[18F]Fluoropropylsulfonyl chloride: A new reagent for radiolabeling primary and secondary amines for PET imaging

Article abstract of DOI:10.1002/jlcr.1466

In vivo molecular imaging with positron emission tomography (PET) requires the preparation of an appropriate positron-emitting radiotracer. New methods for the introduction of F-18 into biologically interesting molecules could increase the availability of

Full text of DOI:10.1002/jlcr.1466

Research Article
Received 22 August 2007,
Accepted 6 September 2007
Published online 3 January 2008 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1466
[18F]Fluoropropylsulfonyl chloride: a new
reagent for radiolabeling primary and
secondary amines for PET imaging
Ã
Zheng Liy, Lixin Lang, Ying Ma, and Dale O. Kiesewetter
In vivo molecular imaging with positron emission tomography (PET) requires the preparation of an appropriate positron-
emitting radiotracer. New methods for the introduction of F-18 into biologically interesting molecules could increase the
availability of specific PET radiotracers and increase the application of PET to the study of human diseases. In this work,
[
18F]fluoropropylsulfonyl chloride was synthesized from 3-toluenesulfonyloxypropyl thiocyanate in two steps and was
successfully incorporated into molecules containing a reactive amino group. Both a primary amine, L-phenylalanine ethyl
ester hydrochloride, and a secondary amine, 1-(2-methoxyphenyl)-piperazine, were successfully radiolabeled by this
method. The entire radiochemical synthesis required 90 min. The products were obtained in 25.7 2.3% (n = 3) and
22.8 9.1% (n = 6) (EOB). This method provides a useful and easy way to make new F-18 labeled radiopharmaceuticals for
PET imaging.
Keywords: fluorine-18; radiolabeling agent; [18F]fluoropropylsulfonyl chloride
These labeling agents are often used to perform [18F]o-
Introduction
fluoroalkylations at nucleophilic centers such as OH, NH2, SH.4
Labeling with [18F]fluoroalkyl moieties as prosthetic groups
Noninvasive molecular imaging using positron emission tomogra-
phy (PET) is playing an increasing role in monitoring biochemical
changes in vivo in various diseases. Despite the increasing reliance
of the biomedical science on imaging, the development of new
radiopharmaceuticals for PET remains a slow process. One
bottleneck is the limited methods available for the introduction
of radionuclide into biologically interesting molecules.1
widely extends the spectrum of biomolecules which can be
labeled.
In this report, we present a new approach using [18F]fluoro-
propylsulfonyl chloride as a prosthetic radiolabeling agent to
radiolabel target molecules with F-18 by forming sulfonamide
derivatives. In some cases sulfonamides are already present in the
drug molecule. For example, short chain sulfonamide moieties are
present in a class of muscarinic acetylcholine antagonists13 and in
a class of glycine transportor inhibitors.14 Compounds [18F]a and
[18F]b were prepared as model compounds by introducing a
[18F]fluoropropylsulfonyl group into the corresponding primary
and secondary amine (Scheme 1). The sequence was rapid and
efficient; the reaction conditions were mild.
Fluorine-18 (t1/2 5 109.8 min) is a very important radionuclide
in PET due to its favorable decay characteristics. Many
radiopharmaceuticals containing F-18 have been found to be
very useful in PET imaging.2,3 For the preparation of fluorine-18
labeled PET radiotracer, the most widely used radiofluorination
method is nucleophilic substitution (SN) reaction employing the
K
222/K18F complex in polar aprotic solvents.4,5 The minimal
structural requirement for the efficient nucleophilic substitution
is the presence of a leaving group such as methanesulfonates
(OMs), trifluoromethanesulfonate (OTf), toluenesulfonate (OTs)
for aliphatic substitution, and nitro or aryltrimethyl anilinium for
aromatic substitution. Once a biologically interesting target is
selected for radiolabeling with fluorine-18, synthesis of a
precursor with an appropriate leaving group is needed. It is
desirable to introduce the radionuclide at the last step of the
synthesis, but usually it is very difficult in more complex
molecules. Not only are suitable precursor molecules with
appropriate leaving group for direct nucleophilic fluorination
frequently not easy to synthesize, but they are also often
unstable under the direct labeling conditions. An alternative
method is using a prosthetic group such as [18F]fluoroalkyl
moieties as labeling agent.6–9 Amongst these agents are
compounds of formula X(CH2)1n8F, where n may range from 1
to 4 and X may be a halogen, OMs, OTf, or OTs.10–12
Results and discussion
In this study, we used L-phenylalanine ethyl ester hydrochloride,
a primary amine, and 1-(2-methoxyphenyl)piperazine, a second-
ary amine, as model substrates for testing the reactivity of a
yCurrent Address: Department of Radiology, The Methodist Hospital Research
Institute, Houston, TX 77030, USA.
