No-carrier added synthesis of 18F-labelled nucleosides using Stille cross-coupling reactions with 4-[18F]fluoroiodobenzene

Article abstract of DOI:10.1002/jlcr.834

The radiosyntheses of 5-(4′-[¹⁸F]fluorophenyl)-uridine [¹⁸F]-11 and 5-(4′-[¹⁸F]fluorophenyl)-2′- deoxy-uridine [¹⁸F]-12 are described. The 5-(4′-[ ¹⁸F]fluoro-phenyl)-substituted nucleosides were prepared via a Stille cross-coupling reaction with 4-[¹⁸F]fluoroiodobenzene followed by basic hydrolysis using 1M potassium hydroxide. The Stille cross-coupling reaction was optimized by screening various palladium complexes, additives and solvents. By using optimized labelling conditions (Pd₂(dba) ₃/CuI/AsPh₃ in DMF/dioxane (1:1), 20min at 65°C), 550MBq of [4-¹⁸F]fluoroiodobenzene could be converted into 120MBq (33%, decay-corrected) of 5-(4′-[¹⁸F]fluorophenyl)-2′- deoxy-uridine [¹⁸F]-12 within 40min, including HPLC purification.

Full text of DOI:10.1002/jlcr.834

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2004; 47: 457–468.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.834
Research Article
1
8
No-carrier added synthesis of F-labelled nucleosides
using Stille cross-coupling reactions with
1
8
4
-[ F]fluoroiodobenzene
Frank R. W u. st* and Torsten Kniess
Institut f u. r Bioanorganische und Radiopharmazeutische Chemie, FZ-Rossendorf e.V.,
Dresden, Germany
Summary
0
18
The radiosyntheses of 5-(4 -[ F]fluorophenyl)-uridine [ F]-11 and 5-(4 -[ F]fluor-
18
0
18
0
18
ophenyl)-2 -deoxy-uridine [ F]-12 are described. The 5-(4 -[ F]fluoro-phenyl)-sub-
0
18
stituted nucleosides were prepared via a Stille cross-coupling reaction with
18
-[ F]fluoroiodobenzene followed by basic hydrolysis using 1 M potassium hy-
4
droxide. The Stille cross-coupling reaction was optimized by screening various
palladium complexes, additives and solvents. By using optimized labelling conditions
(
Pd (dba) /CuI/AsPh in DMF/dioxane (1:1), 20 min at 658C), 550 MBq of
2
3
3
1
8
4- F]fluoroiodobenzene could be converted into 120 MBq (33%, decay-corrected)
[
0
18
0
18
of 5-(4 -[ F]fluorophenyl)-2 -deoxy-uridine [ F]-12 within 40 min, including HPLC
purification. Copyright # 2004 John Wiley & Sons, Ltd.
1
Key Words: Stille cross-coupling; 4-[ F]fluoroiodobenzene; nucleosides; uridine
8
Introduction
The radiosyntheses of nucleosides has attracted significant interest over the
last decade due to the central role that nucleosides and their phosphorylated
derivatives play in biological systems. Thus, nucleoside tracers labelled with
11
18
76
124
positron emitters such as C, F, Br and I have extensively been studied
as markers for imaging proliferation of tumour cells, and for monitoring gene
therapy and gene expression by means of positron emission tomography
1
–9
18
(
PET). Most examples of labelled nucleosides for PET have used F as the
18
radiolabel. The introduction of F into the nucleosides has been accomplished
18
either by direct fluorination with [ F]fluoride of the acylochain or furanose
*
Correspondence to: F. W u. st, Institut f u. r Bioinorganic and Radiopharmaceutical Chemistry, FZ-
Rossendorf PF 51 01 19, 01314 Dresden, Germany. E-mail: f.wuest@fz-rossendorf.de
Contract/grant sponsor: Deutsche Forschungsgemeinschaft
Copyright # 2004 John Wiley & Sons, Ltd.
Received 13 November 2003
Revised 19 March 2004
Accepted 10 April 2004

4
58
¨
F. R. WUST AND T. KNIESS
1
0–12
sugar part of the intact nucleoside
radiofluorinated furanose sugar part with a nucleobase.
Transition metal-mediated C–C bond-forming reactions comprise an
or by the combination of the
1
,4
1
3,14
attractive alternative approach for the synthesis of nucleosides.
