Radiosynthesis of O-[11C]methyl-L-tyrosine and O-[18F]Fluoromethyl-L-tyrosine as potential PET tracers for imaging amino acid transport

Article abstract of DOI:10.1002/jlcr.696

Two positron-emitting analogues of tyrosine, O-[¹¹C]methyl-L-tyrosine and O- [¹⁸F]fluoromethyl-L-tyrosine were prepared as new tumor imaging agents. The alkylating agent, [¹¹C]methyl triflate or [¹⁸F]fluoromethy

Full text of DOI:10.1002/jlcr.696

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2003; 46: 555–566.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.696
Research Article
Radiosynthesis of O-[11C]methyl-L-tyrosine and
O-[18F]Fluoromethyl-L-tyrosine as potential PET
tracers for imaging amino acid transport
Ren Iwata1,*, Shozo Furumoto1,2, Claudio Pascali3, Anna Bogni3 and
Kiichi Ishiwata4
1 CYRIC Tohoku University, Sendai 980-8578, Japan
2 Institute of Development, Aging and Cancer, Tohoku University,
Sendai 980-8575, Japan
3 National Cancer Institute, 20133 Milan, Italy
4 Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0022, Japan
Summary
Two positron-emitting analogues of tyrosine, O-[11C]methyl-l-tyrosine and O-
[18F]fluoromethyl-l-tyrosine were prepared as new tumor imaging agents. The
alkylating agent, [11C]methyl triflate or [18F]fluoromethyl triflate, was simply
bubbled through a dimethylsulfoxide solution of l-tyrosine disodium salt at
room temperature. After subsequent HPLC purification the labeled l-tyrosine
analogues were obtained in decay-corrected radiochemical yields of over 50%,
based on their corresponding labeling agent, with radiochemical purities
always higher than 98%. The quite straightforward preparation, together with
the high radiochemical yields achieved, make both these syntheses suitable for
routine production. Copyright # 2003 John Wiley & Sons, Ltd.
Key Words: PET, C-11; F-18; O-methyl-l-tyrosine; amino acid transport;
tumor imaging
*Correspondence to: R. Iwata, CYRIC Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578,
Japan. E-mail: rencyric@cyric.tohoku.ac.jp
Contract/grant sponsor: Scientific Research, Ministry of Education, Culture, Sports, Science and
Technology, Japan; Contract/grant number: 13470177
Copyright # 2003 John Wiley & Sons, Ltd.
Received 20 November 2002
Accepted 6 January 2003

556
R. IWATA ET AL.
Introduction
Imaging of amino acid transport and following protein synthesis are
expected to be one of the most promising methods for the detection of
tumors by positron emission tomography (PET).1,2 Especially for brain
tumors positron-emitting amino acids are reported to be superior to
[18F]FDG, which is currently the most successful and widely used PET
radiopharmaceutical for cancer imaging. Among the relatively large
number of 11C- and 18F-labeled natural and synthetic amino acids
synthesized so far, L-[11C]methionine is currently the most frequently
used for routine PET studies, owing to its convenient and efficient
synthesis from [11C]methyl iodide. Unfortunately, the metabolism of
this radiopharmaceutical involves also some trans-methylation so that
its use for quantitative imaging makes interpretation of results
complex.3
Using the same simple synthetic strategy several 18F-labeled amino
acids such as 2-[18F]fluoro-l-phenylalanine4,5 and 2-[18F]fluoro-l-
tyrosine6 have been synthesized by electrophilic [18F]fluorination from
[18F]fluorine or [18F]acetyl hypofluorite. However, the well-known
constraints related to these labeling agents (low starting activity; low
specific activity; low production yield) contributes to make these
approaches inconvenient. On the other hand, starting from [18F]fluor-
ide, which can be produced on a large scale by proton irradiation of
