Synthesis and preliminary evaluation of 1-[18F]Fluoro-1-deoxy-2, 5-anhydro-D-mannitol as a PET radiotracer for breast cancer imaging

Article abstract of DOI:10.1002/cjoc.201300489

1-[¹⁸F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol (3, ¹⁸F-FDAM) has been synthesized in 6 steps starting from 2,5-anhydro-D-mannitol (2,5-AM) and evaluated as a new radiotracer for PET imaging of MCF-7 breast tumor. The result of PET imag

Full text of DOI:10.1002/cjoc.201300489

FULL PAPER
DOI: 10.1002/cjoc.201300489
Synthesis and Preliminary Evaluation of
1-[18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol as a PET
Radiotracer for Breast Cancer Imaging
Ben Niu,a,b Xiaoan Wen,a,b Zhijun Jia,c Xiaoming Wu,a,b Wanhua Guo,*,c and Hongbin Sun*,a,b
a Center of Drug Discovery, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 21009, China
c Department of Nuclear Medicine, the Affiliated Drum Tower Hospital of Nanjing University, Nanjing, Jiangsu
210008, China
1-[18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol (3, 18F-FDAM) has been synthesized in 6 steps starting from
2,5-anhydro-D-mannitol (2,5-AM) and evaluated as a new radiotracer for PET imaging of MCF-7 breast tumor. The
result of PET imaging study showed that 3 displayed a slightly higher uptake by breast tumor in comparison with
the normal breast tissue, implying the possibility of development of PET radiotracers based on targeting fructose
transporters.
Keywords PET imaging, radiotracer, 18F-FDAM, fructose transporter, breast cancer
Introduction
Scheme 1
HO
Positron emission tomography (PET) is a nuclear
medical imaging technique to produce an image of
functional processes in the body. The most common
type of PET scan in standard medical care is the use of
2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG, Scheme 1)
as the positron-emitting radionuclide (radiotracer). Like
normal glucose, 18F-FDG is taken up into cells and sub-
sequently converted to 18F-FDG-6-phosphate by hexo-
kinase. Due to lack of 2-hydroxyl group, the 18F-FDG-
6-phosphate can not be further metabolized in cells and
thus can not move out of the cells before radioactive
decay. As a result, the distribution of 18F-FDG can well
reflect the state of glucose uptake and phosphorylation
by cells in the body. Therefore, 18F-FDG PET imaging
can be used for assessment of the glucose metabolism in
the heart, lungs and brain, and for diagnosis, staging and
monitoring treatment of cancers.[1a] Other PET radio-
tracers ever discovered include 3-[18F]fluoro-3-deoxy-
glucose and 3-O-[11C]methylglucose.[1b]
OH
HO
OH
HO
O
OH
OH
O
O
OH
OH
OH
OH
OH
OH
18F
18F-FDG
2,5-AM
β-D-fructose
OH
O
OH
OH
HO
F
HO
OH
18F
OH
O
O
18F
OH
OH
OH
OH
1
2
3
tification of new radiotracers is highly desirable. Herein,
we describe our efforts in discovery of novel radio-
tracers for breast cancer imaging.
Our efforts were focused on targeting fructose
transporters. Presumably, except for glucose, fructose
may also play a pivotal role in energy metabolism of
some tumors as evidenced by the fact that glucose
transporters GLUT-2 (a fructose/glucose transporter)
and GLUT-5 (a fructose transporter) were extensively
expressed in malignant human tissues.[4] Especially, the
breast carcinoma cell line MCF-7 was found to possess
high amounts of GLUT-5 mRNA and protein, and ex-
hibit high rate of fructose transportation. In contrast,
GLUT-5 was poorly expressed in normal mammary
epithelial cells.[5] In this regard, GLUT-5 may represent
a promising target for diagnosis and treatment of breast
Regardless of its widespread use, 18F-FDG is not a
flawless PET radiotracer. For example, there is lack of
sensitivity and specificity for diagnosis of certain can-
cers with low capacity of glucose transportation.[2] Par-
ticularly, in the case of PET-CT (positron emission to-
mography-computed tomography) for breast cancer
imaging, a significant rate of false-negative results was
observed with 18F-FDG as the radiotracer.[3] Thus, iden-
*
E-mail: hbsun2000@yahoo.com, wanhuaguo@163.com; Tel.: 0086-25-83271198; Fax: 0086-25-83271198
Received June 20, 2013; accepted September 3, 2013; published online September 16, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201300489 or from the author.