Such
regioselective C–C bond formations are of great interest because they may
provide a versatile route to various, potentially valuable nucleoside derivatives
exhibiting a structural broad variety. The potential of transition metal-assisted
reactions for the synthesis of nucleosides was recently reviewed by
1
3
14
Agrofoglio and Hocek. In this connection, Samuelsson et al. described
11
0
0
the synthesis of 1-(2 -deoxy-2 -fluoro-b-d-arabinofuranosyl)-[methyl- C]thy-
mine ([ C]FMAU) via a Pd-mediated Stille cross-coupling reaction with
1
1
1
1
15
C]methyl iodide. This work represents the first application of a Pd-
[
11
mediated reaction in the C-labelling of a nucleoside. A former work by Conti
11
et al. has made use of an alkylation reaction with [ C]methyl iodide to
1
6
1
1
synthesize [ C]FMAU.
The Stille reaction has been established in C chemistry as an efficient
1
labelling route for the regioselective introduction of [ C]methyl groups on
1
1
1
1
7,18
aromatic or vinylic substrates under mild reaction conditions.
However,
8
1
there are only a few examples known utilizing a Stille reaction in
1
F
9–21
chemistry.
Recently, we have reported the synthesis of 4-[ F]fluoroiodobenzene and its
1
8
2
use in Sonogashira cross-coupling reactions. Herein, we describe an
2
1
improved method for the synthesis of 4-[ F]fluoroiodobenzene and its
8
0
18
application in Stille-cross coupling reactions to form 5-(4 -[ F]fluorophe-
0
18
nyl)-substituted nucleosides 5-(4 -[ F]fluorophenyl)-uridine [ F]-11 and 5-(4 -
18
0
1
[
8
0
18
F]fluoro-phenyl)-2 -deoxy-uridine [ F]-12.
Results and discussion
Synthesis of labelling precursors and reference compounds
0
0
0
The synthesis of the 5-tributylstannyl-2 ,3 ,5 -triacetyl-uridine 7 and 5-tributyl-
0
0
0
stannyl-3 ,5 -diacetyl-deoxyuridine 8 as labelling precursors, and 5-(4 -fluoro-
0
phenyl)-uridine 11 and 5-(4 -fluorophenyl)-deoxyuridine 12 as reference
compounds is depicted in Figure 1.
Acetylation of uridine 1 and deoxyuridine 2 was accomplished in high yields
2
3
of 97 and 94%, respectively, according to a literature procedure.
Compounds 3 and 4 were treated with ICl in refluxing CH Cl to give 5-iodo
2
2
nucleosides 5 and 6 in 92 and 85% yield after purification by flash chromato-
graphy. The organostannanes 7 and 8 serve as precursors for the subsequent
1
8
Stille coupling with 4-fluoroiodobenzene and 4-[ F]fluoroiodobenzene. For
this purpose compounds 7 and 8 were prepared via a Pd-mediated cross-
coupling reaction between 5-iodo nucleosides 5 and 6 and hexabutyldistan-
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

NO-CARRIER ADDED SYNTHESIS OF
459
O
N
O
NH
NH
O
N
O
HO
AcO
(
AcO) O
ICl
O
2
O
DMPA
CH Cl2
2
OH
R
OAc R
1
2
R = OH
R = H
3 R = OAc (97%)
4 R = H (94%)
O
N
O
I
Bu3Sn
NH
NH
F
O
N
O
AcO
AcO
Sn Bu6
I
O
2
O
Pd(PPh ) Cl
2
3 2
Pd(PPh ) Cl2
3
2
OAc R
OAc R
CuI
5
6
R = OAc (92%)
R = H (85%)
7 R = OAc (43%)
8 R = H (44%)
F
F
O
O
N
NH
NH
N
O
O
AcO
HO
O
O
KOH
OAc
R
OH
R
9
R = OAc (16%)
11 R = OH (46%)
12 R = H (47%)
1
0 R = H (10%)
Figure 1. Synthesis of labelling precursors 7 and 8 and reference compounds 11
and 12
nane in yields of 43 and 44%, respectively. The use of 1,4-dioxane as the
solvent proved to be superior to toluene as the solvent. However, subsequent
Stille coupling of stannanes 7 and 8 with 4-fluoroiodobenzene gave the
corresponding cross-coupled products 9 and 10 in only disappointing low
yields of 16 and 10% after purification by flash chromatography. Copper
iodide was used as an additive to increase the rate of the transmetallation step
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

4
60
F. R. WUST AND T. KNIESS
¨
24
in the catalytic cycle of the Stille reaction. However, no further optimization
of the reaction conditions was performed since sufficient amounts of
compounds 9 and 10 could be obtained. Final cleavage of the acetyl protecting
groups by treatment with 1 M KOH afforded reference compounds 11 and 12
in 46 and 47% yield, respectively.