enriched 18O-water, the high yield radiosyntheses of 4-[18F]fluoro-l-
phenylalanine,7 4-[18F]fluoro-l-proline,8,9 1-amino-3-[18F]fluorocyclo-
butane-1-carboxylic acid10,11 and O-(2-[18F]fluoroethyl)-l-tyrosine
([18F]FET)12 have recently been developed. Especially, the latter,
prepared in a simple way and in high radiochemical yield via 2-
[18F]fluoroethyl tosylate or by direct 18F-fluorination of O-(2-tosylox-
yethyl)-N-trityl-l-tyrosine tert-butylester,13 is expected to be a promis-
ing tracer for imaging amino acid transport.12,14
[11C]Methyl triflate ([11C]CH3OTf, [11C]2) is a powerful [11C]methy-
lating agent prepared on-line from [11C]methyl iodide.15 In general, its
superior reactivity allows the [11C]methylation to proceed faster
and with no need for heating, thus greatly simplifying synthetic
methods.16–18 This main feature has induced us to recently develop
the analogue [18F]fluoromethyl triflate ([18F]CH2FOTf, [18F]4).19 Aim
of the present study is to apply [11C]CH3OTf and [18F]CH2FOTf to the
preparation of O-[11C]methyl-l-tyrosine ([11C]3) and O-[18F]fluoro-
methyl-l-tyrosine ([18F]5), respectively.
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RADIOSYNTHESIS OF O-[11C]METHYL-L-TYROSINE
557
Results and Discussion
The two positron-emitting tyrosine analogues, [11C]3 and [18F]5, were
prepared by bubbling the corresponding triflates, [11C]2 and [18F]4, into
the precursor solution (Schemes 1 and 2). The capacity of the reaction
solvent (0.5 ml) to efficiently retain the flowing alkylating agent was one
of the crucial factors affecting the radiochemical yield. This was even
more relevant for [18F]4 because of the relatively high flow rate (100 ml/
min) coming from the Sep-Pak silica cartridges during its purification.19
Thus, the solvents listed in Table 1 were compared in terms of trapping
efficiency of [18F]4 and radiochemical yield of the subsequent
[18F]fluoromethylation reaction. DMSO was the first choice as it was
used for the preparation of O-[18F]fluoroethyl-l-tyrosine from
[18F]fluoroethyltosylate.12 As expected it showed comparatively high
trapping and [18F]fluoromethylation yield. Conversely, in spite of its
good trapping efficiency, no formation of [18F]5 was observed with
DMF probably due to the low solubility of the precursor in this solvent.
Ethanol afforded a reasonable trapping efficiency and radiochemical
yield, although the latter was remarkably improved by heating at 1108C.
On the other hand, methanol showed a low trapping efficiency and even
lower [18F]fluoromethylation yield, even when heated. Thus, these
results reconfirmed DMSO as the best solvent also for the preparation
of O-[18F]fluoromethyl-l-tyrosine.
The main advantage in using triflates as labeling agents in
nucleophilic substitution reactions is that they are, as a rule, more
reactive than the corresponding halides, a feature which allows the
reaction to proceed rapidly even at room temperature. Our results
followed this line. As shown in Table 2, both [11C]2 and [18F]4 afforded
H2, Ni
400oC
I2
AgOTf
190oC
11CO2
11CH4
11CH3I
11CH3OTf
11C]2
800oC
[
COOH
COONa
H311C
NH2
DMSO, r.t.
NH2
O
NaO
11C]3
1
[
Scheme 1. Radiosynthesis of O-[11C]methyl-L-tyrosine
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R. IWATA ET AL.
18F-/K.222/K+
MeCN, reflux
AgOTf
190oC
CH2Br18
F
CH218FOTf
CH2Br2
[
18F]4
COONa
COOH
DMSO, r.t.
NH2
NH2
NaO
18F
O
18F]5
1
[
Scheme 2. Radiosynthesis of O-[18F]fluoromethyl-L-tyrosine
Table 1. Comparison of trapping yields of [18F]fluoromethyl triflate ([18F]4) and
radiochemical yields of O-[18F]fluoromethyl-L-tyrosine ([18F]5) in various solvent
[18F]Fluoromethylation
Solventa
DMSO
Trapping efficiencyb
75–87%
Temperature
Timec
Yieldd
r. t.
