Radiosynthesis and in vitro evaluation of 1-(tetrahydro-5-hydroxy-6- (hydroxymethyl)-2H-pyran-3-yl)-5-[125I]iodouracil: A new potential agent for HSV1-tk reporter gene monitoring

Article abstract of DOI:10.1002/jlcr.1819

Synthesis, radiolabelling, and in vitro evaluation of a new ¹²⁵I-labelled iodouracil hexitol nucleoside analogue are reported. The target compound was successfully synthesized by an iodination-destannylation method and then purified by reverse

Full text of DOI:10.1002/jlcr.1819

Research Article
Received 19 January 2010,
Revised 4 July 2010,
Accepted 6 July 2010
Published online 16 September 2010 in Wiley Online Library
(
wileyonlinelibrary.com) DOI: 10.1002/jlcr.1819
Radiosynthesis and in vitro evaluation of
1
2
-(tetrahydro-5-hydroxy-6-(hydroxymethyl)-
H-pyran-3-yl)-5-[ I]iodouracil: A new
1
25
potential agent for HSV1-tk reporter gene
monitoring
a
Nam Hyun Jo, Jung Young Kim, Mohammed I. El-Gamal, Won-Kyoung
c
a,b
a
Choi, Jin-Hun Park, Eun Jung Kim, Jung-Hyuck Cho, Hyun-Joon Ha,
Tae Hyun Choi, and Chang-Hyun Oh
a
c
a
d
cy
a,b
Ã
1
25
Synthesis, radiolabelling, and in vitro evaluation of a new
The target compound was successfully synthesized by an iodination–destannylation method and then purified by reverse
I-labelled iodouracil hexitol nucleoside analogue are reported.
phase HPLC. The radiochemical purity of the product was 499% with decay-corrected yields of 4873%. In vitro cellular
uptake testing was carried out using MCA and MCA-tk cell lines for comparison of compound 1 with [ F]FHBG. The newly
1
8
synthesized compound 1 showed higher accumulation in herpex simplex virus type 1 thymidine kinase (HSV1-tk) gene
expression cell line (MCA-tk cell line) than in the wild type MCA cell line compared with [ F]FHBG. The MCA-tk to MCA
1
8
1
8
cellular uptake ratio for compound 1 was higher than that of [ F]FHBG from 2 h after incubation. The radioiodine-labelled
compound 1 (I-125, t1/2 = 59.37 days) has a longer physical half-life than F-18-(t1/2 = 110 min) labelled FHBG. Radioiodine-
labelled compound 1 could be used for monitoring gene expression for a long time. The selectivity for MCA-tk cell line
makes compound 1 a promising imaging agent for HSV1-tk expression.
Keywords: HSV1-tk; nucleoside; hexitol; iodouracil; MCA-tk; MCA; iodine-125; imaging agents
Introduction
In previous studies, it was found that pyrimidine nucleoside
0
0
analogues, such as radioiodine-labelled 1-(2 -fluoro-2 -deoxy-D-
arabinofuranosyl)-5-iodouracil (FIAU), showed better uptake
Gene therapy is a technique that is developing rapidly for the
1
8
treatment of a number of different cancers. Among the various than purine analogues, such as 9-(4-[ F]-fluoro-3-hydroxy-
1
8
gene therapy approaches, the prodrug strategy is the most methylbutyl)guanine ([ F]FHBG), for HSV1-tk gene expression
1
popular. This strategy involves the delivery of a suicide gene (or
14,15
imaging.
Various radiolabelled nucleoside analogues with
reporter gene) to the target cells and administering prodrugs.
The suicide gene encodes novel nonmammalian enzymes, such
as herpes simplex virus type-1 thymidine kinase (HSV1-tk), that
a
Biomaterials Center, Korea Institute of Science and Technology, P.O. Box 131,
can convert a relatively nontoxic prodrug (e.g. ganciclovir) into a Cheongryang, Seoul 130-650, Republic of Korea
2
highly toxic agent. Optimization of the therapeutic effect
requires an adequate radiolabelled probe to image the reporter
gene. Thus, these probes are of high interest in the fields of
b
Department of Biomolecular Science, University of Science and Technology, 113
Gwahangno, Yuseong-gu, Daejeon 305-333, Republic of Korea
c
Molecular Imaging Research Center, Korea Institute of Radiological and Medical
Sciences, Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea
3
radiopharmaceuticals and nuclear medicine.
