A resin-linker-vector approach to radiopharmaceuticals containing 18F: Application in the synthesis of O-(2-[18F]- Fluoroethyl)-L-tyrosine

Article abstract of DOI:10.1002/chem.201202474

A Resin-linker-vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide ¹⁸F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene-bound arylsulfonate linker with [¹⁸F]-fluoride ion. Three model linker-vector molecules 7 a-c containing different alkyl spacer groups were assembled in solution from (4-chlorosulfonylphenyl)alkanoate esters, exploiting a lipase-catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker-vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8 a-c with acetate, butyrate and hexanoate spacers, which were characterised by using magic-angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8 a, b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4-fluorobutyl)phenylcarbamic acid tert-butyl ester (9) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60 %) of the ¹⁸F- labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O-(2-[¹⁸F]-fluoroethyl)-L-tyrosine ([ ¹⁸F]-FET), delivering protected [¹⁸F]-FET in >90 % RCY. Acid deprotection gave [¹⁸F]-FET in an overall RCY of 41 % from the RLV. Copyright

Full text of DOI:10.1002/chem.201202474

DOI: 10.1002/chem.201202474
18
A Resin-Linker-Vector Approach to Radiopharmaceuticals Containing F:
Application in the Synthesis of O-(2-[18F]-Fluoroethyl)-l-tyrosine
Amy C. Topley,[a] Valerio Isoni,[a] Thomas A. Logothetis,[a] Duncan Wynn,[b]
Harry Wadsworth,[b] Alex M. R. Gibson,[b] Imtiaz Khan,[b] Neil J. Wells,[a]
Cꢀcile Perrio,[c] and Richard C. D. Brown*[a]
Dedicated to Professor Philip Parsons on the occasion of his 60th birthday
Abstract: A Resin-linker-vector (RLV)
strategy is described for the radiosyn-
thesis of tracer molecules containing
the radionuclide 18F, which releases the
labelled vector into solution upon nu-
cleophilic substitution of a polystyrene-
bound arylsulfonate linker with [18F]-
fluoride ion. Three model linker-vector
molecules 7a–c containing different
alkyl spacer groups were assembled in
solution from (4-chlorosulfonylphen-
sulfonate ester as a key step. The
linker-vector systems were attached to
aminomethyl polystyrene resin through
amide bond formation to give RLVs
8a–c with acetate, butyrate and hexa-
noate spacers, which were character-
ised by using magic-angle spinning
(MAS) NMR spectroscopy. On fluori-
dolysis, the RLVs 8a,b containing the
longer spacers were shown to be more
effective in the release of the fluorinat-
ed model vector (4-fluorobutyl)phenyl-
carbamic acid tert-butyl ester (9) in
NMR kinetic studies and gave superior
radiochemical yields (RCYꢀ60%) of
the 18F-labelled vector. The approach
was applied to the synthesis of the ra-
AHCTUNGTRENNUNG
diopharmaceutical O-(2-[18F]-fluoroeth-
Keywords: amino acids · positron-
emission tomography · radiochemis-
try · radiopharmaceuticals · solid-
phase synthesis
yl)-l-tyrosine ([18F]-FET), delivering
protected [18F]-FET in >90% RCY.
Acid deprotection gave [18F]-FET in an
overall RCY of 41% from the RLV.
ACHTUNGTRENNUNGyl)alkanoate esters, exploiting a lipase-
catalysed chemoselective carboxylic
ester hydrolysis in the presence of the
Introduction
0.69 MeV), which has a short path in vivo before its annihi-
lation, giving rise to enhanced resolution in comparison to
11C.[5] The half-life of 18F is 109.8 min, over five times that of
11C, offering more flexibility in radiotracer syntheses and the
investigation of biological processes with slower kinetics, in
which PET scans can be acquired over periods of several
hours.