1108C
r. t.
1108C
r. t.
608C
r. t./1108C
5 min
3 min
>99%
>99%
35% (64%)e
90%
EtOH
MeOH
DMF
ꢀ60%
40–60%
ꢀ80%
10 min
10 min
10 min
10 min
10 min
8%
26%
0%
a A volume of 0.5 ml was used for dissolving 1 mg precursor. No effort was made to optimize the
volume.
b Flowing [18F]4 was trapped at room temperature.
c Reaction time after bubbling of [18F]4.
d Reaction yield based on the trapped [18F]4.
e 2 mg of precursor were used.
reasonable conversion rates at room temperature even after just 1 min,
the main difference being that the yield of [18F]4 had a higher
dependence on the amount of precursor used. It is interesting to note
that radiochemical yields of [11C]3 could not be improved over 60% and
were always, all things being equal, lower than those of [18F]5.
The preparation of the ‘cold’ standard O-fluoromethyl-l-tyrosine 5
required a different approach. In fact, the straightforward transfer of
the method used for the hot run failed to afford the fluoroalkylating
agent 4. A carrier-added reaction of [18F]fluoride with CH2Br2 showed
that the presence of large amount of fluoride, as in the cold preparation,
led to the synthesis of [18F]CH2F2 instead of [18F]CH2BrF. Thus,
fluoromethyl tosylate, prepared from CH2I2 via CH2(OTs)2, was
20
selected as an alternative to fluoromethyl triflate.
However, this
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RADIOSYNTHESIS OF O-[11C]METHYL-L-TYROSINE
559
Table 2. Radiochemical yields of O-[11C]methyl-L-tyrosine ([11C]3) and O-
[18F]fluoromethyl-L-tyrosine ([18F]5)
Compound
Precursor amounta
(mg)
Reaction timeb
(min)
RCYc
[11C]3
0.5
0.5
0.5
1
1.6
2.5
1.5
5
10
1
1
1
34%
47%
57%
55%
57%
51%
[18F]5
0.5
0.5
0.5
1
1
2.3
1
5
10
1
5
1
51%
66%
71%
78%
87%
84%
a Dissolved in 0.5 ml DMSO.
b Additional reaction time after bubbling at room temperature.
c Decay-corrected radiochemical yield, based on the labeling agent (n=1).
agent was not highly reactive and hence the reaction with precursor 1
did not afford the desired product 5. Consequently, CH2FOTs was
applied to a protected tyrosine following a method similar to that used
for the synthesis of ‘cold’ FET12 (Scheme 3).
Figure 1 shows the HPLC separation of the desired product, [11C]3 or
[18F]5, from the reaction mixture. It can be seen that the separation was
easily carried out because no other chemical or radiochemical impurity
peaks eluted near the product. Thus, radiochemical purities of both
products after HPLC purification were usually greater than 98%.
Although the number of [18F]fluoromethylated compounds synthe-
sized so far is not large enough to establish a clear pattern of behavior, it
has been reported that some [18F]fluoromethylated compounds are not
stable.21,22 However, an HPLC investigation carried out over a 2-h
period on [18F]5 in saline showed total absence of decomposition, thus
enabling the use of this tracer in PET studies.
Amino acid transport is a relatively rapid process and tumor imaging
based on amino acid transport can be performed within a relatively
short time.2 From this point of view O-[11C]methyl-l-tyrosine, due to its
easy preparation, is expected to serve as a useful imaging agent. On the
other hand, O-[18F]fluoromethyl-l-tyrosine, thanks to its longer-half-
life and high production yield, has the further advantage of possible
distribution to satellite PET centers.
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R. IWATA ET AL.
