Sultone opening with [18F]fluoride: An efficient 18F-labelling strategy for PET imaging

Article abstract of DOI:10.1039/c1cc14435a

Sultones were subject to ring opening by nucleophilic attack with [ ¹⁸F]fluoride to afford easily purified ¹⁸F-labelled hydrophilic sulfonated products in high yields. A two-step sequence including radiofluorination and coupling to l

Full text of DOI:10.1039/c1cc14435a

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 11465–11467
www.rsc.org/chemcomm
COMMUNICATION
18
Sultone opening with [18F]fluoride: an efficient F-labelling strategy for
PET imagingw
´ ´ ´ ´
Sebastien Schmitt, Cedric Bouteiller, Louisa Barre and Cecile Perrio*
Received 21st July 2011, Accepted 13th September 2011
DOI: 10.1039/c1cc14435a
Sultones were subject to ring opening by nucleophilic attack with
[18F]fluoride to afford easily purified 18F-labelled hydrophilic
sulfonated products in high yields. A two-step sequence including
radiofluorination and coupling to lysine was then developed from
a bis-sultone precursor as a model approach for the labelling of
biopolymers.
Scheme 1 Labelling concept using the sultone opening with an
18F]fluoride anion.
[
With its suitable decay properties [97% b+, Emax (b+) =
635 keV, t1/2 = 109.7 min], fluorine-18 represents the ideal
radionuclide for positron emission tomography (PET), a
sensitive and powerful technique for molecular imaging in
animal and human subjects in vivo.1 However, incorporation
of fluorine-18 into biopolymers (i.e. peptides, proteins, oligo-
nucleotides or antibodies) that are becoming more widely
used as in vivo imaging agents remains problematic.2 Despite
recent advances in a direct method by formation of 18F–Si or
18F–B bonds,3 current labelling strategies involve multistep
approaches that include introduction of readily prepared
[18F]FÀ into small organic prosthetic groups, their activation
and subsequent coupling to specific functional groups within
the macromolecule. Every method has limitations in terms of
the number of reaction steps involved, overall reaction time,
labelling yield of the prosthetic group used, efficiency of the
subsequent conjugation to the biomolecule, chemoselectivity
of the conjugation step, complexity for automation, easiness
to purify the final radiolabelled product, specific activity and
in vivo stability of the radiotracer and also the influence of
the prosthetic group on ligand pharmacokinetics. Although
a limited number of chemical reactions have been utilized
to incorporate the prosthetic groups into biopolymers
[mainly acylation, alkylation, oxime or hydrazine formation,
and Huisgen 1,3-dipolar cycloaddition (click chemistry)],
a variety of 18F-labelled prosthetic groups have been reported.
The latter usually are of lipophilic nature that has been
proved to lead to increased hepatobiliary excretion.4 To our
knowledge, 18F-PEGylation5 and glycosylation6 were the two
main strategies developed so far to improve the biokinetics
of labelled peptides. As an alternative, hydrophilic prosthetic
groups were considered highly desirable.
In recognition of the issues discussed above we set out to
develop a platform technology based on the sultone opening
with an [18F]fluoride anion which would allow the production
of water soluble sulfonated 18F-labelled compounds
(Scheme 1). Sultones are known to be prone to ring opening
by nucleophilic attack.7 Surprisingly, no example with fluoride
has been reported so far. Access to 18F-labelled biopolymers
by our chosen method would be achieved starting from
appropriately functionalized sultones according to a two-step
procedure including radiofluorination then ligation to the
target vector. We hypothesized that the apolar sultone/polar
sulfonic derivatives conversion would be advantageous in
terms of the purification of the radiofluorinated sulfonic acid
derivatives, whilst facilitating automation of the process.
Indeed, a simple reverse phase SPE would permit to recover
the sulfonated product whereas any sultone precursor would
be retained on the solid support, thus avoiding the presence of
the excess reactive precursor in the conjugation step.