HSV1-tk is a multifunctional protein that can phosphorylate
d
4
–6
Department of Chemistry, Hankuk University of Foreign Studies, Yongin,
Kyunggi-Do 449-791, Republic of Korea
pyrimidine and purine nucleoside analogues.
human cellular thymidine kinase, because of restricted changes
In contrast,
4
,5
in the sugar moiety, has a higher specificity, phosphorylating *Correspondence to: Chang-Hyun Oh, Biomaterials Center, Korea Institute of
Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650, Republic of
Korea.
higher activity with unnatural nucleoside analogues at the first
E-mail: choh@kist.re.kr
only pyrimidine substrate analogues. Generally, HSV1-tk exhibits
two steps of phosphorylation than the cellular kinase, which is
7
–9
yCorrespondence to: Tae Hyun Choi, Radiopharmaceutical Research Team,
Korea Institute of Radiological and Medical Sciences, 215-4, Gongneung-dong,
Nowon-gu, Seoul 139-706, Republic of Korea.
stimulated at the final step.
molecular imaging has become a standard in various molecular
The reporter gene concept for
1
0–13
biology protocols using the HSV1-tk gene.
E-mail: thchoi@kirams.re.kr
J. Label Compd. Radiopharm 2011, 54 93–97
Copyright r 2010 John Wiley & Sons, Ltd.

N. H. Jo et al.
pyrimidine ring have been synthesized and evaluated for HSV1- chromatography (silica gel, hexanes–ethyl acetate 5:1 v/v) to
3
,15–20
tk imaging.
Herein, we report the synthesis and preliminary in vitro
yield compound 3a (0.85 g, 38%).
1
H NMR (300 MHz, CDCl
evaluation of a new [ I]iodouracil hexitol nucleoside analogue 7.50–7.36 (m, 5H), 5.65 (s, 1H), 4.72 (brs, 1H), 4.37 (dd, J = 4.8 and
for use as a potential probe for monitoring of HSV1-tk gene 10.6 Hz, 1H), 4.28–4.21 (m, 1H), 4.04 (dd, J = 3.5 and 14.2 Hz, 1H),
3
): d(ppm): 9.43 (brs, 1H), 8.57 (s, 1H),
1
25
1
expression.
3.80 (t, J = 10.6 Hz, 1H), 3.74–3.68 (m, 1H), 3.57–3.49 (m, 1H),
2
1
.48–2.42 (m, 1H), 2.09–2.02 (m, 1H). C NMR (75 MHz, CDCl3):
3
d(ppm): 161.3, 156.8, 150.5, 147.0, 137.3, 129.3, 128.4, 126.1,
126.0, 102.1, 74.33, 73.5, 68.9, 68.8, 68.7, 52.2, 32.7. LC-MS (ES1):
1
m/z 457.40 (M1H) .
Experimental
Materials
Synthesis of 5-(tributylstannyl)-1-(hexahydro-2-phenylpyra-
no[3,2-d][1,3]dioxin-7-yl)pyrimidine-2,4(1H,3H)-dione (4)
All reagents and solvents were purchased from Aldrich Chemical
Co. and used without further purification. The solid phase
extraction cartridge (Sep-pak, silica) was purchased from Waters A mixture of compound 3a (90 mg, 0.19 mmol), hexabutyltin
Associates (Milford, MA). The QMA cartridge (SPE cartridge (0.22 ml, 0.43 mmol), and bis(triphenylphosphine)palladium
Chromafix 30-PS-HCO ) was purchased from Macherey-Nagel dichloride (7 mg, 9.97 mmol) in anhydrous dioxane (5 ml) was
3
Inc. Thin layer chromatography (TLC) was performed on Merck heated under reflux for 8 h under N
2
. The reaction mixture was
60 F254 silica plates. Radio-TLC was monitored on a Bioscan evaporated under reduced pressure, and the remaining oily
AR-2000 imaging scanner (Washington, DC) and high-perfor- residue was purified by using column chromatography (silica
mance liquid chromatograph (HPLC) was performed on a Waters gel, hexanes–ethyl acetate 3:1 v/v) to yield compound 4
system using a 515 pump, 2487 UV detector (254 nm), and (54.2 mg, 52%).