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Niu et al.
FULL PAPER
cancer. Indeed, we were delighted to find several reports
witnessing this possibility. Some antisense oligonucleo-
tides against GLUT-5 were reported to exert antiprolif-
erative effect on breast tumor cell lines.[6] Fructose de-
rivatives, e.g. 1-[18F]fluoro-1-deoxy-D-fructose (1,
Scheme 1) and 6-fluoro-6-deoxy-D-fructose (2, Scheme
1), were designed as alternative radiotracers, because
they may be specifically transported by GLUT-5.[7,8]
Nevertheless, both 1 and 2 have obvious drawback since
in solution, they exist as an inseparable mixture of α/β
anomers, resulting in complexity for further research
and product development.
On the other hand, 2,5-anhydro-D-mannitol (2,5-AM,
Scheme 1) attracted our interest in labeling it with 18F
for breast cancer imaging. 2,5-AM is a fructose deriva-
tive with locked anomeric configuration. It is a substrate
of GLUT-5, with affinity for GLUT-5 (ki＝12.6 mmol/L)
similar to β-D-fructofuranose (ki ＝ 15.5 mmol/L).[9]
Moreover, 2,5-AM could be metabolized to its mono-
and di-phosphate esters by fructokinase and hexo-
kinase.[10,11] It was even able to down regulate the level
of fructose-2,6-bisphosphate via inhibition of phos-
phofructokinase-2 (PFK-2).[12] More importantly, a
SAR (structure-activity relationship) study showed that
when the 6-OH (or 1-OH) of 2,5-AM was replaced by a
secondary amine group (NH), the affinity for GLUT-5
was greatly enhanced to be 10-fold over D-fructose,[13]
indicating that this hydroxyl group seems not essential
for binding to GLUT-5. In the above regards, 2,5-AM
might be a promising lead compound for development
of PET radiotracers targeting GLUT-5. Its 6-OH is
probably a proper handle for further modifications. With
this in mind, we designed and synthesized 18F-FDAM (3,
Scheme 1), namely 1-[18F]fluoro-1-deoxy-2,5-anhydro-
D-mannitol. To further test it as a radiotracer, 3 was
evaluated for PET imaging of MCF-7 breast tumor in
rabbit.
with dry pyridine (30 mL×3), was dissolved in dry
pyridine (150 mL). To the solution were added triphe-
nylmethyl chloride (25.5 g, 91.5 mmol) and a catalytic
amount of 4-dimethylaminopyridine (200 mg). After the
solution was stirred at 45 ℃ for 72 h, methanol (10 mL)
was added. The solution was stirred for 30 min at room
temperature and then the solvents were evaporated off
under reduced pressure. The residue was then dissolved
in AcOEt (600 mL), washed with ice-cold H2SO4 aque-
ous solution (1 mol/L) and water, dried over MgSO4,
filtered, and concentrated. The syrupy residue was puri-
fied by column chromatography over silica gel with
hexane/AcOEt (2∶1 to 1∶4, V/V) as the eluent to give
compound 5 as a colorless amorphous material (9.8 g,
1
40%). H NMR spectral data were identical to those
reported in the literature.[16]
2,5-Anhydro-3,4,6-tri-O-benzoyl-1-O-trityl-D-
mannitol (6) To a solution of 5 (2.0 g, 4.9 mmol) in
dry pyridine at 0 ℃ in ice-water bath was dropwise
added BzCl (2.0 mL, 17.6 mmol ). After addition, the
reaction mixture was warmed to room temperature and
stirred overnight. The reaction mixture was quenched
with water and evaporated to dryness. The residue was
purified by column chromatography over silica gel with
hexane/AcOEt (10∶1, V∶V) as the eluent to give
compound 6 as a white solid (3.1 g, 89%). M.p. 65－68
1
℃. H NMR (CDCl3, 300 MHz) δ: 3.35－3.45 (m, 1H,
1-CH2), 3.47－3.68 (m, 1H, 1-CH2), 3.89－3.91 (m, 1H,
C-2-H), 4.31－4.48 (m, 1H, C-5-H), 4.54－4.62 (m, 2H,
6-CH2), 5.61－5.76 (m, 2H, C-3-H and C-4-H), 7.14－
8.01 (m, 30H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ:
166.2, 166.0, 165.7, 146.9, 144.6, 143.8, 133.64, 133.60,
133.1, 129.9, 129.8, 128.8, 128.7, 128.59, 128.56, 128.4,
127.94, 127.91, 127.85, 127.7, 127.2, 126.8, 84.1, 81.4,
79.6, 78.9, 64.0, 62.3. ESI-MS m/z: 741.1 [M＋Na]＋.