PET Radiochemistry Group, National Institute of Biomedical Imaging and
Bioengineering, NIH, Bethesda, MD 20892, USA
*Correspondence to: Dale O. Kiesewetter, PET Radiochemistry Group, National
Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD 20892,
USA.
E-mail: dkiesewetter@mail.nih.gov
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Z. Li et al
Scheme 1
novel radiolabeled prosthetic agent, [18F]fluoropropylsulfonyl displacement of bromide using KSCN, followed by treatment
chloride, and optimizing the labeling reaction conditions. The with toluenesulfonyl chloride (Scheme 3).
synthesis of the non-radioactive standard compounds for
[18F]]Fluoropropylsulfonamides were synthesized in three
analytical purposes including high-performance liquid chroma- steps (Scheme 1) beginning by heating 3-toluenesulfonyloxy-
tography (HPLC) and gas chromatography mass spectrometry propyl thiocyanate with [18F]fluoride, K2CO3, and Krypto-
(GC-MS) was achieved according to Scheme 2. The reference fix[2.2.2.]. In our initial radiochemical synthesis, the intermediate,
amides a and b were prepared in three steps from 1-bromo-3- [18F]fluoropropyl thiocyanate, was obtained with a radiochemi-
fluoropropane and corresponding amines, respectively. The cal yield of 75.276.1% (n 5 7) (decay corrected) following
structure of compounds a and b were confirmed by 1H NMR, 13
NMR, and MS. Fluoropropylsulfonyl chloride was prepared from silica gel (ꢀ5 mm).
C
elution with ether through a short pipette column containing
1-bromo-3-fluoropropane in two steps following literature
In order to investigate optimal reaction conditions for the
methods.15,16 The radiolabeling precursor, 3-toluenesulfonyloxy- chlorination step, small-scale reactions were conducted with
propyl thiocyanate, was prepared from 3-bromopropanol by non-radioactive fluoropropyl thiocyanate. Chlorine gas was
Scheme 2
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Z. Li et al
Scheme 3
bubbled through the aqueous solution and the reaction was extraction, that cause loss of the desired radioactive product.
monitored by GC-MS. From the model reactions, we found that In order to simplify these procedures, we investigated chlorina-
water is the only suitable solvent for the reaction; mixtures of tion of the thiocyanate on a C-18 solid phase extraction column
water with CH3CN and/or ether failed to provide the sulfonyl (100 mg). After the fluoride incorporation reaction, water was
chloride. The GC peak at 2.85 min identified as the fluoropro- added to the solution and the [18F]fluoropropyl thiocyanate was
pylsulfonyl chloride was observed to increase within 2–3 min, trapped on a C-18 column. Chlorine gas was passed through the
but after additional time the amount of product decreased and column to convert thiocyanate into sulfonyl chloride. After
more by-products were observed. Thus, optimal conditions for purging with argon to remove excess chlorine, [18F]fluoropro-
the conversion of thiocyanate to sulfonyl chloride were pylsulfonyl chloride was eluted with CH2Cl2 through a Na2SO4
bubbling chlorine through an aqueous solution for 2–3 min.