Positron-emission tomography (PET) is recognised as the
most specific and sensitive means of quantitatively imaging
molecular pathways and interactions in vivo, having a level
of sensitivity unmatched by using other imaging tech-
ACHTUNGTRENNUNG
niques.[1] PET imaging is routinely used in medical diagnos-
tics to locate and assess abnormalities in neurology,[2] cardi-
ology[3] and oncology.[4] Of the radionuclides commonly em-
ployed in PET radiotracers, 18F may be considered to possess
superior properties in the context of nuclear medicine. For
example, 18F emits a relatively low energy positron (up to
Despite the longer half-life of 18F, radiotracers incorporat-
ing this radionuclide still need to be synthesised, purified,
analysed and formulated ready for injection into the subject
as rapidly as possible. In radiofluorination, purification of
the product is complicated by the use of very large, typically
>1000 fold, excess of the labelling precursor. As a conse-
quence, technologies that simplify the isolation and purifica-
tion of the final radiotracer have been of intense interest to
radiochemists.[6] Examples include captive solvent meth-
ods,[7] solid-phase extraction (SPE) techniques by using cat-
[a] Dr. A. C. Topley, V. Isoni, Dr. T. A. Logothetis, Dr. N. J. Wells,
Prof. R. C. D. Brown
Department of Chemistry, University of Southampton
Southampton, Hampshire, SO17 1BJ (U.K.)
Fax : (+44)23-80597574
ACHUTNGERNiNUG onAHCTUNGTRNENiUGN c ion-exchange resins, and the use of solid-supported
aryl–metal intermediates as substrates for electrophilic fluo-
rination.[8–10] The application of tagged or solid-supported
precursors have emerged as technologies to facilitate separa-
tion of the labelled product from reaction co-products and
the large excess of starting material present in reaction mix-
tures.[6] For example, Gouverneur and co-workers have de-
scribed the use of fluorous-tagged sulfonate ester precursors
to 18F-labelled radiotracers and 18F-labelled building blocks,
in which the fluorous tag allows easy clean up by using fluo-
E-mail: rcb1@soton.ac.uk
[b] Dr. D. Wynn, Dr. H. Wadsworth, Dr. A. M. R. Gibson, I. Khan
GE Healthcare, The Grove Centre, White Lion Road
Amersham, Bucks, HP7 9 LL (U.K.)
[c] Prof. C. Perrio
Laboratoire de Dꢀveloppements Mꢀthodologiques en TEP
CNRS, Universitꢀ de Caen-Basse Normandie, Cyceron
Bd Henri Becquerel, 14074 CAEN Cedex 5 (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202474.
1720
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Chem. Eur. J. 2013, 19, 1720 – 1725

FULL PAPER
rous solid-phase extraction (FSPE).[11] It was reported that
the presence of the fluorous tag caused a decrease in the
specific activity of the product compared to a non-fluorous
precursor, possibly due to leaching of [19F]-fluoride ion from
the tag. Sulfonate-tagged intermediates have been obtained
from nucleophilic opening of sultones with [18F]-fluoride
ion, enabling removal of the precursor from the polar sulfo-
nate by using reverse-phase SPE.[12]
We introduced an alternative approach, namely, the resin-
linker-vector (RLV) strategy, for the synthesis of radiotrac-
ers-containing 18F by nucleophilic cleavage of a sulfonate
ester linker by using [18F]-fluoride ion.[13] The RLV approach
was initially developed for the radiosynthesis of [18F]-2-
fluoro-2-deoxy-d-glucose ([18F]-FDG, 2) utilising a perfluor-
oalkylsulfonate linker to immobilise a d-mannose derivative
on polystyrene resin beads, liberating protected [18F]-FDG
into solution upon treatment with [18F]-fluoride ion
(Scheme 1). Unreacted precursor and sulfonate by-product
Results and Discussion
Linkers based on arylsulfonates were identified as suitable
targets based on the widespread application of sulfonate
leaving groups in solution [18F]-fluoridation.[5] The length of
the spacer between the polystyrene support and reactive
centre is important in determining reaction rates in solid-
phase synthesis. Therefore, three 4-alkylphenylsulfonate
linkers with different alkyl spacers were prepared, com-
mencing by Fischer esterification of commercially available
phenylalkanoic acids to give methyl esters 3a–c
(Scheme 2).[16] Chlorosulfonylation of the aryl groups result-
Scheme 2. Synthesis of 4-alkylphenylsulfonate RLVs 8a–c. Reagents and
conditions: a) i) ClSO2OH, CH2Cl2, 08C to RT; ii) AcCl, MeOH, CH2Cl2,
08C; b) (4-hydroxybutyl)phenylcarbamic acid tert-butyl ester (5), Et3N,
DMAP, CH2Cl2, RT (reflux for 4c); c) Novozym 435ꢂ, phosphate buffer
(pH 7), CH2Cl2/acetone, 508C; d) aminomethyl polystyrene resin, HOBt,
DIC, DMF/CH2Cl2. [*] Estimated from sulphur elemental analysis.