18
Improved synthesis of 4-[ F]fluoroiodobenzene
18
18
As it was shown previously, 4-[ F]fluorohalobenzenes such as 4-[ F]bromo-
18
18
fluorobenzene and 4-[ F]fluoroiodobenzene are versatile F-labelling pre-
1
9–22,25
cursors for C–C bond forming reactions.
Our group has recently
18
described the synthesis of 4-[ F]fluoroiodobenzene via thermal decomposition
0
of symmetrical 4,4 -diiododiphenyliodonium salts in the presence of
1
8
22
F]fluoride. One major drawback of the procedure is the inevitable
[
formation of 1,4-diiodobenzene as a side-product interfering subsequent cross-
coupling reactions. Thus, we set up a modified synthesis to provide
1
8
0
radiochemically and chemically pure 4-[ F]fluoroiodobenzene. 4,4 -Diiododi-
phenyliodonium triflate proved to be the best labelling precursor to afford 4-
1
8
[
F]fluoroiodobenzene in 35–45% yield and high radiochemical purity
0
(
>95%) after a single solid phase extraction step. Moreover, 4,4 -diiododi-
phenyliodonium triflate as labelling precursor is readily soluble in DMF
enabling the performance of the reaction in a remotely controlled synthesis
module. Removal of 1,4-diiodobenzene was accomplished by elution 4-
1
[
8
F]fluoroiodobenzene from the solid-phase extraction (SPE) cartridge by
means of 70% CH CN/H O. This procedure allows the selective elution of 4-
3
2
1
[
8
F]fluoroiodobenzene from the cartridge while 1,4-diiodobenzene is retained.
The eluate was diluted with water and the resulting mixture was subjected to a
18
second SPE-cartridge. 4-[ F]Fluoroiodobenzene can finally be eluted from the
second cartridge via a drying cartridge (Na SO ) with THF or DMF,
2
4
1
8
respectively. This modified protocol gives 4-[ F]fluoroiodobenzene in high
radiochemical purity >95 without 1,4-diiodobenzene contamination in decay-
corrected radiochemical yields of 25–36% within 45 min after EOB.
1
Optimization of Stille cross-coupling reaction with 4-[ F]fluoroiodobenzene
8
Stannane compound 7 was used for the optimization of the Stille cross-
18
coupling reaction conditions with 4-[ F]fluoroiodobenzene (Figure 2).
The radiochemical yields were determined by radio-HPLC of aliquots
withdrawn from the reaction mixture representing the percentage of cross-
18
coupled product [ F]-9 present in the reaction mixture.
It was shown that the radiochemical yields of Stille reactions with 4-
1
[
8
F]bromo-fluorobenzene strongly depend on the catalyst system (Pd-source
18
When 4-[ F]bromofluorobenzene was
19–21
and additives) and the solvent.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

NO-CARRIER ADDED SYNTHESIS OF
461
18F
O
N
O
NH
Bu Sn
3
NH
18F
O
N
O
AcO
AcO
O
O
I
Catalyst system
OAc OAc
OAc OAc
[18F]-9
7
1
Figure 2. Stille reaction of stannane 7 with 4-[ F]fluoroiodobenzene
8
used as a the coupling partner, reaction temperatures in the range of 110–
9–21
1
1
308C were necessary to achieve satisfactory radiochemical yields.
The use
18
of the more reactive 4-[ F]fluoroiodobenzene in terms of an accelerated
oxidative addition of the aryl halide to the Pd-complex prompted us to lower
the reaction temperature to have milder reaction conditions. Thus, all
reactions were conducted at 658C for 20 min. The effects of various Pd-
sources (Pd(PPh ) Cl , Pd[PPh ] , Pd (dba) , Pd(CH CN) Cl , and Pd(OAc) )
3
2
2
3 4
2
3
3
2
2
2
and additives like CuI, LiCl and AsPh on the radiochemical yield were
3
studied. The use of AsPh in the coupling of stannanes with halides is known
3
to increase the rate of the transmetallation of the stannane to Pd, which is
2
thought to be the rate-determining step of the catalytic cycle. The results of
6
1
8
the Stille cross-coupling reaction of stannane 7 with 4-[ F]fluoroiodobenzene
are summarized in Table 1.
In a first set of reaction we studied the effect of several Pd(II) catalyst in the
presence of CuI as additive and DMF/dioxane as the solvent on the
radiochemical yield (entry 1–3). Best results were obtained when Pd(PPh ) Cl
2
3
2
was used. Comparable radiochemical yields of 52% were found when Pd(0)-
complex Pd (dba) was used (entry 9). Moreover, Pd(0)-complex Pd (dba)
2
3
2
3
gives also better results in direct comparison with Pd(0)-complex Pd[PPh3]4
entry 7 vs entry 8). The benefit of DMF/dioxane as the solvent was shown by
(
comparison the radiochemical yields when the reaction was conducted in a
mixture of THF/dioxane (entry 3 (50%) vs entry 4 (24%)). Compared to CuI,
LiCl proved to be ineffective as an additive in the Stille reaction, since no
product formation was found when stannane 7 was reacted with 4-
1
[
8
F]fluoroiodobenzene in THF/dioxane using Pd(PPh ) Cl as Pd-catalyst
3 2 2
(
entry 4 vs entry 5).