CH2(OTs)2
CH2(OTs)2
CH2FOTs
a
b
6
7
COOCH3
COOCH3
c
NHBoc
NHBoc
HO
F
O
8
9
d, e
COOH
NH2
F
O
5
Scheme 3. Synthesis of O-fluoromethyl-L-tyrosine (a) AgOTs, MeCN, reflux; (b)
TBAF, MeCN, reflux; (c) K2CO3, acetone, reflux; (d) aqueous NaOH, MeOH,
708C; (e) HCl/Et2O, CH2Cl2
Experimental
All reagents and solvents were commercially available and used without
further purification. Anhydrous acetonitrile (MeCN), anhydrous
dimethysulfoxide (DMSO), dibromomethane and 1 M hydrogen chlor-
ide in ether were purchased from Aldrich, disodium salt of L-tyrosine 1
from Sigma, Kryptofix 222 (K. 222) from Merck, and O-methyl-l-
tyrosine from Bachem. Solid-phase extraction columns (Sep-Pak Plus
silica and AC-2) were obtained from Waters.
Reactions were monitored by thin layer chromatography (TLC) using
Merck silica gel 60 F254 TLC plates (aluminum) or RP-18 F254 TLC
plates (glass). Column chromatography was performed using Silica Gel
1
60 (spherical, 40–50 mm) purchased from Kanto Chemical Co., Inc. H
NMR spectra were recorded on a Bruker AM-600 (600 MHz). Low-
resolution mass spectra (MS) and high-resolution mass spectra (HRMS)
were recorded on a JEOL JMS-DX303 and -DX500, respectively.
A silver triflate-Graphpac (AgOTf, Aldrich; Graphpac GC, Alltech)
column (4 Â 60 mm) was prepared as previously described.17 The
column was heated at 190oC under He flow (30 ml/min) for at least
20 min before starting the synthesis.
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RADIOSYNTHESIS OF O-[11C]METHYL-L-TYROSINE
561
Figure 1. HPLC purification of O-[11C]methyl-L-tyrosine (A) and O-[18F]fluor-
omethyl-L-tyrosine (B)
HPLC analysis was performed on
a Puresil C18 column
(4.6 Â 150 mm, Waters) with a solvent system of MeOH/AcOH/1 mM
sodium octylsulfate-1 mM EDTA (250:6:744) at a flow rate of
2.0 ml/min. Retention times of O-methyl-l-tyrosine and O-fluoro-
methyl-l-tyrosine were 4.1 min and 4.3 min, respectively.
Fluoromethyl tosylate (7, Scheme 3)20
Bis(tosyloxy)methane 6 was prepared from diiodomethane and silver
tosylate in dry acetonitrile by heating at reflux according to the
literature.23 To a solution of bis(tosyloxy)methane 6 (7.40 g, 20.7 mmol)
in dry MeCN (50 ml) was added a solution of tetra-n-butylammonium
fluoride (5.42 g, 21.0 mmol) in dry MeCN (10 ml) and the solution was
stirred under reflux. After 2 h, the solvent was removed under reduced
pressure and the residue dissolved in AcOEt and washed with H2O. The
organic solution was dried over MgSO4, filtrated, and removed under
reduced pressure. The residue was purified by chromatography on silica
gel eluted with hexane/AcOEt (5:2) to afford 1.30 g (6.37 mmol, 31%) of
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R. IWATA ET AL.
7 as a colorless oil. 1H NMR (CDCl3/TMS): d 2.46 (3 H, s), 5.74 (2 H, d,
J=50.7 Hz), 7.36 (2 H, d, J=7.8 Hz), 7.83 (2 H, d, J=8.1 Hz). EI-MS
(m/z, %): 204 (M+, 57), 155 ([M-OCH2F]+, 86), 91 ([M-SO3CH2F]+,
100). EI-HRMS (M+): calculated for C8H9FO3S 204.0254, found
204.0245.