For the radiochemical conversion, evaporation of the ethereal hydrochloride containing
column and into a solution of 1-phenylalanine ethyl ester
equivalent triethylamine. This
1
solution led to loss of the volatile intermediate [18F]fluoropropyl improved procedure increased the yield of sulfonyl chloride
thiocyanate. We found that the addition of water (1 mL) to the from thiocyanate to 71.274.2% (n 5 3) (decay corrected), the
ethereal solution of [18F]fluoropropyl thiocyanate, cooling to overall radiochemical yield from fluoride to 25.772.3% (n 5 3)
01C, followed by gentle evaporation of the organic solvents (decay corrected), and shortened the overall reaction time from
under an argon stream effectively reduced the loss of radio- delivery of aqueous [18F]fluoride until isolation of the product
activity to less than 5%. Residual amounts of ether or CH3CN from HPLC to 90 min. The radiochemical purity was 499%.
that may have been left in the aqueous solution did not seem to
The secondary amine, 1-(2-methoxyphenyl)-piperazine, was
adversely affect the chlorination reaction. Chlorine gas was radiolabeled using a similar procedure. Because the substrate is
bubbled slowly (single bubbles observed) through the ice-cold a free base, no triethylamine was required. The radiochemical
solution for 3 min, followed by slowly bubbling argon to purge yield for the reaction between 1-(2-methoxyphenyl)-piperazine
the excess chlorine. The aqueous solution was extracted with and [18F]fluoropropylsulfonyl chloride was 69.478.7% (n 5 6)
CH2Cl2. The radiochemical yield of [18F]fluoropropylsulfonyl and the overall yield was 22.879.1% (n 5 6) (decay corrected).
chloride from [18F]fluoropropyl thiocyanate in water was The radiochemical purity was 499%.
59.4711.6% (n 5 7) (decay corrected).
Sulfonyl chloride coupling reactions were also explored on a Experimental
small scale using the product from chlorination of non-
General
radioactive fluoropropyl thiocyanate to guide the radiochemical
procedure. Initially reactions between fluoropropylsulfonyl
Kryptofix [2.2.2] was purchased from EM Reagents and chlorine
chloride and L-phenylalanine ethyl ester hydrochloride using
gas was obtained from Air Products and Chemicals Inc. L-
Phenylalanine ethyl ester hydrochloride (99%), 1-(2-methoxy-
GC-MS analysis showed that the fluoropropylsulfonyl chloride
phenyl)-piperazine (98%), 1-bromo-3-fluoropropane (98%), 3-
bromo-1-propanol (97%), and other common reagents were
retrospect, we may have predicted the deleterious effects of
purchased from Aldrich Chemical Company and used as
two equivalents of triethylamine in methylene chloride failed.
peak at 2.85 min disappeared, but no new peak was observed. In
residual water. At pH46.7 sulfonyl chlorides are known to
received. Solvents were obtained from commercial sources
hydrolyze by direct nucleophilic attack by water.17,18 Removal of
water from methylene chloride extract with a small Na2SO4
column and using one equivalent of triethylamine permitted the
reaction to proceed. We dissolved the amine and 1 equivalent of
triethylamine in CH2Cl2 and then added the Na2SO4 dried
solution of fluoropropylsulfonyl chloride. The mixture was
heated at 851C for 10 min and then at 1051C for an additional
5 min. From GC-MS, the sulfonyl chloride peak at 2.85 min
disappeared and a new peak at 7.43 min formed, which was
identified as the expected product based on comparison of the
mass spectral fragment ions at 208, 226, and 176 with an
authentic product.
We subsequently carried out the radiochemical reaction
between [18F]fluoropropylsulfonyl chloride and L-phenylalanine
ethyl ester hydrochloride utilizing the conditions described
above to produce compound a. High radiochemical yield was
achieved (80.576.5%; n 5 7) for this coupling step (decay
corrected).
and were used without further purification. 1H NMR and 13C
NMR were obtained on a Bruker Avance 300 spectrometer at
300 and 75 MHz, respectively, using tetramethylsilane as internal
standard. HPLC-MS was obtained on a ThermoFinnigan LCQ
spectrum coupled to a HP1100 HPLC system using electrospray
as the ionization method with HPLC employing a Phenomenex
Luna C-18 column (150 mm ꢁ 4.6 mm) and isocratic elution (50%
CH3CN: 50% NH4OAc) unless otherwise noted. Analytical HPLC
employed a Phenomenex C-18 column (150 mm ꢁ 4.6 mm)
eluted with 40% CH3CN and 60% NH4OAc (50 mM) at 1 ml/
min. Gas chromatography utilized a Restek RTX5-MS column
with oven temperature programming (501C for 2 min, pro-
grammed at 301C/min to 2701C).