In an other set of reactions we tested the composition of the catalyst system
Pd (dba) /CuI/AsPh in DMF/dioxane on the radiochemical yield (entry 9–
2
3
3
1
1). A combination of a 1:1:1 molar ratio of Pd (dba) /CuI/AsPh gave the
2 3 3
highest radiochemical yield of 69% (entry 10). The combination Pd (dba) /
2
3
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

4
62
F. R. WUST AND T. KNIESS
¨
Table 1. Reaction conditions for Stille cross-coupling of stannane 7 with 4-
1
8
a
[
F]fluoroiodobenzene
b
c
d
Radiochemical yield (%)
Entry
Catalyst system
Solvent
1
2
3
4
5
6
7
8
9
Pd(CH
Pd(OAc) /CuI
3
CN)
2
Cl
2
/CuI
DMF/dioxane
DMF/dioxane
DMF/dioxane
THF/dioxane
THF/dioxane
THF/dioxane
DMF/dioxane
DMF/dioxane
DMF/dioxane
DMF/dioxane
DMF/dioxane
THF/dioxane
DMF/dioxane
11
33
50
24
0
2
Pd(PPh ) Cl /CuI
3
3
3
2
2
2
2
2
2
Pd(PPh
Pd(PPh
)
)
Cl
Cl
/CuI
/LiCl
Pd[PPh ] /CuI
15
3
3
4
4
3
Pd[PPh
3
]
Pd
Pd
2
(dba)
(dba)
34
52
69
21
32
2
3
/CuI
10
11
12
13
Pd (dba) /CuI/AsPh
2
2
2
3
3
3
3
Pd
Pd
(dba)
(dba)
/AsPh
/CuI/AsPh
3
3
3
e
Pd (dba) /CuI/AsPh
2
12
3
a
All reactions were conducted at 658C for 20 min.
Molar ratios of stannane 7/Pd-source/CuI/LiCl/AsPh
b
c
3
: 1:1:2:10:1.
Solvents in a 1:1 mixture.
Radiochemical yield determined by radio-HPLC representing the percentage of radioactivity area of
cross-coupled product [ F]-9 related to the total radioactivity area.
Reaction was carried out at 1108C.
d
18
e
CuI alone (entry 9) and Pd (dba) /AsPh alone (entry 11) gave in both cases
2
3
3
lower radiochemical yields of 52 and 21%, respectively. The importance of
DMF/dioxane as the solvent of choice was demonstrated by direct comparison
of the radiochemical yields obtained by using the optimal catalyst system
(Pd (dba) /CuI/AsPh ) in DMF/dioxane and THF/dioxane, being 69 and
2 3 3
3
2%, respectively (entry 10 vs entry 12). The beneficial effect to perform the
reaction at lower reaction temperature (658C) rather than at elevated
1
8
temperatures (110–1308C) as reported for Stille reactions with 4-[ F]bromo-
1
9–21
fluorobenzene
is shown in entries 10 and 13. The radiochemical yield
drops drastically to 12% when a higher reaction temperature of 1108C is used.
Using optimized reaction conditions (Pd (dba) /CuI/AsPh , DMF/dioxane,
2
3
3
0
18
58C for 20 min) we performed a large-scale preparation of 5-(4 -[ F]fluoro-
6
0
18
phenyl)-2 -deoxy-uridine F-12 by the reaction of stannane 8 with 4-
1
8
[
F]fluoro-iodobenzene and subsequent basic hydrolysis by means of 1 M
KOH. Similar reaction conditions were applied to the synthesis of compound
1
8
F-11 (Figure 3).
Thus, in a typical experiment 550 MBq of 4-[ F]fluoroiodobenzene could be
1
8
1
8
converted into 120 MBq (33%, decay-corrected, related to 4-[ F]fluoro-
0
18
0
18
iodobenzene) of 5-(4 -[ F]fluorophenyl)-2 -deoxy-uridine
0 min, including HPLC purification.
The radiochemical purity of the isolated product exceeded 95%. The
F-12 within
4
1
8
18
radiopharmacological investigation of the new F-labelled nucleosides F-11
1
and F-12 is currently in progress.