2-tert-Butoxycarbonylamino-3-(4-fluoromethoxyphenyl)-propionic acid
methyl ester (9, Scheme 3)
To a solution of 2-tert-butoxycarbonylamino-3-(4-hydroxyphenyl)-
propionic acid methyl ester 8 (610 mg, 2.06 mmol) and K2CO3
(552 mg, 3.99 mmol) in acetone (8.0 ml) a solution of 7 (520 mg,
2.54 mmol) in acetone (2.0 ml) was added and thereafter refluxed for 2
days. After being cooled to room temperature, the reaction solution was
diluted with saturated aqueous NH4Cl solution and extracted with
AcOEt. The organic layer was dried over MgSO4, filtrated, and
removed under reduced pressure. The residue was purified by
chromatography on silica gel eluted with hexane/AcOEt (2:1) to give
273 mg (0.83 mmol, 40%) of 9 as a white solid. 1H NMR (CDCl3/TMS):
d 1.49 (9 H, s), 3.02 (1 H, dd, J=13.9, 5.9 Hz), 3.09 (1 H, dd, J=13.8,
5.8 Hz), 3.72 (3 H, s), 4.54–4.58 (1 H, m), 4.97 (1 H, d, J=7.7 Hz), 5.69
(2 H, d, J=54.7 Hz) 7.01 (2 H, d, J=8.5 Hz), 7.08 (2 H, d, J=8.4 Hz).
EI-MS (m/z, %): 327 (M+, 1.6), 139 ([CH2C4H4OCH2F]+, 100), EI-
HRMS (M+): calculated for C16H22FNO5 327.1476, found 327.1459.
2-Amino-3-(4-fluoromethoxyphenyl)-propionic acid (O-fluoromethyl-l-
tyrosine, 5, Scheme 3)
To a solution of 9 (264 mg, 0.806 mmol) in MeOH (3.0 ml) 2N NaOH
(600 ml) was added and the reaction mixture heated for 2.5 h at 708C.
After cooling down to room temperature, the mixture was concentrated
under reduced pressure. The residue was diluted with H2O, acidified
with 2N HCl (650 ml), and extracted with CHCl3. The organic phase was
dried over MgSO4, filtered, and removed under reduced pressure. The
residue was dissolved in dry CH2Cl2 (2.0 ml) and then treated with a 1 M
solution of HCl in ether (1.0 ml, 1.0 mmol). After stirring the reaction
solution for 18 h, a white precipitate was formed which was filtered,
washed with Et2O and dried to afford a white powder (85 mg). A
portion of this powder (11 mg) was purified with reversed-phase HPLC
(YMC-Pack ODS-A column, 300 Â 10 mm) eluted with EtOH/H2O/
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RADIOSYNTHESIS OF O-[11C]METHYL-L-TYROSINE
563
AcOH (10:87.5:2.5) to afford, after evaporation, pure 5 as a white
1
powder (7 mg). H NMR (D2O/TSP): d 3.12 (1 H, dd, J=14.7, 7.7 Hz),
3.26 (1 H, dd, J=14.8, 5.3 Hz), 3.97 (1 H, dd, J=7.7, 5.3 Hz), 5.82 (2 H,
d, J=54.5 Hz), 7.17 (2 H, d, J=8.5 Hz), 7.32 (2 H, d, J=8.6 Hz). EI-MS
(m/z, %): 213 (M+, 3.7), 168 ([M-CO2H]+, 5.5), 139
([CH2C4H4OCH2F]+, 100), EI-HRMS (M+): calculated for
C10H12FNO3 213.0798, found 213.0775.
O-[11C]Methyl-l-tyrosine ([11C]3, Scheme 1)
[11C]Carbon dioxide was produced by the 14N(p,a)11C reaction on a N2
target containing 0.5% O2 with 12 MeV protons from a Cypris HM12
cyclotron (SHI) at CYRIC. It was then converted into [11C]methyl
iodide by gas phase iodination via [11C]CH4 with a MeI MicroLab
system (GE). The [11C]methyl iodide produced was then passed through
the heated AgOTf column (1908C) with a He flow (35 ml/min) and
converted to [11C]methyl triflate ([11C]2).