Chemistry
Synthesis of 3-Toluenesulfonyloxypropyl Thiocyanate
3-Bromopropanol (2 g, 14.4 mmol) and potassium thiocyanate
(1.4 g, 14.4 mmol) were dissolved in MeOH (30 mL). The reaction
mixture was stirred at 601C for 5 h.
The conversion of thiocyanate into sulfonyl chloride during
this three-step radiosynthesis still contained procedures, includ-
ing tedious evaporation of solvents and
a liquid–liquid
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Z. Li et al
Solvent was removed under reduced pressure. The residue for 60–90 min. Generally, this method produces [18F]fluoride ion
was taken up in water (20 mL) and extracted with CHCl3 with a specific radioactivity exceeding 400 GBq/mmol. Aliquots
(2 ꢁ 50 mL) and the combined organic layers were dried (20–200 ml) of the irradiated water were used for individual
(Na2SO4) and evaporated. The 3-hydroxypropyl thiocyanate experiments in this study.
was used for the next reaction without further purification.
3-Hydroxypropyl thiocyanate (1.5 g, 12.8 mmol) and triethyla-
mine (1.78 mL, 12.8 mmol) were dissolved in CHCl3 (25 mL).
Synthesis of [18F]Fluoropropylsulfonyl Amides
To a 1 mL V-vial containing 4 mmol of potassium carbonate in
20 mL of water and 8 mmol of Kryptofix 2.2.2. in 40 mL of
acetonitrile, aqueous F-18 fluoride activity (10–15 mCi) was
added. The water was evaporated with an argon stream while
heating to 1051C in a heating block. In order to encourage
further removal of residual water, three portions of anhydrous
acetonitrile (100 mL) were added and each, in turn, evaporated
under the argon stream while heating in the hot block. To the
above vial containing the anhydrous [18F]fluoride ion, 3-
toluenesulfonyloxypropyl thiocyanate (4 mg) in 100 mL acetoni-
trile was added. The vial was sealed and heated on the heating
block at 1051C for 10 min. The reaction mixture was cooled to
room temperature and diluted with water (1 mL). The solution
was passed through a 1 mL (100 mg) C-18 BondElut column,
excess liquid blown out with argon, and chlorine gas was passed
through the C-18 column for 2 min. The column was purged
with argon for 15 s and [18F]fluoropropylsulfonyl chloride, which
had formed on the column, was eluted with dichloromethane
(1 mL). The dichloromethane solution was passed through a
sodium sulfate column into a 10 mL test tube containing 5 mg
amine (for 1-phenylalanine ethyl ester hydrochloride, 1.5 mL
triethylamine was added) in 1 mL dichloromethane. The test
tube was heated at 801C for 10 min and 1051C for 5 min until the
solvent was evaporated. Acetonitrile (250 mL) was added and the
entire solution was injected onto a semipreparative HPLC
column (Phenomenex Luna C-18(2) 250 ꢁ 10 mm) and eluted
with 50% CH3CN, 50% 50 mM NH4OAc at 5 mL/min. The eluate
was monitored with online radioactivity and UV detectors
(220 nm). The fraction containing the product was collected.
Radioactivity assay of the product was corrected for decay to the
start of the reaction and radiochemical yield calculated. An
aliquot of the product was reinjected onto an analytical HPLC
column (Phenomenex Luna C-18(2) 150 ꢁ 4.6 mm eluted with
40% CH3CN, 60% 50 mM NH4OAc at 1 mL/min) to verify
radiochemical purity and identity based on retention time. For
each of the two radiochemical products, the radioactivity peak
co-eluted with the peak of the authentic product. In addition we
were able to obtain mass spectral data on the co-eluting mass
peak from these no-carrier-added syntheses. [18F](S)-ethyl 2-(3-
Toluenesulfonyl chloride (2.5 g, 12.8 mmol) in CHCl3 (5 mL)
was added dropwise to this solution at 01C. The reaction
mixture was stirred overnight at room temperature. The solvent
was evaporated and the residue taken up in CHCl3 (25 mL). The
solution was washed with water (10 mL ꢁ 2), dried (Na2SO4), and
1
evaporated. H NMR (CDCl3) d: 2.19 (tt, 2H, J 5 5.7, 6.6 Hz), 2.47
(s, 3H), 3.02 (t, 2H, J 5 6.9 Hz), 4.19 (t, 2H, J 5 5.7 Hz), 7.38 (d, 2H,
J 5 8.1 Hz), 7.79 (dd, 2H, J 5 1.5, 8.6 Hz); 13C NMR (CDCl3) d: 21.7,
29.1, 29.9, 66.8, 111.4, 127.9 (2C), 130.1 (2C), 132.5, 145.3.