2,5-Anhydro-3,4,6-tri-O-benzoy-D-mannitol (7)
The suspension of compound 6 (3.0 g, 4.2 mmol) in
80% AcOH (10 mL) was stirred at 45 ℃ until TLC
showed complete hydrolysis (ca. 6 h). The mixture was
concentrated, neutralized by saturated NaHCO3 aqueous
solution and extracted with AcOEt. The organic layer
was washed with H2O and brine, dried over MgSO4,
filtered, and concentrated. The syrupy residue was puri-
fied by column chromatography over silica gel with
hexane/AcOEt (4∶1, V∶V) as the eluent to yield
compound 7 as a white solid (1.7 g, 83%). M.p. 123－
Experimental
Chemistry
General Melting points were determined with a
1
Büchi capillary apparatus and were not corrected. H,
13C and 19F NMR spectra were recorded on an ACF*
300Q Bruker spectrometer in CDCl3, with TMS as the
internal reference, or in D2O. Mass spectra (ESI) and
high resolution mass spectra (HRMS) were recorded on
a MA1212 instrument under standard conditions. Reac-
tions were monitored by TLC on Silica Gel 60 F254
(Qindao Ocean Chemical Company, China) plates ex-
posed to H2SO4 (10% in EtOH) spray followed by char-
ring (≈50 ℃ ). Column chromatography was per-
formed with Silica Gel Geduran Si 60 (Qindao Ocean
Chemical Company, China). Unless noted, commer-
cially purchased reagents (chemicals) were directly used
without further treatment.
1
125 ℃. H NMR (CDCl3, 300 MHz) δ: 2.22 (br, 1H,
OH), 3.96－3.98 (m, 2H, 1-CH2), 4.39－4.43 (q, J＝4.7
and 8.9 Hz, 1H, C-2-H), 4.61－4.75 (m, 3H, C-2-H and
6-CH2), 4.31－4.48 (m, 1H, C-5-H), 5.67－5.70 (q, J＝
2.8 and 4.7 Hz, 1H, C-3-H), 5.76－5.78 (m, 1H, C-4-H),
7.35－8.10 (m, 15H, Ar-H); 13C NMR (CDCl3, 75 MHz)
δ: 166.2, 166.0, 165.7, 133.6, 133.59, 133.1, 129.9,
129.8, 129.0, 128.6, 128.5, 128.4, 84.0, 81.4, 79.6, 78.8,
77.4, 77.0, 76.6, 64.0, 62.3. ESI-MS m/z: 477.1 [M＋
H]＋.
2,5-Anhydro-1-O-trityl-D-mannitol (5)
2,5-
2,5-Anhydro-3,4,6-tri-O-benzoyl-1-O-p-tolylsul-
fonyl-D-mannitol (8) To a solution of 7 (2.5 g, 5.3
AM[14,15] (10.0 g, 61.0 mmol), dried by coevaporation
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Chin. J. Chem. 2013, 31, 1159—1163

Synthesis and Preliminary Evaluation of 1-[18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol
mmol) in dry pyridine (20 mL) at 0 ℃ was added tosyl
chloride (4.0 g, 21.2 mmol) in chloroform (40 mL). The
reaction was stirred overnight at room temperature.