8
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

NO-CARRIER ADDED SYNTHESIS OF
463
18F
18F
O
O
N
O
N
NH
NH
Bu Sn
3
NH
18F
N
O
O
O
AcO
HO
AcO
O
O
1
M KOH
O
I
Pd (dba) /CuI/AsPh
OH R
2
3
3
OAc R
OAc R
DMF/dioxane
[18F]-9 R = OAc
18
7
8
R = OAc
R = H
[
F]-11 R = OH
[18
[18F]-12 R = H
F]-10 R = H
0
18
Figure 3. Synthesis of 5-(4 -[ F]fluorophenyl)-uridine
18
0
F-11 and 5-(4 -
1
8
0
18
F]fluorophenyl)-2 -deoxy-uridine F-12
[
Conclusions
The convenient no-carrier added synthesis of 5-(4 -[ F]fluorophenyl)-uridine
0
18
18
1
8
0
18
0
F-11 and 5-(4 -[ F]fluorophenyl)-2 -deoxy-uridine F-12 via a Stille cross-
18
coupling reaction with 4-[ F]fluoroiodobenzene has been developed. The
8
synthesis of 4-[ F]fluoroiodobenzene was further improved to provide the
compound without contamination with 1,4-diiodobenzene. The easy access to
1
18
radiochemical and chemical pure 4-[ F]fluoroiodobenzene and the mild
reaction conditions of the Stille reaction make this approach an interesting
1
8
route for the no-carrier added synthesis of other 4-[ F]fluorophenyl-contain-
ing radiotracers via a C–C bond formation.
Experimental
General
1 19
H-NMR and F-NMR spectra were recorded on a Varian Inova-400 at 400
and 376 MHz, respectively. Chemical shifts (d) are determined relative to the
solvent and converted to the TMS scale. Mass spectra were obtained on a
Quattro/LC mass spectrometer (Micromass) by electrospray ionization. Flash
2
7
chromatography was conducted according to Still et al. using MERCK silica
gel (mesh size 230–400 ASTM). Thin-layer chromatography (TLC) was
performed on Merck silica gel F-254 plastic plates with visualization under UV
(254 nm).
All chemicals were obtained from commercial suppliers of reagent grade
0
0
0
0
0
and used without further purification. 2 ,3 ,5 -triacetyluridine 3 and 3 ,5 -
0
diacetyl-2 -deoxyuridine 4 were synthesized by the reaction of uridine 1 and
0
2
-deoxyuridine 2 with acetic anhydride in the presence of 4-dimethylamino-
2
pyridine (DMAP) according to the literature. 4,4 -Diiododiphenyliodonium
3
0
2
2
triflate was prepared according to W u. st et al.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

4
64
F. R. WUST AND T. KNIESS
¨
Chemical synthesis
General procedure for the synthesis of 5-iodo-uridines 5 and 6. A solution of
acetyl uridines 3 or 4 (4.1 mmol) in CH Cl (50 ml) was refluxed with ICl (1.0 g,
2
2
6
.15 mmol) for 8 h. The mixture was washed thoroughly with 1 M Na SO -
2 3
solution and the organic layer was separated, dried (Na SO ) and evaporated.
4
2
The residue was purified by flash chromatography (EtOAc) to give compounds
and 6 as white foams.
5
0
0
0
1
5
-iodo-2 ,3 ,5 -triacetyl-uridine 5. Yield: 92%. H-NMR (DMSO-d ), d 2.05
6
0
(
(
s, 3 H, CH ), 2.07 (s, 3 H, CH ), 2.08 (s, 3 H, CH ), 4.24 (m, 2 H, 5 -H), 4.33
3
3
3
m, 1 H), 5.34 (m, 1 H), 5.45 (dd, J=6.2 Hz, J=5.1 Hz, 1 H), 5.87 (d,
J=5.1 Hz, 1 H), 8.18 (s, 1 H, 6-H), 11.84 (s, 1 H, NH). LRMS (ESI positive)
97 [M+H].
4
0
0
0
1
5
-iodo-3 ,5 -diacetyl-2 desoxyuridine 6. Yield: 85%. H-NMR (DMSO-d ),
6
d 2.06 (s, 3 H, CH ), 2.10 (s, 3 H, CH ), 2.30 (m, 1 H), 2.48 (m, 1 H),
3
3
4
.19 (m, 1 H), 4.25 (m, 2 H), 5.18 (m, 1 H), 6.15 (dd, J=7.8 Hz, J=5.9 Hz,
1
H), 8.04 (s, 1 H, 6-H), 11.76 (s, 1 H, NH). LRMS (ESI positive) 461
[
M+Na].