Synthesis of (S)-ethyl 2-(3-fluoropropylsulfonamido)-3-phenylpro-
panoate (a)
L-Phenylalanine ethyl ester hydrochloride (1.15 g, 5 mmol) and
triethyl amine (1.50 mL, 10 mmol) were dissolved in CH2Cl2
(20 mL). Fluoropropylsulfonyl chloride (0.80 g, 5 mmol) was
added. The solution was heated at reflux for 2 h. NaOH (1 N,
20 mL) was added and the organic layer was separated. The
aqueous layer was extracted with CH2Cl2 (20 mL ꢁ 2) and the
combined organic layers were dried (Na2SO4) and evaporated.
The residue was subjected to flash chromatography eluting with
Hexane:EtOAc [80:20] to yield the desired product (1.38 g, 92%).
1H NMR (CDCl3) d: 1.29 (t, 3H, J 5 7.2 Hz), 2.02 (m, 2H), 2.86 (t, 2H,
J 5 7.5 Hz), 3.01 (dd, 1H, J 5 7.5, 13.8 Hz), 3.16 (dd, 1H, J 5 5.1,
13.8 Hz), 4.23 (q, 2H, J 5 7.2 Hz), 4.35 (m, 2H), 4.49 (dd, 1H,
J 5 5.7 Hz), 4.79 (d, NH, J 5 9.3 Hz), 7.18–7.36 (m, 5H); 13C NMR
(CDCl3) d: 14.1, 24.9 (J 5 20), 39.6, 49.9 (J 5 4.5), 57.2, 62.1, 81.54
(J 5 166), 127.5, 128.8 (2C), 129.5 (2C), 135.4, 171.4. GC-MS
7.49 min, m/z 5 244.30 [M1HꢂC3H5O2]1, 226.21 [M1HꢂC7H7]1,
and 176.35 [M1HꢂC3H7SO2FN]1.
Synthesis of 1-(3-fluoropropylsulfonyl)-4-(2-methoxyphenyl)pipera-
zine (b)
1-(2-Methoxyphenyl)-piperazine (0.96 g, 5 mmol), triethyl amine
(0.75 mL, 5 mmol), and fluoropropylsulfonyl chloride (0.80 g,
5 mmol) were dissolved in CH2Cl2 (20 mL). The solution was
heated at reflux for 2 h. NaOH (1 N, 20 mL) was added and the
organic layer was separated. The aqueous layer was extracted
with CH2Cl2 (20 mL ꢁ 2) and the combined organic layers were
dried (Na2SO4) and evaporated. The residue was subjected to
flash chromatography on silica gel eluting with 25% ethyl
fluoropropylsulfonamido)-3-phenylpropanoate:
HPLC-ESI-MS:
m/z [M11] 5 318: calculated (C14H20FNO4S) m/z 317.11. [18F]1-
(3-fluoropropylsulfonyl)-4-(2-methoxyphenyl)piperazine]: HPLC-
ESI-MS: m/z [M11] 5 317; calculated (C14H21FN2O3S) 316.13.
1
acetate in hexane to yield the desired product (1.40 g, 89%). H
NMR (CDCl3) d: 2.31 (m, 2H), 3.08–3.18 (m, 6H), 3.49–3.52 (m, 4H),
3.90 (s, 3H), 4.43 (t, 1H, J 5 5.7 Hz), 4.73 (t, 1H, J 5 5.7 Hz),
6.89–6.96 (m, 3H), 7.06 (m, 1H); 13C NMR (CDCl3) d: 24.6 (J 5 21), Conclusion
44.9 (J 5 4.5), 46.1 (2C), 50.5 (2C), 55.5, 81.8 (J 5 166), 111.3,
118.6, 121.1, 123.8, 140.4, 152.2.