Scheme 1. Radiosynthesis of [18F]-FDG (2). Reagents and conditions:
a) Kryptofix 2.2.2, K18F, MeCN, reflux, 10 min; b) HCl (6m), reflux,
10 min.
were retained on the resin and conveniently separated from
the product by a simple filtration process.
ed in partial carboxylate ester cleavage,[17] which was rem-
edied by re-esterification of the crude reaction mixtures
leading to improved yields of the desired sulfonyl chlorides
4a–c. Direct chlorosulfonylation of the free acids was also
investigated, but this returned the desired products in com-
paratively lower yields. The sulfonyl chlorides 4a–c were
then coupled to a model vector molecule, (4-hydroxybutyl)-
phenylcarbamic acid tert-butyl ester (5), to form linker-
vector constructs 6a–c. To complete the synthesis of RLVs
8a–c, the linker-vector constructs would be coupled to ami-
nomethyl polystyrene resin beads by selective formation of
activated carboxylate ester derivatives. Standard conditions
for basic hydrolysis of methyl esters were incompatible with
the sulfonate ester functionality present in 6a–c, so chemo-
selective enzyme-catalysed hydrolysis was applied by using
the supported lipase Novozym 435ꢂ to return the free acids
7a–c in acceptable yields (45–59%).[18] The linker-vector
systems were then coupled to aminomethyl polystyrene
The radiosynthesis of [18F]-FDG required an RLV system
1 containing an exceptionally reactive “triflate-like” sulfo-
nate linker due to the inherent challenge of nucleophilic
substitution with fluoride ion in a sterically encumbered
electron-deficient substrate, namely, the 2-position of a pro-
tected mannose derivative. However, broader application of
the RLV approach would require sulfonate ester linkers
with a spectrum of reactivities that match the demands im-
posed by radiosyntheses of different tracer molecules.[13c,14]
Furthermore, polymer-supported precursors are suited in ap-
plication in automated radiosyntheses. Herein, the develop-
ment of a model RLV system containing an arylsulfonate
linker, suitable for nucleophilic fluoridation, is described.
The utility of the optimised resin-linker system was then il-
lustrated by the radiosynthesis of the radiophamacuetical O-
(2-[18F]-fluoroethyl)-l-tyrosine ([18F]-FET).[15]
Chem. Eur. J. 2013, 19, 1720 – 1725
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1721

R. C. D. Brown et al.
resin by using carbodiimide coupling conditions to give
ples from the NMR probe to agitate the resin. The results
indicate that the rate of cleavage of the fluorinated product
improved with alkyl-chain length for the 4-alkylphenylsulfo-
nate linker, which can be attributed to the relatively greater
flexibility and “solution-like” character provided by the
longer spacers present in RLVs 8a and 8b (Figure 1). The
RLVs 8a–c. Successful coupling was supported by negative
1
ninhydrin tests, on-bead IR, H and 13C NMR spectroscopy.
Loadings were estimated by using sulfur elemental analysis.
To confirm that RLVs 8a–c were suitable substrates for
nucleophilic fluoridation, [19F]-fluoridolysis reactions were
carried out by using KF and Kryptofix 2.2.2 in CH3CN at
808C (Scheme 3).[19] Purification of the fluorinated product
Scheme 3. Nucleophilic fluoridation of the model RLVs 8a–c.
[19F]-9 simply involved filtration of the reaction mixture to
remove the resin followed by elution through a short silica
plug to remove the Kryptofix 2.2.2. In these experiments, in
which a modest excess of [19F]-KF (1.2 equiv) was employed
relative to RLVs 8a–c, the desired fluorinated product [19F]-
9 was the only product obtained in isolated yields of 28, 28
and 27%, respectively. The yields obtained by using limiting
RLV were based upon the loading of the resin obtained
from sulfur analysis and were approximately half of those
obtained from fluoridolysis by using the linker vectors 6a–c
as substrates. However, subsequent radiochemical experi-
ments were carried out by using a large excess of resin rela-
tive to the amount of [18F]-fluoride ion, and given the clean
fluorination chemistry observed, were expected to deliver
high radiochemical yields. To confirm that unreacted linker
vector remained on the resin after reaction with a deficiency
of fluoride ion, RLV 8a was subjected to a series of [19F]-flu-
oridolysis reactions. It is difficult to directly replicate the
conditions typical of radiofluoridation, in which a massive
excess of the labelling precursor is employed, and herein
0.25 equivalents of [19F]-KF were used with respect to the
RLV to facilitate quantification of the released fluorinated
product [19F]-9. The fluorinated product [19F]-9 was obtained
over a total of seven cycles, the first five of which gave con-
sistent yields (34, 41, 45, 30, 45, 4 and 7%, respectively,
based on limiting K19F). These results are consistent with
the majority of unreacted vector remaining attached to the
solid phase through the 4-alkylphenylsulfonate linker.
