Synthesis and biological evaluation of technetium-labeled d-glucose-MAG3 derivative as agent for tumor diagnosis

Article abstract of DOI:10.1016/j.bmcl.2009.03.059

A d-glucose-MAG₃ derivative was successfully synthesized and radiolabeled in high labeling yield. Biodistribution studies in Ehrlich tumor-bearing mice were performed. This compound showed high accumulation in tumor tissue with high tumor-to-muscle ratio and moderate tumor-to-blood ratio. Thus, d-glucose-MAG₃ is a potential agent for tumor diagnosis.

Full text of DOI:10.1016/j.bmcl.2009.03.059

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2497–2499
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of technetium-labeled D-glucose-MAG3
derivative as agent for tumor diagnosis
André Luís Branco de Barros, Valbert Nascimento Cardoso, Luciene das Graças Mota, Elaine Amaral Leite,
*
Mônica Cristina de Oliveira, Ricardo José Alves
Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, 31279-901 Belo Horizonte, Minas Gerais, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A
D
-glucose-MAG3 derivative was successfully synthesized and radiolabeled in high labeling yield. Biodis-
Received 10 December 2008
Revised 11 March 2009
Accepted 12 March 2009
Available online 18 March 2009
tribution studies in Ehrlich tumor-bearing mice were performed. This compound showed high accumu-
lation in tumor tissue with high tumor-to-muscle ratio and moderate tumor-to-blood ratio. Thus,
glucose-MAG3 is a potential agent for tumor diagnosis.
D-
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Glucose
Technetium-99m
MAG3
Tumor
Diagnosis agents
Tumor is among the most common causes of death in the world.
Diagnosticians have traditionally been trained to interpret infor-
mation provided by anatomically based imaging techniques. With
the advent of molecular biology-based medicine, a transition is
being made to incorporate into diagnostic interpretation informa-
tion based on biochemical perturbations that exist in the disease.
In vivo functional imaging technique can help to diagnose and
stage tumors, optimize drug scheduling, and predict response to
a therapeutic modality, which would be advantageous to both pa-
tient and oncologist.1,2 In this manner, this method allows for the
viewing of physiopathological process in the initial stages, which
runs contrary to the images conventional methods based on ana-
tomical alterations.3
and evaluated as tumor diagnosis agents.1,11,12 As carbohydrates
are generally weak ligands for chelating with 99mTc, functionaliza-
tion with an external chelating group or the insertion of some
functional groups is essential to obtain strong metal-binding com-
pounds. The mercaptoacetyl triglycine (MAG3) is an efficient com-
plexing agent for 99mTc which has been used as tubular renal
radiotracer.13,14 Its structure has an carboxylic acid that allows
the coupling with some derivatives bearing an amino group.
The purpose of this study was to conjugate
D-glucose with
MAG3 and to evaluate the feasibility of the 99mTc-labeled glucose
derivative as candidate for tumor diagnosis agent.
The D-glucose-MAG3-SBz derivative 6 was synthesized accord-
ing to the procedure outlined in Scheme 1.
The radioactive labeled glucose analogue [18F]-2-fluorodeoxy
glucose ([18F]-FDG) has gained relevance in clinical tumor diagno-
sis in recent years. [18F]-FDG has been used to measure normal tis-
sue and tumor glucose utilization rates.4–7 Although tumor
metabolic imaging with [18F]-FDG has been studied for more than
two decades, the use of this examination in clinical practice is still
limited by such factors as difficult access, limited availability, and
high cost.8
The glucopyranosyl azide 1 was reduced to glucopyranosyl
amine
2 using catalytic hydrogenation. The glucopyranosyl
amine 2 was then reacted with benzoylated MAG3 5, previously
synthesized from 3, using N-(3-dimethylaminopropyl)-N’-ethyl-
carbodiimide (EDAC) as coupling agent to obtain 6. All com-
pounds were characterized by 1H NMR and 13C NMR
spectroscopy. The technetium-99m labeled
D-glucose-MAG3
(
99mTc-MAG3-G) was prepared by ligand-exchange reaction with
Technetium-99m (99mTc) has been mostly used for labeling
radiopharmaceuticals owing to its suitable physical and chemical
characteristics and inexpensive isotope cost.9–11 Some 99mTc-la-
beled D-glucosamine derivatives have been synthesized recently
99mTc-tartarate at pH 6–8. In these conditions the benzoyl pro-
tecting group of 6 is removed.13
After radiolabeling the product was purified by column chroma-
tography on Florisil mesh 60–100, using, first, acetone to remove
TcO4 and next, 0.9% saline to elute the 99mTc-MAG3-G. The radio-
À
labeling yield of 99mTc-MAG3-G was determined by Instant Thin
Layer Chromatograph (ITLC) on two systems: 0.9% saline to
* Corresponding author. Tel.: +55 31 3409 6955; fax: +55 31 3409 6935.
E-mail address: ricardodylan@farmacia.ufmg.br (R.J. Alves).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.059

2498
A. L. B. de Barros et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2497–2499
O
O
H
N
NH
2
HO
N
H
O
3
(b)
OH
O
HO
HO
N
O
O
3
H
H
OH
N
N
1
HO
N
Cl
H
O
O
4
(a)
(c)
OH
O
O
O
O
H
H
HO
HO
N
N
NH
2
HO
(d)
N
S
H
OH
O
O
2
5
OH
O
O
O
H
H
N
HO
HO
N
S
N
N
OH
H
H
O
O
O
6
Scheme 1. Synthesis of D-glucose-MAG3-SBz 6. Reagents and conditions: (a) H2, Pd/C, solvent: methanol, yield: 100%; (b) chloroacetylchloride, solvent: diethylether and
water; (c) thiobenzoic acid, solvent: methanol, yield: 78%; two steps (d) EDAC, solvent: dry DMF, yield: 15%.
determine TcO2 and acetone to determine TcO4À, as published else-
where.15 The radiochemical purity was higher than 90%.
the biodistribution study was performed with 99mTc-MAG3 in the
same time intervals, a tumor-to-muscle ratio of approximately
1.0 was obtained at all times (data not shown). Therefore, the data
of the present study suggest a tropism of 99mTc-MAG3-G to tumor.
Biodistribution of this complex was performed in Ehrlich tu-
mor-bearing Swiss mice (25–30 g) at 5, 30, 120, 240 and 480 min
post injection.16 The results are summarized in Table 1. 99mTc-
MAG3-G was excreted rapidly through kidneys and presented
low heart uptake. It had high tumor-to-muscle (T/M) ratio that in-
creased up to 480 min post injection. The results showed also fast
blood clearance with moderate tumor-to-blood (T/B) ratio. When
In summary, the D-glucose-MAG3 derivative 6 was synthesized
and labeled with technetium-99m successfully. It presented high
tumor-to-muscle ratio in Ehrlich tumor-bearing mice. Biodistribu-
tion results showed the feasibility of 99mTc-MAG3-G as a functional
agent for tumor diagnosis. Further studies will be carried out to
evaluate the real potential of 6 for tumor diagnosis and will be re-
ported in due course.
Table 1
Biodistribution of 99mTc-MAG3-G in Ehrlich tumor-bearing mice (%ID/g)a
Acknowledgements
Tissue
5 min
30 min
120 min
240 min
480 min
We thank CNPq, CAPES and FAPEMIG for grant and fellowships.
References and notes
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a
All data are the mean percentage (n = 5) of the injected dose of 99mTc-MAG3-G
per gram of wet tissue, standard deviation of the mean.

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