Water (1 mL) was added dropwise and the reaction
mixture was stirred for another 10 min, poured into
ice-water and extracted with CH2Cl2. The extract was
washed with ice-cold H2SO4 aqueous solution (1 mol/L)
and water, dried over MgSO4, filtered, and concentrated.
The syrupy residue was purified by column chromatog-
raphy over silica gel with hexanes/AcOEt (8∶1, V∶V)
as the eluent to yield compound 8 as a white solid (2.8 g,
85%). M.p. 95－97 ℃. 1H NMR (CDCl3, 300 MHz) δ:
2.39 (s, 3H, ArCH3), 4.37－4.42 (m, 2H, 6-CH2), 4.46
－4.53 (m, 2H, 1-CH2), 4.56－4.68 (m, 2H, C-2-H and
C-5-H), 5.55－5.57 (m, 1H, C-4-H), 5.68－5.70 (m, 1H,
C-3-H), 7.26－8.10 (m, 19H, Ar-H); 13C NMR (CDCl3,
75 MHz) δ: 165.6, 145.0, 133.7, 133.1, 132.9, 130.0,
129.9, 129.8, 128.8, 128.6, 128.4, 128.1, 82.1, 81.6,
79.2, 79.1, 68.9, 63.8, 21.6. ESI-MS m/z: 653.1 [M＋
Na]＋.
1-[18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol (3)
350 mCi [18F]fluoride was produced by an ultracompact
cyclotron (CYPRIS 325R, Sumitomo Heavy Industry
Ltd) via an 18O(p, n)18F reaction with a 11 MeV proton
beam of 35 μA bombarding the target for 15 min, trans-
ferred in a pneumatic way to the fluorine multifunc-
tional synthesis modules, adsorbed to a strong basic an-
ion exchange resin (Bio-Rad) and eluted with a mixture
of K2CO3 solution (18 mg in 0.5 mL) and Kryptofix 222
acetonitrile solution (4 mg in 1 mL). The solvent of col-
lected eluent was removed azeotropically with anhy-
drous acetonitrile at 120 ℃ under a nitrogen stream to
give [18F]fluoride reagents. To the reaction vessel con-
taining [18F]fluoride reagents was added a solution of
tosylate precursor 8 (24 mg) in acetonitrile (1.5 mL).
The mixture was heated at 95 ℃ for 15 min and then
evaporated to dryness. To the residue of [18F]fluoride 10
was added NaOH solution (0.3 mol/L, 2 mL). The mix-
ture was heated for 7 min at 65 ℃, acidified with 1
mol/L HCl solution (1.5 mL) and passed over anion
exchange AG50, AG11-A8, alumina column and C-18
SepPak. The C-18 SepPak was washed with normal sa-
line to afford 13.5 mL of normal saline solution con-
taining 18F-FDAM (3) with approximately 114－137
mCi [(36±6)% radiochemical yield, ≥95% purity].
2,5-Anhydro-3,4,6-tri-O-benzoyl-1-fluoro-D-man-
nitol (9) To a solution of 8 (600 mg, 0.96 mmol) in
THF (10 mL) was added THF solution of TBAF (1
mol/L, 4 mL). After refluxed for 2 h, the mixture was
evaporated to dryness and extracted with ethyl ether.
The organic layer was concentrated and purified by
column chromatography over silica gel with hexane/
AcOEt (15∶1, V∶V) as the eluent to yield compound 9
Evaluation for breast cancer imaging
Experimental animals 2 Female New Zealand
white rabbits weighing 2.0－2.5 kg were provided by
Nanjing Jinling Breeding Rabbit Farm (Animals certifi-
cate No. SCXK [(Su) 2007-0004]).