General procedure for the synthesis of 5-tributylstannyl-uridines 7 and 8. A
solution of 5 or 6 (3.6 mmol), Pd(PPh ) Cl (125 mg, 0.16 mmol) and Sn Bu
6
3
2
2
2
(1.90 ml, 6.55 mmol) in dry 1,4-dioxane (30 ml) was refluxed for 24 h under
nitrogen. The reaction mixture was filtered and the solvent was evaporated.
The residue was purified by flash-chromatography (EtOAc) to afford
compounds 7 or 8 as pale yellow oils.
0
0
0
1
5
-Tributylstannyl-2 ,3 ,5 -triacetyl-uridine 7. Yield: 43%. H-NMR (DMSO-
d ), d 0.83 (t, J=7.3 Hz, 9 H, CH ), 0.97 (m, 6 H, CH ), 1.26 (m, 6 H, CH ),
6
3
2
2
1
4
.46 (m, 6 H, CH ), 2.02 (s, 3 H, CH ), 2.04 (s, 3 H, CH ), 2.06 (s, 3 H, CH ),
2 3 3 3
0
.20 (m, 2 H, 5 -H), 4.30 (dd, J=10.6 Hz, J=2.3 Hz, 1 H), 5.36 (m, 1 H), 5.52
(dd, J=6.2 Hz, J=5.1 Hz, 1 H), 5,87 (d, J=4.5 Hz, 1 H), 7.31 (s, 1 H, 6-H),
1
1.31 (s, 1 H, NH). LRMS (ESI positive) 661 [M+H].
0
0
1
5
-Tributylstannyl-3 ,5 -diacetyl-uridine 8. Yield: 44%. H-NMR (DMSO-d ),
6
d 0.84 (t, J=7.3 Hz, 9 H, CH ), 0.98 (m, 6 H, CH ), 1.28 (m, 6 H, CH ), 1.47
3
2
2
(m, 6 H, CH ), 2.03 (s, 3 H, CH ), 2.06 (s, 3 H, CH ), 2.31 (m, 1 H), 2.44 (m,
2 3 3
1
H), 4.19 (m, 1 H), 4.21 (m, 2 H), 5.18 (m, 1 H), 6.11 (dd, J=8.0 Hz,
J=6.2 Hz, 1 H), 7.23 (s, 1 H, 6-H), 11.24 (s, 1 H, NH). LRMS (ESI positive)
6
02 [M+H].
0
General procedure for the synthesis of 5-(4 -fluorophenyl)-substituted uridines
9
and 10. A solution of tributylstannyl compounds 7 or 8 (1 mmol),
Pd(PPh ) Cl (350 mg, 0.5 mmol), CuI (100 mg, 0.5 mmol) and 4-fluoroiodo-
3
2
2
benzene (450 mg, 2 mmol) in dry 1,4-dioxane (20 ml) was heated at 1008C for
4 h under a nitrogen atmosphere. The solvent was evaporated and the residue
was purified by flash-chromatography (50% EtOAc/n-hexane).
2
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

NO-CARRIER ADDED SYNTHESIS OF
465
0
0
0
0
1
-(4 -Fluorophenyl)-2 ,3 ,5 -triacetyl-uridine 9. Yield: 16%. H-NMR
5
(
(
CDCl ), d 2.11 (s, 3 H, CH ), 2.13 (s, 3 H, CH ), 2.14 (s, 3 H, CH ), 4.21
m, 1 H), 4.36 (m, 2 H), 4.38 (m, 1 H), 5.35 (m, 1 H), 5.40 (m, 1 H), 6.14 (m,
3
3
3
3
1
1
H), 7.09 (m, 2 H, Ar–H), 7.45 (m, 2 H, Ar–H), 7.70 (s, 1 H, 6-H), 8.82 (bs,
1
9
H, NH). F-NMR (CDCl ), d ꢀ113.32 (m). LRMS (ESI positive) 487
3
[
M+Na].
0
0
0
1
5
-(4 -Fluorophenyl)-3 ,5 -diacetyl-uridine 10. Yield: 10%.
H-NMR
(
CDCl ), d 1.87 (s, 3 H, CH ), 2.10 (s, 3 H, CH ), 2.21 (m, 1 H), 2.53 (m,
3
3
3
1
H), 4.27 (m, 1 H), 4.35 (m, 2 H), 5.21 (m, 1 H), 6.36 (m, 1 H), 7.07 (m, 2 H,
1
9
Ar–H), 7.45 (m, 2 H, Ar–H) 7.62 (s, 1 H, 6-H), 8.86 (bs, 1 H, NH). F-NMR
(
CDCl ), d ꢀ113.30 (m). LRMS (ESI positive) 407 [M+H].