A new and efficient radiolabeling agent, [18F]fluoropropylsulfonyl
chloride, was developed and successfully reacted with both
primary and secondary amines. Optimal reaction conditions were
determined for each step and all the reactions had very good
reproducibility. The optimized three-step procedure required
90min from delivery of aqueous [18F]fluoride until isolation of the
product. The overall yields for the reaction with phenylalanine
ethylester and 1-(2-methoxyphenyl)-piperazine were 25.772.3%
(n 5 3) and 22.879.1% (n 5 6) (EOB), respectively. Since many
Radiochemistry
Radionuclide Production
[18F]Fluoride aqueous solutions were prepared by a 18O(p, n)18F
reaction in a GE PETrace cyclotron using a 1.8 ml target of 95%
18O-enriched water irradiated by a 14.1 MeV beam at 20–25 mA
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Z. Li et al
interesting biological compounds contain an amino group, this
new method may prove useful in the preparation of new F-18-
labeled radiopharmaceuticals for PET imaging.
[6] R. A. Ferrieri, in Handbook of Radiopharmaceuticals, Chapter 7 (Eds.: M.
J. Welch, C. S. Redvanly), Wiley, Chichester, UK, 2003, pp. 229–282.
¨
[7] D. Block, H. H. Coenen, G. Stocklin, J. Label. Compd. Radiopharm.
1987, 24, 1029–1042.
[8] D. Block, H. H. Coenen, G. Stocklin, J. Label. Compd. Radiopharm.
1988, 25, 201–215.
¨
Acknowledgement
[9] D. Y. Chi, M. R. Kilbourn, J. A. Katzenellenbogen, M. J. Welch, J. Org.
Chem. 1987, 52, 658–664.
[10] K. C. Lee, D. Y. Chi, J. Org. Chem. 1999, 64, 8576–8581.
Funding for this research was provided from the intramural
research program of the National Institute of Biomedical
Imaging and Bioengineering. We acknowledge the cyclotron
¨
[11] S. Comagic, M. Piel, R. Schirrmacher, S. Hohnemann, F. Rosch, Appl.
¨
Radiat. Isot. 2002, 56, 847–851.
group in the NIH Positron Emission Tomography Department for [12] A. A. Wilson, J. N. Da Silva, S. Houle, Appl. Radiat. Isot. 1995, 51,
765–770.
the isotope production.
[13] Y. Wang, S. Chackalamannil, W. Chang, W. Greenlee, V. Ruperto, R.
A. Duffy, R. McQuade, J. E. Lachowicz, Biorg. Med. Chem. Lett. 2001,
11, 891–894.
[14] C. W. Lindsley, Z. Zhao, W. H. Leister, J. O’Brien, W. Lemaire, D. L.
Williams Jr., T.-B. Chen, R. S. L. Chang, M. Burno, M. A. Jacobson, C.
References
Sur, G. G. Kinney, D. J. Pettibone, P. R. Tiller, S. Smith, N. N. Tsou, M. E.
Duggan, P. J. Conn, G. D. Hartman, J. Med. Chem. 2006, 1, 807–811.
[1] J. S. Fowler, A. P. Wolf, Acc. Chem. Res. 1997, 30, 181–188.
[2] M. E. Phelps, J. C. Mazziotta, Science 1985, 228, 799–809.
[3] M. E. Phelps, Proc. Natl. Acad. Sci. USA 2000, 97, 9226–9233.
[4] K. Hamacher, H. H. Coenen, G. Stockling, J. Nucl. Med. 1986, 27,
235–238.
[15] W. C. Howell, J. E. Millington, F. L. M. Pattison, J. Am. Chem. Soc.
1956, 78, 3843–3845.
[16] J. E. Millington, G. M. Brown, F. L. M. Pattison, J. Am. Chem. Soc.
1956, 78, 3846–3847.
[17] H. K. Hall, J. Am. Chem. Soc. 1956, 78, 1450–1454.
[18] J. F. King, J. Y. L. Lam, S. Skonieczny, J. Am. Chem. Soc. 1992; 114,
1743–1749.
[5] M. C. Lasne, C. Perrio, J. Rouden, L. Barre, D. Roeda, F. Dolle, C.
Crouzel, Contrast Agents II: Top. Curr. Chem. 2002, 222, 201–258.
J. Label Compd. Radiopharm 2008, 51 23–27
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