1
as a white solid (136 mg, 30%). M.p. 90－93 ℃. H
NMR (CDCl3, 300 MHz) δ: 4.67 － 4.54 (dq, 1H,
C-1-CH2), 4.66－4.73 (m, 4H, C-1-CH2, C-2-H, C-5-H
and C-6-CH2), 4.86－4.88 (m, 1H, C-6-CH2), 5.70－
5.72 (m, 1H, C-3-H), 5.77－5.78 (m, 1H, C-4-H), 7.37
－8.10 (m, 15H, Ar-H); 13C NMR (CDCl3, 75 MHz) δ:
166.2, 165.8, 165.7, 133.7, 133.6, 129.91, 129.90, 129.8,
129.1, 129.0, 128.62, 128.56, 128.4, 84.0, 82.8, 82.6,
81.9, 81.7, 79.2, 78.84, 78.76, 64.0. ESI-MS m/z: 479.1
[M＋H]＋.
Establishment of rabbit MCF-7 breast tumor
model The solution of MCF-7 cells in logarithmic
growth phase was inoculated to the back muscle of a
rabbit hind leg. The rabbit was feeded until the tumor at
the injection site grew up to 1－2 cm in diameter. The
tumor was excised from the rabbit, shreded into pieces
of 1－2 mm under sterile conditions and mixed with
normal saline to form a suspension preparation of tumor
cells for use. The tumor suspension was injected into
breast tissue underneath the left 2nd nipple of a rabbit
anesthetized by intravenous 3% pentobarbital sodium (1
mL/kg) throung ear vein catheters. When the tumor
grew up to 1－2 cm in diameter, PET/CT imaging was
conducted.
PET-CT imaging Imaging was carried out in
PHILIPS Gemini GXL16 PET/CT system. The breast
tumor model rabbit fasting for 6－8 h was anesthetized.
18F-FDAM (3, 1.6－2.0 mCi) was injected through ear
vein catheters. After 30 min, radioactive data collection
began. The bed location was adjusted to make the rabbit
locate in the center of collection field according to the
calibration laser. During data collection, anesthesia was
maintained to ensure no big movement by the rabbit.
The collected imaging data were in three-dimensional
model. The collection program was set as follows: first
16-row CT emission, then transmission. The collected
data were attenuation-corrected, followed by CT-recon-
1-Fluoro-1-deoxy-2,5-anhydro-D-mannitol
(4)
To a solution of 9 (150 mg, 0.31 mmol) in dry methanol
(5 mL) was added freshly prepared methanol solution of
NaOMe (1 mol/L, catalytic amount). After stirred for 24
h at room temperature, the solution was neutralized with
excess Amberlite IR 120 H＋ resin, filtered and washed
with MeOH. The combined filtrate was evaporated to
dryness. The residue was purified by column chroma-
tography over silica gel with CH2Cl2/CH3OH, (6∶1,
V∶V) as the eluent to give fluoride 4 as a colorless
1
solid (40 mg, 68%). [α]2D0 ＝31.9° (c 0.49, H2O). H
NMR (CDCl3, 300 MHz) δ: 3.58－3.64 (dd, J＝5.2 and
12.5 Hz, 1H, C-6-H), 3.68－3.73 (dd, J＝3.1 and 12.5
Hz, 1H, C-6-H), 3.81－3.86 (m, 1H), 3.91－3.95 (m,
1H), 3.98－4.06 (m, 2H), 4.39－4.68 (ddd, J＝1.5, 2.2
and 6.1 Hz, 2H, C-1-H2); 13C NMR (75 MHz, D2O) δ:
86.5, 85.1, 84.3, 83.4, 83.2, 78.7, 78.2, 78.1, 63.6; 19F
NMR (282 MHz, D2O) δ: −154.1 (td, J＝24.4 and 48.4
Hz); ESI-MS m/z: 331.0 [2M−H]−. HRMS calcd for
C6H11FO4: 166.0641, found 166.0642.
Chin. J. Chem. 2013, 31, 1159—1163
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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Niu et al.
FULL PAPER
struction to give transverse, coronal and sagittal images.
of MCF-7 breast tumor in rabbit. The PET-CT images
are shown in Figure 1. Imaging results showed that the
radioactivity was concentrated to some degree in the
tumor-inoculated left anterior chest and slightly higher
than in the normal breast tissues, indicating that 3 could
weakly target breast cancer tissues.