General procedure for the synthesis of 5-(4 -fluorophenyl)-substituted uridines
3
0
1
1 and 12. A solution of 9 or 10 (120 mmol) and 0.5 M KOH (0.5 ml) in
acetonitrile (3 ml) was stirred for 2 h at room temperature. The solvent was
partially removed under reduced pressure and the residue was purified by
flash-chromatography to yield compounds 11 or 12 as white solids.
0
1
5
-(4 -Fluorophenyl)-uridine 11. Yield: 46%. Melting point: 156–1588C. H-
NMR (DMSO-d ), d 3.58 (dd, J=11.9 Hz, J=2.2 Hz, 1 H), 3.68 (m, 1 H), 3.88
6
(
m, 1 H), 4.04 (t, J=4.8 Hz, 1 H), 4.13 (m, 1 H), 5.84 (m, 1 H), 7.19 (m, 2 H,
1
Ar–H), 7.56 (m, 2 H, Ar–H), 8.29 (s, 1 H, 6-H), 11.51 (bs, 1 H, NH). F-NMR
9
(
DMSO-d ), d ꢀ115.53 (m). LRMS (ESI positive) 339 [M+H].
6
0
0
5
-(4 -Fluorophenyl)-2 -desoxyuridine 12. Yield: 47%. Melting point: 198–
1
2
018C. H-NMR (DMSO-d ), d 2.16 (m, 1 H), 2.24 (m, 1 H), 3.60 (m, 1 H),
6
3
.80 (m, 1 H), 4.28 (m, 1 H), 5.13 (m, 1 H), 5.60 (d, J=4.4 Hz, 1 H), 6.22 (t,
0
J=6.9 Hz, 1 H), 5.84 (m, 1 H, 1 -H), 7.21 (m, 2 H, Ar–H), 7.58 (m, 2 H, Ar–H),
19
8
.20 (s, 1 H, 6-H), 11.51 (bs, 1 H, NH). F-NMR (DMSO-d ) d -115.51 (m).
6
LRMS (ESI positive) 345 [M+Na].
Radiochemical synthesis
18
No-carrier added aqueous [ F]fluoride ion was produced in a IBA
1
CYCLONE 18/9 cyclotron by irradiation of [ O]H O via the O(p,n) F
8
18
18
2
1
nuclear reaction. Resolubilization of the aqueous [ F]fluoride was accom-
8
1
plished with Kryptofix 2.2.2 and K CO by an automated nucleophilic
2
3
fluorination module (Nuclear Interface, M u. nster) as described by R o. mer
2
8
et al.
HPLC analyses were carried out with a SUPELCOSIL LC-18S column
(
4.6 ꢁ 250 mm, 5 mm) using an indicated isocratic eluent (CH CN/H O) from
3
2
a gradient pump L2500 (Merck, Hitachi) with a flow rate of 1 ml/min. The
products were monitored by an UV detector L4500 (Merck, Hitachi) at
254 nm and by g-detection with a scintillation detector GABI (X-RAYTEST).
Semi-preparative HPLC was performed with a Merck LiChroCart 250-10
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

4
66
F. R. WUST AND T. KNIESS
¨
column using isocratic elution with CH CN/H O (50/50) at a flow rate of
3
2
4
.0 ml/min.
18
Synthesis of 4-[ F]fluoroiodobenzene
18
Cyclotron-produced [ F]HF (3–4 GBq) was dried in the automated fluorina-
28
0
tion module according to R o. mer et al. Then, 4,4 -diiododiphenyliodonium
triflate (20 mg, 29.3 mmol) dissolved in DMF (0.7 ml) was added and the
reaction mixture was heated at 1408C for 20 min. After cooling the reaction
vessel to 508C, water (8 ml) was added and the reaction mixture was passed
through a LiChrolut RP18 cartridge (500 mg). The cartridge was washed with
18
water (5 ml). 4-[ F]Fluoroiodobenzene was eluted from the cartridge using
0% CH CN/H O (2.5 ml). The eluate was diluted with water (15 ml) and the
7
3
2
resulting mixture was passed through a second LiChrolut RP18 cartridge
1
200 mg). 4-[ F]Fluoroiodobenzene was finally eluted from the second
8
(
cartridge via a drying cartridge (Na SO ) with THF or DMF (1 ml),
2
4
respectively. This procedure provides radiochemical and chemical pure 4-
8
1
[
F]Fluoroiodobenzene. Yield: 25–36% (decay-corrected). HPLC-analysis:
CH CN/H O (60/40), t =5.6 min.