[11C]2 was bubbled over about 1 min through a DMSO solution of
precursor 1 (1 mg/0.5 ml) in a small vented vial (Wheaton V vial, 5 ml) at
room temperature. A disposable charcoal column (Sep-Pak AC-2)
placed on the vent adsorbed the unretained [11C]2 and was used to
determine the trapping efficiency. The reaction was immediately
quenched by adding water (0.5 ml). The resulting mixture was
transferred to an HPLC sample loop and then injected onto a semi-
preparative C18 column (YMC ODS A-324, 10 Â 300 mm) and eluted
with a solvent system of ethanol/acetic acid/water (10:2.5:87.5) at a flow
rate of 4 ml/min. As seen in Figure 1 (A), the desired product eluted
between 9 and 11 min. This fraction was collected, evaporated to
dryness under reduced pressure and the residue dissolved in saline. The
total synthesis time from the end of bombardment (EOB) was about
40 min. The final product was identified as O-[11C]methyl-l-tyrosine by
analytical HPLC. Its radiochemical purity was also determined at the
same time.
[18F]Fluoromethyl triflate ([18F]4, Scheme 2)
[18F]Fluoride was produced by 12 MeV proton irradiation of 18O-
enriched water (0.7 ml) and recovered onto an anion exchange resin.
The [18F]fluoride retained by the resin was eluted with an aqueous
K2CO3 solution (33 mM, 1 ml).
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R. IWATA ET AL.
The detailed procedure for the preparation of [18F]fluoromethyl
triflate ([18F]4) from [18F]fluoride is described elsewhere.19 Briefly, the
[18F]fluoride was added to a MeCN solution of K.222 (15 mg, 40 mmol)
in a septum-sealed round bottom flask, which was then dipped in an
oil bath (1108C) to evaporate off the solvent under a stream of He
(200 ml/min). A solution of CH2Br2 (50 ml) in dry MeCN (1 ml) was
added to the residue and the solution was stirred and heated for 4 min.
After reaction the flask was allowed to cool to room temperature and
[18F]CH2BrF formed was then passed through four Sep-Pak silica
cartridges connected in series by a He flow (100 ml/min) to separate the
product from CH2Br2. When [18F]CH2BrF began to elute from the Sep-
Paks, it was allowed to flow through the heated (1908C) AgOTf column
to convert it to [18F]4. The decay-corrected radiochemical yield of [18F]4
from [18F]fluoride was usually 50%.
O-[18F]Fluoromethyl-l-tyrosine ([18F]5, Scheme 2)
The preparation and purification of O-[18F]fluoromethyl-l-tyrosine
from [18F]4 was performed with the same procedure used for O-
[11C]methyl-l-tyrosine. The [18F]4 was passed at a flow rate of 100 ml/
min through a DMSO solution of precursor (0.5 ml) in a small vial
(Wheaton V vial, 5 ml) vented to a Sep-Pak AC-2 cartridge. The
concentration of precursor was varied from 1 to 4 mg/ml to optimize the
reaction. After trapping [18F]4 the reaction was continued by either
standing at room temperature for another several minutes or heating in
the oil bath for up to 10 min at 1108C and then quenched by adding
water (0.5 ml). The whole solution was injected onto a semi-preparative
C18 column (YMC ODS A-324, 10 Â 300 mm) and eluted with a solvent
system of ethanol/acetic acid/water (10:2.5:87.5) at a flow rate of 4 ml/
min. As seen in Figure 1 (B), the desired product eluted between 10 and
12 min. This fraction was collected, evaporated to dryness under
reduced pressure, and the residue dissolved in saline (2 ml). The overall
synthesis time from the EOB was about 50 min.The final product was
identified as O-[18F]fluormethyl-l-tyrosine by analytical HPLC. Its
radiochemical purity was also determined at the same time and chemical
stability in saline was checked by HPLC over a 2-h range.