Results and Discussion
Chemistry
For synthesis of 18F-FDAM (3), an approach to its
non-radiolabeled counterpart 4 was first developed. As
shown in Scheme 2, the readily prepared 2,5-AM[14,15]
was selectively protected at 1-hydroxyl group by treat-
ment with trityl chloride in pyridine to afford trityl ester
5. Full benzoylation of 5 gave benzoylate 6, which was
deprotected of trityl group by 80% aqueous acetic acid
at 55 ℃ to provide alcohol 7 without transesterifi-
cation observed. Alcohol 7 was treated with tosyl chlo-
ride at room temperature to give tosylate 8. Upon reac-
tion with TBAF in THF at 65 ℃, tosylate 8 was con-
verted to fluoride 9, which was further treated with
catalytic amount of NaOMe in MeOH to furnish
fluoroanhydromannitol 4.
Scheme 2
Figure 1 (A) PET-CT image of breast tumor in rabbit; (B)
PET-CT image of full body of rabbit.
HO
ref. 14,15
HO
OH
O
OH
OH
O
O
a
HO
HO
OH
OH
OTr
It is not surprising that 3 was highly distributed in
the liver since 3 might be metabolized by fructokinase,
which is rich in the liver. Besides the liver, the kidney
and bladder were also found to have high concentration
of 3, indicating that it was mainly excreted by these two
organs. This finding is identical to the reported excre-
tion pathway of 2,5-AM.[18]
NH2HCl
OH
OH
5
2,5-AM
b
BzO
BzO
d
BzO
OBz
OBz
O
OBz
O
c
O
OTs
OH
OTr
OBz
OBz
OBz
8
7
6
e
g
Conclusions
BzO
HO
OBz
OH
BzO
HO
OBz
O
O
f
O
Radiolabeling 2,5-AM to identify selective radio-
tracers for breast cancer imaging has been proposed. As
the first example, 18F-FDAM (3) has been synthesized
in 6 steps starting from 2,5-AM, and evaluated as a PET
radiotracer for imaging of MCF-7 breast tumor in rabbit.
The imaging results showed that 3 displayed slightly
higher uptake by breast tumor in contrast to normal
breast tissues. Moreover, the metabolic pathway of 3
might be similar to natural fractose or 2,5-AM. Taken
together, further studies based on targeting fructose
transporters to search for novel specific PET radio-
tracers for breast cancer imaging are warranted.
18F
F
F
OBz
OH
OBz
10
9
4
h
OH
O
18F
OH
3
Reagent and conditions: (a) TrCl, pyridine, DMAP, 45 °C; (b) BzCl,
pyridine, r.t., (c) 80% AcOH, 45 °C; (d) TsCl, pyr, CH2Cl2, 0 °C to r.t.;
(e) TBAF, THF, reflux; (f) MeOH, NaOMe, r.t.; (g) [18F]KF, kry222,
K2CO3, CH3CN, 95 °C; (h) 0.3 mol/L NaOH, 65 °C.
18F-FDAM (3) was then synthesized following the
above procedures. Briefly, tosylate 8 was converted to
[18F]fluoride 10 by nocarrier-added (NCA) nucleophilic
substitution reaction with dried [18F]KF in the presence
of Kryptofix and K2CO3 in CH3CN at 95 ℃. Hydroly-
sis of [18F]fluoride 10 with 0.3 mol/L NaOH gave crude
3, which was purified on anion exchange resins AG50
and AG11-A8, followed by alumina and C-18 column
chromatography to afford 18F-FDAM (3).
Acknowledgement
This project was supported by the “111 Project”
from the Minisry of Education of China, the State Ad-
ministration of Foreign Expert Affairs of China (No.
111-2-07), and program for Changjiang Scholars and
Innovative Research Team in University (IRT1193).
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Synthesis and Preliminary Evaluation of 1-[18F]Fluoro-1-deoxy-2,5-anhydro-D-mannitol
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