1
Raytest GABI g-detector using a semi-preparative C18 reverse
3
H NMR (300 MHz, CDCl ): d(ppm): 8.09 (s, 1H), 7.61–7.37
phase column (7.9 ꢀ 250 mm, deltapack; Waters). HPLC grade (m, 5H), 5.55 (s, 1H), 4.76–4.70 (m, 1H), 4.39–4.35 (m, 1H),
solvents were used for chromatography. Sodium [ I]iodide 4.22–4.20 (m, 1H), 4.06–4.01 (m, 1H), 3.74–3.67 (m, 2H), 3.64–3.46
1
25
solution was produced by PerkinElmer. The radioactivity was (m, 1H), 2.43–2.36 (m, 1H), 2.22–1.96 (m, 1H), 1.39–1.12 (m, 12H),
3
1
measured with a dose calibrator (Capintec). The MCA-RH7777 1.12–1.06 (m, 6H), 0.92 (t, J = 10.6 Hz, 9H). C NMR (75 MHz,
MCA, CRL1601) rat hepatoma cell line was purchased from CDCl ): d(ppm): 160.5, 156.8, 146.5, 137.0, 131.0, 130.6, 129.3,
the American Type Culture Collection (ATCC, Rockville, MD). 128.4, 126.0, 102.1, 74.0, 73.2, 68.4, 68.3, 67.9, 52.0, 32.6, 27.8,
(
3
1
Thymidine kinase transduced MCA cell line (MCA-tk) was derived 27.4, 13.8, 9.9. LC-MS (ES1): m/z 620.82 (M1H) .
from HSV1-tk expressing cells using a retroviral vector. It was
Iodine-125 labelling method
kindly provided by Dr Kwon, the Molecular Oncology Laboratory
of Korea Institute of Radiological and Medical Sciences (KIRAMS).
A solution of compound 4 (1 mg, 1.6 mmol) in ethanol (50 ml) was
1
8
[
illustrated by Alauddin and Conti.
F]FHBG was prepared according to the literature method
2
125
added to sodium [ I]iodide solution (100 mCi/10 ml) at pHꢁ4–5,
1
2 2
adjusted with 3% H O (50 ml) and 1 M HCl (1 ml), in a 5-ml
volume reaction vial. The mixture was kept at room temperature
for 30 min. After adding 80% acetic acid (300 ml), the reaction vial
was sealed and placed in a heating block at 801C for 10 min. The
Synthesis of 1-(hexahydro-2-phenylpyrano[3,2-d][1,3]diox-
in-7-yl)-5-iodopyrimidine-2,4-(1H,3H)-dione (3a)
2
2
A suspension of the sodium salt of 5-iodouracil (2.60 g, 10 mmol) reaction vial cover was slowly opened, and the mixture was
and 2 (1.95 g, 5 mmol) in dry DMF (80 ml) was heated at 1001C added to CH CN (300 ml) and then dried at 80–1001C under
3
for 20 h under N . The reaction mixture was evaporated under supplying nitrogen gas for 20 min. The mixture was washed with
2
reduced pressure. The residue was dissolved in ethyl acetate and 10% ethanol, and then purified by reverse phase HPLC using a
the resulting solution was washed with aqueous NaHCO
3 ꢀ 50 ml). The organic layer was separated and the aqueous including installed g-radioactivity detector with 5% EtOH/H
3
semi-preparative C18 column (7.9 ꢀ 250 mm, deltapack; Waters)
O at
(
2
layer was extracted with ethyl acetate (3 ꢀ 20 ml). The combined a flow rate of 2.0 ml/min. The product (average 48 mCi,
organic layer extracts were washed with brine and dried over compound 1) was collected at 10.9–12.3 min (Figure 2) with
Na SO
2 4
. The organic solvent was evaporated under reduced radiochemical yield of 4873%. The product was added to
pressure and the residue was purified by using flash column ascorbic acid (1 mg). The radiochemical purity determined by
Figure 1. Synthesis of the target compound 1.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 93–97

N. H. Jo et al.
1
25
Figure 2. HPLC chromatograms of purified
I-labelled compound 1 by g-radioactivity detector (A) and ascorbic acid (additive for radioprotection) at 254 nm by UV
O = 5:95 (v/v), flow rate: 2.0 ml/min, retention time of compound 1: 10.9–12.3 min).
detector (B) (Waters; deltapack RP-18, 10 m, 7.9 ꢀ 250 mm, EtOH/H
2
125
Figure 3. HPLC chromatograms of co-injection of purified
I-labelled compound 1 (A; g-radioactivity detector) and standard compound (B; UV detector). (Waters;
deltapack RP-18, 10 m, 7.9 ꢀ 250 mm, EtOH/H O = 5:95 (v/v), flow rate: 2.0 ml/min, retention time: 10.9–12.3 min).