3
2
R
18
Optimization of Stille reaction with 4-[ F]fluoroiodobenzene
To a vial containing tin precursor 7 (5 mg, 7.6 mmol ), palladium catalyst
(
7.5 mmol) and CuI (3 mg, 15 mmol) in dioxane (0.5 ml) was added 4-
F]fluoro-iodobenzene (25–75 MBq in 0.5 ml of THF or DMF). To some
1
8
[
experiments AsPh (3 mg, 7.5 mmol) or LiCl (3 mg, 71 mmol) was added. The
3
sealed reaction vial was heated at 658C for 20 min. Aliquots (50 ml) were taken
and after dilution with acetonitrile the samples were subjected to radio-HPLC
analysis. The reaction yield was determined from the radio-HPLC chromato-
gram representing the percentage of radioactivity area of cross-coupled
1
8
product [ F]-9 related to the total radioactivity area.
0
18
-(4 -[ F]fluorophenyl)-2 ,3 ,5 -triacetyl-uridine [ F]-9. HPLC-analysis:
0
0
0
18
5
CH CN/H O (60/40), t =3.5 min.
2
3
R
0
18
Radiosynthesis of 5-(4 -[ F]fluorophenyl)-uridine ½ Fꢂ-11 and 5-(4 -
18
0
1
8
0
18
[
F]fluorophenyl)-2 -desoxyuridine ½ Fꢂ-12 using optimized Stille cross-
coupling reaction conditions (analytical scale)
To a vial containing tin precursors 7 or 8 (5 mg), Pd (dba) (8 mg, 7.5 mmol),
2
3
CuI (3 mg, 15 mmol) and AsPh (3 mg, 7.5 mmol) in 0.5 ml of dioxane was
3
1
8
added 4-[ F]fluoroiodobenzene (50 MBq in 0.5 ml DMF). The sealed reaction
vial was heated at 658C for 20 min and aliquots (50 ml) were taken for radio-
HPLC analysis.
Copyright # 2004 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2004; 47: 457–468

NO-CARRIER ADDED SYNTHESIS OF 467
-(4 -[ F]fluorophenyl)-2 ,3 ,5 -triacetyl-uridine [ F]-9. Yield: 69% (related
0
18
0
0
0
18
5
1
8
to 4-[ F]fluoroiodobenzene). HPLC-analysis: CH CN/H O (60/40),
3
2
t =3.5 min.
R
0
18
0
0
18
-(4 -[ F]fluorophenyl)-3 ,5 -diacetyl-uridine [ F]-10. Yield: 61% (related
5
1
to 4-[ F]fluoroiodobenzene). HPLC-analysis: CH CN/H O (60/40),
8
3
2
tR=3.3 min.
M KOH (0.5 ml) was added to the Stille cross-coupling reaction mixture
1
and stirring was continued for 10 min at 658C. The reaction mixture was
filtered through a PTFE syringe filter and aliquots (50 ml) were take for radio-
HPLC analysis.
0
18
18
18
5
-(4 -[ F]Fluorophenyl)-uridine [ F]-11. Yield: 100% (related to [ F]-9).
HPLC-analysis: CH CN/H O (60/40), t =2.8 min.
3
2
R
0
18
0
18
-(4 -[ F]Fluorophenyl)-2 -desoxyuridine [ F]-12. Yield: 100% (related to
5
1
[
8
F]-10). HPLC-analysis: CH CN/H O (60/40), t =2.8 min.
3 2 R
0
18
Preparation of 5-(4 -[ F]fluorophenyl)-2 -desoxyuridine ½ Fꢂ-12 (large-scale
preparation)
0
18
To a vial containing stannane 8 (5 mg, 8.3 mmmol), Pd (dba) (8 mg, 7.5 mmol),
2
3
CuI (3 mg, 15 mmol) and AsPh (3 mg, 7.5 mmol) in 0.5 ml of dioxane was
3
1
8
added 4-[ F]fluoroiodobenzene (550 MBq in 0.5 ml DMF). The sealed
reaction vial was heated at 658C for 20 min. One molar KOH (0.5 ml) was
added to the Stille cross-coupling reaction mixture and stirring was continued
for 10 min at 658C. The reaction mixture was filtered through a PTFE syringe
filter and the mixture was subjected onto a semi-preparative HPLC column.
The fraction eluting at 5.5 min was collected. Yield: 120 MBq (33% decay-
18
corrected, related to 4-[ F]fluoroiodobenzene).
Acknowledgements
Financial support from the Deutsche Forschungsgemeinschaft (to F. W.) is
gratefully acknowledged. The authors wish to thank S. Preusche for
radioisotope production, and H. Kasper and T. Krauss for technical
assistance.
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Copyright # 2004 John Wiley & Sons, Ltd.
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