Figure 1. Relative rates of release of the model fluorinated vector [19F]-9
estimated by using 19F NMR against an internal standard (BnF). Experi-
ments were carried out in duplicate. RLV (19 mmol, BnF (5.3 mmol) in
~
&
CD3CN (0.5 mL) at 408C. 8a: ; 8b: ; 8c: ꢃ.
rate of product formation was seen to be slower during the
initial 20 min, probably because the RLVs were not pre-
swollen in the reaction solvent and the lack of sample agita-
tion in the NMR probe.
Radiolabelling experiments were carried out manually by
using cyclotron-generated [18F]-fluoride with low activity
levels (40–150 MBq), RLV 8a–c, K2CO3 and Kryptofix 2.2.2
in CH3CN with a reaction time of 15 min. Radiochemical
yields of the labelled vector [18F]-9 were established by re-
verse-phase HPLC analysis of the crude reaction mixture
with g-detection, and/or by using radioTLC (Figure 2). The
desired labelled vector [18F]-9 was formed as the major ra-
ACHUTNGRENdNUG ioACHUTNGTRENcNGUN hemical product of the reaction and its identity was con-
firmed by co-injection of the cold standard [19F]-9 and
HPLC analysis. RLVs 8a and 8b containing the longer alkyl
spacers resulted in the highest incorporation of [18F]-fluoride
(ca. 60%), whereas RLV 8c delivered reduced incorpora-
tion (40%). The incorporation for the radiolabelling from
In view of the time constraints imposed when working
with 18F, establishing the relative rates of fluoridolysis for
the different linkers is of interest. Towards this end [19F]-flu-
oridolyses of RLVs 8a–c were conducted at 408C, which
gave a rate of product formation that was convenient to es-
tablish by 19F NMR spectroscopy through integration against
an internal standard (Bn19F). Each reaction was run in du-
plicate, by using 19 mmol of RLV with 1.5 equiv of K19F to
ensure a good level of conversion, and spectra were ac-
quired at 12–15 min intervals periodically removing the sam-
Figure 2. Reverse-phase HPLC analysis of the [18F]-fluoridolysis reaction
mixture from RLV 8b, before Sep-pack filtration. a) UV trace (l=
254 nm) co-injected with [19F]-9 (13.3 mg) as a reference. b) Radioactivity
trace.
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A Resin-Linker-Vector Approach to Radiopharmaceuticals
FULL PAPER
RLV 8a decreased to 34% when carried out without me-
chanical stirring, showing good agitation of the polystyrene
beads to be important, although care is needed to avoid ex-
cessive mechanical damage of the resin beads. Residual
RLV was easily removed by filtration and so the analyses
were not complicated by the presence of large excesses of
unreacted starting material, underscoring the value of the
RLV approach in radiosynthesis.
The HPLC analysis of the [18F]-fluoridolysis reaction of
RLV 8b showed three radioactive peaks due to unreacted
[18F]-fluoride salts, the [18F]-fluorinated product [18F]-9, and
an unidentified radioactive by-product (not observed by ra-
dioTLC; Figure 2b). The UV trace shows a major peak cor-
responding to the co-injected [19F]-9, and a number of minor
UV-active impurities that were not identified due to the
very small amounts of material produced (Figure 2a). The
formation of significant quantities of eliminated or hydro-
lysed by-products was excluded by HPLC comparison of the
reaction mixture against synthesised samples. However, pro-
longed heating of RLV 8b in CH3CN at 1108C in a sealed
vessel, either with or without base, did lead to the formation
of N-phenylpyrrolidine, which co-eluted with the major UV-
active impurity formed during the radiosynthesis. This chem-
ical impurity was not observed at lower temperature (808C),
although no further efforts were made to minimise its for-
mation, because it was produced in a cyclisation side reac-
tion specific to the model RLV system.