Initial efforts were focused on studying radiofluorination
of simple model propane and butane sultones 1–6. The
non-radioactive (fluorine-19) fluorosulfonates 7–12 used as
reference compounds for the corresponding labelled products
were obtained quantitatively by reaction of the sultones 1–6 in
acetonitrile at 110 1C for 3 h with either TBAF or KF in the
presence of an equimolar amount of the Kryptofix2.2.2s
(K222) cryptand. Under these conditions, no difference of
reactivity between the sultones 1–6 was observed. Radiofluori-
nation reactions were carried out in acetonitrile using azeo-
tropically ‘‘dried’’ [18F]fluoride in the form of its K+/
Kryptofix2.2.2s/18FÀ complex in the presence of K2CO3.
Conversion of sultones 1–6 to the corresponding [18F]fluoro-
sulfonates [18F]7–[18F]12 was found to be strongly dependent
on the reaction conditions and on the starting sultones.
LDM-TEP, CEA/DSV/I2BM/CI-NAPS UMR6232, CNRS,
´
Universite de Caen Basse-Normandie, Cyceron, Boulevard Henri
Becquerel, 14074 Caen cedex, France. E-mail: perrio@cyceron.fr;
Fax: 0033 (0)231470275; Tel: 0033 (0)231470281
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/c1cc14435a
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11465–11467 11465

View Article Online
Fig. 1 Opening of sultones 1–6 with FÀ or 18FÀ (scheme) and results for the synthesis of [18F]fluorosulfonates [18F]7 ( ), [18F]8 ( ), [18F]9 ( ),
[
18F]10 ( ), [18F]11 ( ) and [18F]12 ( ) at 110 1C (graph).
Results obtained for radiofluorinations at 110 1C showed that
the highest radiochemical yields (RCYs 4 80%) were
obtained using the benzyl propane sultone 1 and the benzo-
sultone 6 (Fig. 1). Benzyl and cyanobenzyl butane sultones 2
and 4 were slightly less reactive (60–65% RCYs). The RCY
from cyanobenzyl propane sultone 3 was only moderate
(45%), whereas it did not exceed 15% from the benzoyl
propane sultone 5. It is noteworthy that in all assays, the
[18F]fluorosulfonates [18F]7–[18F]12 were the only radioactive
products recovered besides the unreacted [18F]fluoride. More-
over, the optimum RCYs were reached at 5 min, and did not
move after a prolonged reaction time.
Although highly reactive, the benzosultone 6 may be of minor
interest as the resulting sulfonate [18F]12 displays the fluorine
atom at the poorly stable benzylic position.8
The facility for purification was checked with the conversion
of the sultone 1 to the [18F]fluorosulfonate [18F]7 taken as the
representative example. After radiofluorination of the sultone
1 (5 mg) for 5 min at 50 1C in acetonitrile (500 mL), the
reaction mixture was subject to purification by SPE using
a Sep-pak C-18 cartridge. The overall radioactive fraction
collected (1 mL) containing both [18F]fluorosulfonate [18F]7
and unreacted [18F]fluoride was injected into HPLC. The UV
trace displayed the presence of sultone 1 in an amount less than
10 mg (o50 nmol), lower than those of the final fluorosulfonate
product 7 (92 mg; 0.4 mmol).
The next step was to validate the sultone opening with
[18F]fluoride for biopolymer labelling. The starting sultone
was supposed to bear a functionality appropriate for ligation
with a biopolymer and compatible with the radiofluorination.
Having in hands the cyano[18F]fluorosulfonate [18F]9, we first
thought to develop hydrolysis of the cyano group into carboxylic
acid for further ligation to the biopolymer by acylation with
a free amino group. However, attempts to perform hydrolysis
of the non-radioactive cyanofluorosulfonate 9 under basic9
In order to find milder conditions, we examined the radio-
fluorination of sultones 1–6 at rt and 50 1C (Table 1). The
optimum RCYs were obtained at rt for 5 min for the sultone 6
(entry 6), and at 50 1C for 2 min for both the sultones 1 (entry 1)
and 3 (entry 3). The RCYs dramatically decreased for sultones
2, 4 and 5 (entries 2, 4 and 5). In regard to the overall results, a
significant or larger superiority in ring opening with [18F]fluoride
for benzyl sultones over benzoyl sultones, for benzyl sultones
over cyanobenzyl sultones, and finally in general for propane
sultones over butane sultones (as previously demonstrated
with nucleophiles other than fluorides7) could be concluded.