2
radio-TLC scanner was 499%. The purified product 1 was
confirmed by reverse phase HPLC by co-injection with the
standard compound (Figure 3).
Cellular uptake test
5
MCA and MCA-tk cells were grown to 5 ꢀ 10 cells/well in six-
well culture plates and incubated at 371C for 24 h. Compound 1
was added to each well (1 mCi/2 ml) and the mixture was
Cell lines and cultures
2
incubated for 0.5, 1, 2, 4, and 8 h at 371C in 5% CO atmosphere.
1
8
MCA and MCA-tk cells were grown in Dulbecco’s Modified Eagle’s Accordingly, [ F]FHBG was added to each well (20 mCi/2 ml)
medium (DMEM; Welgene, Seoul, Republic of Korea), supple- and the mixture was incubated for 0.5, 1, and 2 h at the
mented with 20% horse serum (Gibco, Carlsbad, CA), 5% fetal same conditions. After that, the media were removed, the
bovine serum (FBS; JHR Biosciences, Lenexa, KS), and 1% cells were rinsed with Dulbecco’s phosphate-buffered saline
penicillin–streptomycin (Gibco, Carlsbad, CA). The medium was (DPBS), and the adherent cells were harvested. Finally, the
changed twice or three times per week. The cells were cultured at radioactivity was determined by using gamma counter. Tripli-
2
371C in a 5% CO atmosphere. The MCA-tk cell line was selected cate cellular uptake assay at each time point was performed
in the presence of G418 (600mg/ml; Gibco, Carlsbad, CA).
Figure 4.
J. Label Compd. Radiopharm 2011, 54 93–97
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

N. H. Jo et al.
increasing through 2 h (Table 2). On the other hand, no
significant increase in the uptake of compound 1 in MCA cell
line after 1, 2, and 4 h (Table 1). This limited cellular uptake of
compound 1 into MCA may contribute to its increased
selectivity to HSV1-tk gene expression cell line (MCA-tk).
Results and discussion
Chemistry
Synthesis of the target compound 1 was achieved according to
the sequence illustrated in Figure 1. Hexahyrdo-2-phenylpyr-
ano[3,2-d][1,3]dioxin-7-yl p-toluenesulfonate (2) was synthesized
18
MCA-tk/MCA uptake ratios of compound 1 and [ F]FHBG at
different testing times are summarized in Table 3. In case of
2
3
according to a previously described seven-steps procedure.
-(Hexahydro-2-phenylpyrano[3,2-d][1,3]dioxin-7-yl)-5-iodopyri-
midine-2,4-(1H,3H)-dione (3a) was prepared by heating the tosyl
18
[
F]FHBG, this ratio was high at 0.5 and 1 h (7.47 and 8.44,
1
respectively) then suddenly decreased at 2 h to reach 3.77. This
sudden decrease may be attributed to the relatively short half-
life of fluorine-18 (t1/2 = 110 min) compared with that of iodine-
125. However, the MCA-tk/MCA uptake ratio in case of
compound 1 was continuously increasing through the whole
2
2
compound 2 with sodium salt of 5-iodouracil in dry DMF.
The iodine atom of 3a was replaced by a tributyl–stannyl
group by refluxing with hexabutylditin in the presence of a
palladium catalyst, Pd(PPh
derivative 4. Labelling with I-125 was carried out using sodium
3 2 2
) Cl , to afford the tributyl–stannyl
testing period to reach 11.63 at 8 h. In addition, the MCA-tk/MCA
ratio of the newly synthesized hexitol compound 1 at 2 h was
1
[
25
I]iodide in the presence of hydrogen peroxide at pHꢁ4–5
18
.56, 1.5 times higher than that of [ F]FHBG.