Scheme 4. Synthesis of [19F] and [18F]-FET. Reagents and conditions:
a) 2-bromo-2-methylpropane, K2CO3, benzyltriethylammonium chloride
(BTEAC), N,N-dimethylacetamide (DMAC), 558C; b) bromoethanol,
K2CO3, BTEAC, DMF, 508C; c) sulfonyl chloride 4a, Et3N, 4-dimethyl-
AHCTUNGTRENNUNG
aminopyridine (DMAP), CH2Cl2; d) Novozym 435ꢂ, aqueous phosphate
Having demonstrated that high levels of [18F] incorpora-
tion could be achieved from the RLVs 8a and 8b for a
model-vector molecule, attention turned to extend the ap-
proach to an established radiotracer, the tyrosine derivative
buffer (pH 7), CH2Cl2/acetone, 508C; e) amino methyl polystyrene resin,
HOBt, DIC, DMF/CH2Cl2; f) KF, Kryptofix 2.2.2, MeCN, 808C; g) TFA,
DCE, 708C. [*] Estimated from sulphur elemental analysis.
O-(2-[18F]-fluoroethyl)-l-tyrosine
([18F]-10,
[18F]-FET,
Figure 3). [18F]-FET is promising clinically for imaging of
ACHTUNGTRENrNUGN ide linker 4a. Enzymatic hydrolysis of the methyl ester
functionality and coupling of the free acid to the solid sup-
port afforded RLV 16. [19F]-Fluoridolysis of RLV 16 gave a
yield of 50% of protected FET [19F]-17, a significant im-
provement in comparison to the model-fluorinated vector
molecule [19F]-9.
Manually operated radiofluoridolysis of RLV 16 gave a
single major radioactive product, which was shown to be
protected FET [18F]-17 from HPLC analysis (UV and g-de-
tection) of a sample co-injected with authentic [19F]-refer-
ence compound. Furthermore, excellent radiochemical yield
(94%) and radiochemical purity were realised. Deprotection
of the tert-butyl ester and N-Boc groups from [18F]-17 was
achieved by exposure to trifluoroacetic acid (TFA) in 1,2-di-
chloroethene (DCE) at 708C to afford the radiotracer [18F]-
FET ([18F]-10) with a radiochemical yield of 41 and 97.5%
radiochemical purity, the identity of which was confirmed by
HPLC analysis against the unlabelled reference [19F]-10. In
a separate radiolabelling experiment starting with 100 MBq
of [18F]-fluoride, the specific activity of HPLC purified pro-
tected [18F]-FET was determined to be approximately 0.4
MBqmmolꢁ1 by comparison against the reference standard
[19F]-17. No further optimisation of the deprotection process
was carried out although a number of protecting group strat-
egies have been applied in [18F]-FET synthesis.[20]
Figure 3. Structure of the radiotracer O-(2-[18F]-fluoroethyl)-l-tyrosine
([18F]-FET).
gliomas, through exploitation of active uptake of amino acid
derivatives.[15,20] The RLV approach described herein for
[18F]-FET will also be more generally applicable to PET
tracers containing [18F]-fluoroalkyl groups, which reduces
the radiosynthesis time by avoiding the requirement for iso-
lation, purification and further reaction of volatile and/or
sensitive radioactive fluoroakylating reagents.[21]
The solid-phase route to FET commenced with the syn-
thesis of the RLV 16 from N-(tert-butoxycarbonyl)-l-tyro-
sine (11) and the sulfonyl chloride linker 4a (Scheme 4).
First, N-Boc tyrosine was protected as its tert-butyl ester,[22]
followed by phenolic alkylation to give hydroxyethyl deriva-
tive 13 in an overall yield of 67%. Alcohol 13 was subse-
quently O-sulfonylated by reaction with the sulfonyl chlo-
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1723

R. C. D. Brown et al.
Conclusion
[1] T. Jones, Eur. J. Nucl. Med. 1996, 23, 207–211.
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[3] R. Nutt, Mol. Imaging Biol. 2002, 4, 11–26.