Conclusion
O-[11C]Methyl-l-tyrosine and O-[18F]fluoromethyl-l-tyrosine were pre-
pared in satisfactorily high radiochemical yields from [11C]methyl
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RADIOSYNTHESIS OF O-[11C]METHYL-L-TYROSINE
565
triflate and [18F]fluoromethyl triflate, respectively (>50%, decay-
corrected, based on the labeling agent). Owing to the high reactivity
of the labeling agents the reactions proceeded rapidly without heating,
resulting in a simplified synthesis procedure feasible for routine
production. A biodistribution study of O-[18F]fluoromethyl-l-tyrosine
in comparison to O-[18F]fluoroethyl-l-tyrosine is currently in progress.
Acknowledgements
The authors wish to thank Dr F. Brady (Imaging Research Solutions
Limited, Cyclotron Building, Hammersmith Hospital, London) for
helpful and critical discussion. This study was supported by a Grant-in-
Aid (No. 13470177) for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
References
1. Jager PI, Vaalburg WV, Pruim J, de Vries EGE, Langen K-J, Piers DA.
J Nucl Med 2001; 42: 432–445.
2. Laverman P, Boerman OC, Cortens FHM, Oyen WJG. 2002; Eur J Nucl
Med 29: 681–690.
3. Pascali C, Bogni A, Iwata R, Decise D, Crippa F, Bombardieri E. J Label
Compds Radiopharm 1999; 42: 715–724.
4. Hoyte RM, Lin SS, Christman DR, Atokins HL, Hauser WL, Wolf AP.
J Nucl Med 1971; 12: 280–286.
5. Murakami M, Takahashi T, Kondo Y, et al. J Label Compds Radiopharm
1988; 25: 573–578.
6. Coenen HH, Kling P, Stoecklin G. J Nucl Med 1989; 30: 1367–1372.
7. Lemaire C, Guillaume M, Palmer AJ, Cantineau R. Appl Radiat Isot 1987;
38: 1033–1038.
8. Hamacher K. J Label Compds Radiopharm 1999; 42: 1135–1144.
9. Mazza SM. J Label Compds Radiopharm 2000; 43: 1047–1058.
10. Shoup TM, Goodman MM. J Label Compds Radiopharm 1999; 42:
215–225.
11. Shoup TM, Olson J, Hoffman JM, et al. J. Nucl. Med. 1999; 40: 331–338.
12. Wester HJ, Herz M, Weber W, et al. J Nucl Med 1999: 40: 205–212.
13. Hamacher K, Coenen HH. Appl Radiat Isot 2002; 57: 853–856.
14. Weber WA, Wester HJ, Grosu AL, et al. Eur J Nucl Med 2000; 27:
542–549.
15. Jewett DM. Appl Radiat Isot 1992; 43: 1383–1385.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 555–566

566
R. IWATA ET AL.
16. Nagren K, Muller L, Halldin C, Swahn C-G, Lehikoinen P. Nucl Med Biol
1995; 22: 235–239.
17. Iwata R, Pascali C, Bogni A, Miyake Y, Yanai K, Ido T. Appl Radiat Isot
2001; 55: 17–22.
18. Iwata R, Pascali C, Bogni A, et al. J Label Compds Radiopharm 2002; 45:
271–280.
19. Iwata R., Pascali C, Bogni A, Furumoto S, Terasaki K, Yanai K. Appl
Radiat Isot 2002; 57: 347–352.
.
20. Block D, Coenen HH, Stocklin G. J Label Compds Radiopharm 1987, 24:
1029–1042.
21. Petric A., Barrio JR, Namavari M, Huang SC, Satyamurthy N. Nucl Med
Biol 1999; 26: 529–535.
22. Zessin J, Eskola O, Brust P, et al. Nucl Med Biol 2001; 28: 857–863.
23. Emmons WD, Ferries AF. J Am Chem Soc 1953; 75: 2257.
Copyright # 2003 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2003; 46: 555–566