymes,
thereby reducing toxicity [6,7]. Gd-DTPA however, is a small-
molecule ionic contrast agent that has a high osmotic pressure
in vivo and unfavorable pharmacokinetics; it also shows undesir-
able background enhancement due to fast extravasation into the
extracellular fluid [8]. Most of the small molecule Gd(III) chelate
is confined to the extracellular regions. As a result, the contrast
372 W. Zhang et al. / European Journal of Radiology 79 (2011) 369–374

Fig. 3. Representative T1 -weighted 2D spin-echo magnetic resonance images of a transverse slice of a mouse bearing A549 tumor; a – precontrast, b – 15 min, c – 30 min, d
– 45 min, e – 90 min and f – 120 min after injection of Gd-DTPA-DG at a dose of 0.2 mmol-Gd/kg.

agent is therefore confined to vascular regions, reducing its abil-
ity to assist in gathering information about cellular physiology or
molecular pathology [9,10]. For this reason, new contrast agents
that target specific organs or body tissues and/or aggregate in spe-
cific regions of tumors are needed [11].
In recent years, contrast agent research, development and appli-
cations have focused mainly on improving the molecular ligand; in
general, Gd(III) is still the metal ion of choice. Chemical modifi-
cation of the ligand skeleton of the chelate can introduce various
functional groups that improve the targeting to specific tissues or
organs. Tumor-targeted MR imaging is aimed at implementing the
use of paramagnetic contrast agent aggregation at the site of the
tumor. To achieve targeted MR imaging, appropriately high affinity
molecular probes must be employed as one of the prerequisites for
in vivo molecular imaging [12]. Probes that are amenable to label-
ing with radiometals for SPECT or PET can also be chelated using
Gd(III) for use in MR imaging.
Based on the characteristics of hypermetabolism and rela-
tively rapid proliferation, carcinoma cells require a large supply
of glucose, much more than that needed by normal cells [13].
This inherent metabolic need could be such that in tumor cell
membranes, there exist a much higher glucose transporter expres-
sion, for example Glut-1 and/or Glut-4. Among all the glucose
transporters, the Glut-l subtype is expressed in almost all tumor
cell lines, and consequently is closely identified with tumor
tissues. Analogs are available that have similar structure to d-

Fig. 4. Representative T1 -weighted 2D spin-echo magnetic resonance images of a transverse slice of a mouse bearing A549 tumor; a – precontrast, b – 15 min, c – 30 min, d
– 45 min, e – 90 min, and f – 120 min after the injection of Gd-DTPA at a dose of 0.2 mmol-Gd/kg.
 W. Zhang et al. / European Journal of Radiology 79 (2011) 369–374
Fig. 5. Representative graph of tumor rim signal intensity (SI) after the injection of
each contrast agent at a dose of 0.2 mmol-Gd/kg and measured over the time points
for the two groups.
glucose and can be transported by Glut-l to Glut-4, at that
time the increased metabolic needs of the tumor cells cause
increased uptake of these analogs. These analogs block the catalytic
activity of hexose phosphate isomerase to transform d-glucose-
6-phosphate into 1,6 diphosphate. This blockade in the pathway
causes an inability for further metabolism and thus remains in
the cell. Yang et al. [14,15] have generated a glucose deriva-
tive Ethylenedicysteine-deoxyglucose (EC-DG) and found that it is
involved in cell proliferation and growth activities. This continued
involvement in the cell-cycle pathway would allow for contin-
uous post-treatment follow-ups since glucosamine and glucose
share the same pathway(s). Whereas glucose may only share 4%
of the hexosamine biosynthetic pathway, glucosamine is possi-
bly sharing upwards of 96% of glycolytic/TCA and the hexosamine
pathways.
Similarly, Chen et al. [16–19] have generated a glucose deriva-
tive through linking the –COOH group of DTPA to the amino group
of glucosamine. This reaction produced DTPA-DG (diethylenetri-
amine pentaacetic acid-deoxyglucose). Labeling of DTPA-DG with
99m Tc could reach 99.2% involvement in the glycolytic/TCA path-
way. After a series of studies, they found that 99m Tc-DTPA-DG
participates in a variety of tumor cell proliferation mechanisms:
it can reflect the activity in the nucleus; it can be used for early
detection of tumor lesions and also be used to evaluate the efficacy
of chemotherapy. Given the results of the Chen study, we decided
to chelate Gd2 O3 with DTPA-DG, thereby synthesizing Gd-DTPA-
DG. Catalytic amination is one of the most promising methods to
build the C-N key for which a high degree of regional selectivity and
high enantioselectivity exist. There is very important academic sig-
nificance in the synthesis of some of these natural products and
other organic compounds which have biological activity. In this
study, we use a simple catalyst to activate functional nitrogen trans-
fer reactions leading to highly regioselective and efficient direct
introduction of nitrogen bonding on the deoxy-glucose SP2 C-H
position. Gd2 O3 is easy to generate as compared to other tradi-
tional synthesis methods, thus making it a relatively inexpensive
product.
This contrast agent has similar biological characteristics and
molecular structure to 99m Tc-DTPA-DG. In our present study using
a human lung adenocarcinoma xenograft model, we found the
contrast performance after a bolus injection of Gd-DTPA-DG was
greatly enhanced. Gd-DTPA-DG also has a longer retention time
than the more conventional imaging agent Gd-DTPA in tumor tis-
sue. Additionally, the tumor tissue was more visible from the edge
to the center after injection with the Gd-DTPA-DG contrast agent.
373
Noting that contrast agents may easily escape from leaky blood
vessels and infiltrate into the extravascular regions; may lead to
incorporation via glucose transporter into other high metabolically
active cells.
5. Conclusions
We have designed, synthesized, and tested a novel functional
d-glucosamine based contrast agent for MR molecular imaging.
Through MR imaging in vitro and using a human lung carci-
noma xenograft animal model in vivo, the agent yielded excellent
T1 and visual enhancement of the tumor. The imaging of can-
cer structures remained enhanced for 2 h after administration of
Gd-DTPA-DG. Compared to the conventional contrast agent, Gd-
DTPA, Gd-DTPA-DG has a longer retention time in tumor tissue
and better reflects the increased level of tumor cell metabolism
as compared to normal tissues. The use of Gd-DTPA-DG may
allow for early monitoring of primary tumors, discovery of tumor
metastasis, and offers great promise in the discovery of tumor
recurrence.
Conflict of interest statement
There is no any conflict of interest.
Acknowledgements
The authors would like to thank the National Natural Science
Foundation of China for funding this work, 30970858. We are also
grateful to Dr. Ling He for the synthesis of Gd-DTPA-DG and Dr.
Da-Jing Guo for his technical support in Magnetic resonance imag-
ing.
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