Table 1 Selected reaction conditions for the radiofluorination of sultones 1–6 to [18F]fluorosulfonates [18F]7–[18F]12a
Entry
Sultone
[
18F]-Fluorosulfonate
T/1C
Time/min
2
RCYb (%)
80
110
50
rt
2
10
80
83
1
2
3
4
1
2
3
4
[
[
[
[
18F]7
18F]8
18F]9
18F]10
110
50
5
15
65
32
110
50
2
2
45
42
110
50
5
15
60
20
5
6
5
6
[
[
18F]11
18F]12
110
15
15
110
50
rt
5
5
5
82
83
85
b
a 18F-Labelling was carried out from 4–6 mg of sultones 1–6 in 500 mL of CH3CN. Radiochemical yield (RCY) of [18F]fluorosulfonates
[
18F]7–[18F]12, calculated after HPLC isolation, decay corrected. Mean value from 4–7 runs (range: Æ5%).
c
11466 Chem. Commun., 2011, 47, 11465–11467
This journal is The Royal Society of Chemistry 2011

View Article Online
Scheme 2 Opening of the bis-sultone 13 with FÀ or 18FÀ then with amine (a conversion rate determined by 1H NMR; b RCY calculated from
[
18F]TBAF, determined after HPLC separation, and decay corrected, mean value from 5 runs, range: Æ2%, *—SPE included).
or acidic10 conditions failed. Defluorination was observed in
all cases (data not shown). Based on the results obtained with
benzylsultone 1, we then designed the bis-sultone 13 as an
attractive labelling precursor (Scheme 2). The strategy for
biopolymer labelling starting from the bis-sultone 13 would
be the consecutive ring opening of the two sultone moieties
first with [18F]fluoride to lead to the intermediate [18F]14, then
with amine without the need for any additional reagents. In the
non-radioactive synthesis, the fluorination of the bis-sultone
13 to the fluorosulfonate 14 was performed with TBAF in
acetonitrile at rt for 24 h (94% conversion). Amination with
ethylamine and lysine chosen as model amine compounds was
achieved in an acetonitrile/water mixture at rt for 24 h to yield
the disulfonates 15 and 16 (87 and 82% conversion from 13
respectively). Radiofluorination of the bis-sultone 13 was
carried out in acetonitrile using azeotropically ‘‘dried’’
[18F]TBAF in the presence of nBu4NHCO3. The highest
RCY of [18F]fluorosulfonate 14 (67% before SPE, 50% after
SPE) was obtained at 70 1C for 5 min. Amination of the
[18F]fluorosulfonate 14 was performed in a water/acetonitrile
mixture and was nearly quantitative when achieved at 110 1C
for 15 min. According to a one-pot procedure (no SPE of
[18F]14), final disulfonates [18F]15 and [18F]16 were obtained in
60 and 55% RCYs, respectively, from [18F]TBAF. The total
synthesis of [18F]16 including SPE for both [18F]14 and [18F]16
was carried out in 36% RCY from [18F]TBAF. No traces of
the starting bis-sultone 13 were detected by HPLC analysis
(UV trace) of [18F]16.
radiofluorination approach and opened new perspectives in
targeted PET imaging using biopolymers. Further develop-
ments in both radiochemistry and radiotracer development
are underway in the laboratory.