5
inside a reactor. The benzylidene-protected compound 3b was
deprotected by heating with 80% acetic acid to give the target
hexitol product 1.
18
[
F]FHBG is a purine type nucleoside. However, compound 1
contains an iodouracil base. The size of iodouracil is nearly
similar to purine but the iodine group is not charged and its
polarity is very low. According to the literature, the pyrimidine
nucleoside analogues have shown better cellular uptake
Purification by HPLC
than purine types nucleosides for HSV1-tk gene expression
14,15
The product was purified by reverse phase HPLC using 5%
EtOH/H O as a mobile phase system to yield the target
I-labelled compound 1 with radiochemical purity 499%
and decay-corrected yields of 4873%.
imaging.
base for HSV1-tk gene imaging probe.
One can conclude that iodouracil base is a good
2
1
25
125
According to the in vitro cellular uptake data, the I-labelled
iodouracil compound 1 demonstrated higher selectivity for
HSV1-tk gene expression cell line (MCA-tk) over the wild type
In vitro cellular uptake testing
18
MCA, compared with [ F]FHBG. This selectivity for MCA-tk
The cellular uptake profile of the hexitol compound 1 was
1
8
compared with that of [ F]FHBG using the same cell lines, MCA
and MCA-tk. Upon comparing the cellular uptake of both
compounds in MCA cell line, we find that the uptake of
1
8
Table 2. In vitro cellular uptake of [ F]FHBG (20 mCi) in
MCA and MCA-tk cell lines
1
8
[
F]FHBG into MCA and MCA-tk cell lines was continuously
Time (h)
0.5
1
2
MCA
MCA-tk
0.1770.02
1.2770.04
0.3270.01
2.770.37
1.6370.27
6.1470.14
1
Values are expressed as mean of the %ID of [ F]FHBG
8
1
8
cellular uptake. %ID is the %injected dose of [ F]FHBG into
the wells of MCA and MCA-tk cell lines.
Table 3. Comparison of MCA-tk/MCA uptake ratio
MCA-tk/MCA uptake ratio
18
[ F]FHBG
Time (h)
Hexitol compound 1
0
1
2
4
8
.5
1.75
2.29
5.56
5.82
7.47
8.44
3.77
—
Figure 4. Results of cellular uptake of compound 1 in MCA (HSV1-tk negative) and
MCA-tk (HSV1-tk positive) cell lines. Cells were incubated with 2 ml of incubation
medium containing 1 mCi of compound 1. The uptake is expressed as mean
11.63
—
%
injected dose7standard error of mean (n = 3).
Table 1. In vitro cellular uptake of compound 1 (1 mCi) in MCA and MCA-tk cell lines
Time (h)
0.5
1
2
4
8
MCA
MCA-tk
0.0870.01
0.1470.01
0.1770.02
0.3970.01
0.1670.13
0.8970.01
0.2270.03
1.2870.05
0.2770.01
3.1470.12
125
Values are expressed as mean of the %ID of compound 1 cellular uptake. %ID is the %injected dose of [ I]hexitol compound 1
into the wells of MCA and MCA-tk cell lines.
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J. Label Compd. Radiopharm 2011, 54 93–97

N. H. Jo et al.
makes compound 1 a promising imaging agent for HSV1-tk
expression.
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A novel
I-labelled iodouracil hexitol nucleoside analogue 1
[
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was successfully synthesized by an iodination–destannylation
method and was then purified by using reverse phase HPLC. The
radiochemical purity of the product was 499% with decay-
corrected yields of 4873%. In vitro cellular uptake testing was
carried out using MCA and MCA-tk cell lines for comparison of
compound 1 with [ F]FHBG. The newly synthesized compound
demonstrated higher accumulation in MCA-tk cell line than in
the wild-type MCA cell line from 2 h after incubation compared
with [ F]FHBG. The longer physical half-life of the radioiodine-
labelled compound 1 (I-125, t1/2 = 59.37 days) than F-18
t1/2 = 110 min) labelled FHBG may enable compound 1 to be
used for monitoring gene expression for a long time. In addition,
the selectivity for MCA-tk cell line makes compound 1 a
promising imaging agent for HSV1-tk expression.
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[
This work was supported by the Seoul Research and Business
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J. Label Compd. Radiopharm 2011, 54 93–97
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org