A RLV strategy has been described for the radiosynthesis of
tracer molecules containing the radionuclide 18F, in which
the linker has tosylate-like reactivity. The potential for the
application of the 4-alkylphenylsulfonate in practical radio-
syntheses has been illustrated herein by the synthesis of the
radiopharmaceutical [18F]-FET, which is used for imaging of
brain tumours. 4-Alkylphenylsulfonate linkers, containing
varying spacer lengths, were evaluated for application in the
synthesis of a model [18F]-containing radiotracer with longer
alkyl linkers (n=3 and 5) being more effective. The RLV
approach allows facile separation of excess starting material
and sulfonate by-product at the end of the radiosynthesis by
using a straight forward filtration process, leading to good
radiochemical yields in time scales commensurate with prac-
tical application in PET imaging. The 4-alkylphenylsulfonate
linkers described herein compliment the highly reactive per-
fluorosulfonate linkers that we reported previously.
[4] H. Anderson, P. Price, Eur. J. Cancer 2000, 36, 2028–2035.
[5] a) R. Littich, P. J. H. Scott, Angew. Chem. 2012, 124, 1132–1135;
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[6] For reviews, see: a) S. Boldon, I. S. R. Stenhagen, J. E. Moore, S. K.
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Experimental Section
[8] For examples of radiosyntheses using [18F]-fluoride ion trapped on
cationic ion-exchange resins, see: a) G. H. Tang, M. F. Wang, X. L.
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Radiosynthesis of [18F]-FET ([18F]-10): Step 1 ([18F]-labelling): Cyclotron-
produced [18F]-fluoride was separated from 18O-enriched water by using
ion-exchange resin (QMA light, Waters, ABX) after elution with a 1:1
mixture (600 mL) of aqueous potassium carbonate K2CO3 (5 mgmLꢁ1
)
and MeCN. A fraction of the resulting [18F]-fluoride solution [18F]-fluo-
ride (300 mL, 4.83 mCi, 179 MBq) was drawn into a Wheaton vial fol-
lowed by 4,7,13,16,21,24-hexaoxa-1,10-diazabicycloACTHUNRTGNEUNG[8.8.8]hexacosane
(Kryptofixꢂ K222, 4 mg, 10.6 mmol). No additional K2CO3 was used to
avoid the presence of excess base. MeCN (1 mL) was added, and the
mixture was azeotropically dried under a flow of N2 at 1008C. The proc-
ess was repeated three times in a total time of 15 min. The reaction
vessel was cooled to RT, and RLV 16 (30–40 mg) was added followed by
MeCN (500 mL). The stirred reaction mixture was heated to 1108C for
15 min before being cooled and filtered through an acrodisc (syringe
filter). The solution containing the protected [18F]-FET ([18F]-17) was an-
alysed by radioTLC and reverse-phase HPLC (Phenomenex Luna C18(2)
column, 250ꢃ4.6 mm, 5 mm, 20 mL loop, 1 mLminꢁ1 flow rate, l=
254 nm, eluent MeCN/water, linear gradient 40!95% MeCN (25 min)
then 95% MeCN (5 min), 30 min total run time). Step 2 (deprotection):
MeCN was removed under a flow of N2 and a TFA/DCE mixture (1:2,
1 mL) was added in the reaction vessel. The resulting mixture was stirred
at 708C for 10 min, cooled to RT followed by the addition of CH2Cl2
(5 mL) and passed through a silica-gel cartridge (Sepack normal phase,
pre-conditioned with CH2Cl2). The cartridge was washed twice with
Et2O/pentane (1:1, 5 mL), and the [18F]-fluorinated product was eluted
with warm MeOH (2 mL). The solution containing [18F]-FET ([18F]-10)
was analysed by reverse-phase HPLC (Phenomenex Luna C18(2)
column, 250ꢃ4.6 mm, 5 mm, 20 mL loop, 1 mLminꢁ1 flow rate, l=
254 nm, eluent MeCN/water, linear gradient from 5!50% MeCN
(25 min) then 50% MeCN (5 min), 30 min total run time).
[9] For a synthesis of 6-[18F]fluoro-l-DOPA by electrophilic fluorination
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The authors acknowledge financial support from GE Healthcare (T.A.L.,
A.C.T.), EPSRC for a CASE studentship award (A.C.T.) and the Euro-
pean Regional Development Fund (ERDF, ISCE-Chem & INTERRE-
G IVa, program 4061) for a studentship (V.I.).
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Chem. Eur. J. 2013, 19, 1720 – 1725

A Resin-Linker-Vector Approach to Radiopharmaceuticals
FULL PAPER
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Received: July 11, 2012
Revised: November 13, 2012
Published online: December 19, 2012
Chem. Eur. J. 2013, 19, 1720 – 1725
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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