Notes and references
1 M. E. Phelps, Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 9226;
S. M. Orkavi, Eur. J. Nucl. Med., 2001, 28, 929; M. C. Lasne,
C. Perrio, J. Rouden, L. Barre, D. Roeda, F. Dolle and C. Crouzel,
Top. Curr. Chem., 2002, 222, 201; H. H. Coenen, PET-radio-
pharmaceuticals: fluorinated compounds, Clinical Molecular
Anatomic Imaging: PET, PET/CT and SPECT/CT, Lippincott
Williams & Wilkins, 2003, ch. 16; S. M. Ametamey, M. Honer and
P. A. Schubiger, Chem. Rev., 2008, 108, 1501; L. Cai, S. Lu and
V. W. Pike, Eur. J. Org. Chem., 2008, 2853.
2 H. J. Wester and M. Schottelius, Ernst Schering Res. Found.
Workshop, 2007, 79; S. Lee, J. Xie and X. Chen, Chem. Rev.,
2010, 110, 3087; D. E. Olberg and O. K. Hjelstuen, Curr. Top.
Med. Chem., 2010, 10, 1669; B. Kuhnast and F. Dolle
Radiopharm., 2010, 3, 174.
´
, Curr.
3 R. Schirrmacher, G. Bradtmoller, E. Schirrmacher, O. Thews,
J. Tillmanns, T. Seissmeier, H. G. Buchholz, P. Bartenstein,
B. Wangler, C. M. Niemeyer and K. Jurkschat, Angew. Chem.,
Int. Ed., 2006, 45, 6047; R. Ting, C. Harwig, U. auf dem Keller,
S. McCormick, P. Austin, C. M. Overall, M. J. Adam, T. J. Ruth
and D. M. Perrin, J. Am. Chem. Soc., 2005, 127, 13094.
4 M. Glaser, M. Morrison, M. Solbakken, J. Arukwe, H. Karlsen,
U. Wiggen, S. Champion, G. M. Kindberg and A. Cuthbertson,
Bioconjugate Chem., 2008, 19, 951.
5 Z. Wu, Z. B. Li, W. Cai, L. He, F. T. Chin, F. Li and X. Chen, Eur.
J. Nucl. Med. Mol. Imaging, 2007, 34, 1823; Z. Wu, Z. B. Li,
K. Chen, W. Cai, L. He, F. T. Chin, F. Li and X. Chen, J. Nucl.
Med., 2007, 48, 1536; D. E. Olberg, A. Cuthbertson,
M. Solbakken, J. M. Arukwe, H. Qu, A. Kristian, S. Bruheim
and O. K. Hjelstuen, Bioconjugate Chem., 2010, 21, 2297.
6 J. Auernheimer, I. Dijkgraaf and H. J. Wester, in Recent Advances
of Bioconjugation Chemistry in Molecular Imaging, Carbohydration
of Radiolabeled Peptides, ed. X. Chen, 2008, p. 95.
7 For a review, see: D. W. Roberts and D. L. Williams, Tetrahedron,
1987, 43, 1027.
8 Y. Magata, L. Lang, D. O. Kiesewetter, E. M. Jagoda,
M. A. Channing and W. C. Eckelman, Nucl. Med. Biol., 2000,
27, 163.
9 G. Getvoldsen, A. Fredriksson, N. Elander and S. Stone-Elander,
J. Labelled Compd. Radiopharm., 2004, 47, 139.
10 S. F. Wnuk, S. M. Chowdhury, P. I. Garcia Jr. and M. J. Robins,
J. Org. Chem., 2002, 67, 1816.
In summary, we have developed a new efficient and clean
radiofluorination method based on the sultone opening with
[18F]fluoride. This method has led for the first time to water
soluble [18F]fluoro sulfonates which can be easily purified by
simple SPE. The methodology has been successfully extended to
a two-step sequence including radiofluorination then coupling
to lysine starting from a bis-sultone. This sequence was achieved
with high radiochemical yields without any additional reagents.
In this context, we believe that this procedure has a strong
potential to label macromolecular substrates with fluorine-18.
The overall work enlarged the scope of the nucleophilic
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11465–11467 11467