Enantiospecific synthesis of 2-[18F]fluoro-l-phenylalanine and 2-[18F]fluoro-l-tyrosine by isotopic exchange

Article abstract of DOI:10.1039/c0ob00440e

2-[¹⁸F]Fluoro-l-phenylalanine and 2-[¹⁸F]fluoro-l- tyrosine have been developed as promising radiopharmaceuticals for molecular imaging using positron emission tomography (PET). However, the lack of a convenient radiosynthetic pathwa

Full text of DOI:10.1039/c0ob00440e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantiospecific synthesis of 2-[18F]fluoro-L-phenylalanine and
2-[18F]fluoro-L-tyrosine by isotopic exchange†
Johnny Castillo Melea´n, Johannes Ermert* and Heinz H. Coenen
Received 16th July 2010, Accepted 4th October 2010
DOI: 10.1039/c0ob00440e
2-[18F]Fluoro-L-phenylalanine and 2-[18F]fluoro-L-tyrosine have been developed as promising
radiopharmaceuticals for molecular imaging using positron emission tomography (PET). However, the
lack of a convenient radiosynthetic pathway has limited their practical use. In this work a new three-step
nucleophilic synthesis of these compounds starting from [18F]fluoride is described. Corresponding
precursors (1a and 1b) were 18F-fluorinated by isotopic exchange, followed by the removal of an
activating formyl group with Rh(PPh3)3Cl and subsequent hydrolysis of protecting groups in acidic
medium. All reactions were carried out using both conventional and microwave heating. Conventional
heated reactions yielded the desired products 2-[18F]Fphe and 2-[18F]Ftyr in 43% and 49% whereas
radiochemical yields of 34% and 43%, respectively, were obtained when they were heated by microwaves.
Under optimized conditions the enantiomeric purity was ≥94% for both radiopharmaceuticals.
As an alternative,
a nucleophilic method for the no-
Introduction
carrier-added (n.c.a.) regiospecific radiofluorination of 2-
[18F]Ftyr has been developed.9 However, the required multi-
step and built-up synthesis starting from small benzaldehyde
derivatives10 is technically complex and thus difficult to auto-
mate. Recently, a three-step procedure allowed the radiosyn-
thesis of c.a. 6-[18F]fluoro-L-DOPA starting from the pre-
cursor (2S,5S)-tert-butyl-5-(4-benzyloxy-2-fluoro-formylbenzyl)-
2-tert-butyl-3-methyl-4-oxoimidazolidine-1-carboxylate 1b fol-
lowing the sequence: isotopic exchange – Baeyer–Villiger oxi-
dation – hydrolysis.11 In the work here the reaction sequence
has been modified and instead of the Baeyer–Villiger oxidation
a decarbonylation reaction using Rh(PPh3)3Cl was performed
(Scheme 1).
2-[18F]Fluoro-L-phenylalanine (2-[18F]Fphe) 3a has proven to be
a useful radiopharmaceutical for the study of neutral amino acid
transport at the blood brain barrier in vivo in humans.1 On the
other hand, 2-[18F]fluoro-L-tyrosine (2-[18F]Ftyr) 3b, unlike other
halogenated amino acids, is almost quantitatively incorporated
into proteins lending it as interesting tracer for imaging of the
protein synthesis in vivo.2 Since the accumulation of 2-[18F]Fphe
and 2-[18F]Ftyr enable to distinguish tumours from normal tissue,
positron emission tomography (PET) studies of their uptake are
of clinical value for the diagnosis of brain tumors.3,4 In spite
of the potential of these compounds the lack of a convenient
radiosynthetic methodology for their preparation has limited a
wider use in nuclear medicine practice.
Up to now, the synthesis of [18F]fluoroaromatic amino acids have
predominantly been performed via electrophilic radiofluorination.
The electrophilic approach is applicable because many of those
compounds have a low toxicity and therefore they can be used
in carrier-added (c.a.) form.5 Direct electrophilic synthesis of
these tracers was carried out with [18F]F2 and [18F]AcOF on
phenylalanine and tyrosine as well as on O-acetylated tyrosine.
However, their radiochemical yield and isomeric purity were not
satisfactory.6 Fluorodemetallation and specially fluorodestanny-
lation have been found most efficient in order to achieve aromatic
[18F]fluoroamino acids in routine production. In the case of
2-[18F]Ftyr, O,N-di-Boc-2-triethylstannyltyrosine ethyl ester has
proven to be a suitable precursor for its radiosynthesis.7 In spite
of the success of this method, the electrophilic pathway is limited
to relatively low amounts of radioactive product at elevated cost.8
Furthermore, the electrophilic radiofluorination methodology is
not established in every PET centre.
Scheme 1 General radiosynthetic pathway to 2-[18F]Fphe and 2-[18F]Ftyr.
Results and discussion
Radiofluorination
The first step of the radiosynthetic pathway pursued here for
labelling of the title compounds is an isotopic 18F-for-19F ex-
change. Previous work on nucleophilic aromatic 18F-substitution
of benzaldehydes using both, model compounds and complex
Forschungszentrum Ju¨lich GmbH, Institut fu¨r Neurowissenschaften und
Medizin, INM-5: Nuklearchemie, D-52425, Ju¨lich, Germany. E-mail:
j.ermert@fz-juelich.de; Fax: +492461612119; Tel: +492461613110
† This publication is part of the web themed issue on fluorine chemistry.
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Table 1 Influence of temperature, time and kind of anion activation on the RCY of the isotopic exchange reaction on 1aa,b
10 min
20 min
Entry
PTCc/mmol
Temp ◦
C
[18F]1a (%)
4a (%)
[18F]1a (%)
4a (%)
1
2
3
4
5
6
TBAHCO3 [2.3]
TBAHCO3 [5.2]
TBAHCO3 [8.5]
TBAHCO3 [17.0]
TBAHCO3 [5.2]
[K222]2CO3 [13.0]
130
130
130
130
150
130
28
51
60
61
26
26
0
6
10
17
24
40
39
57
59
52
—
14
0
7
14
30
—
50
a 1 mL DMF, 15 mmol 1a, conventional heating (oil bath). b SD = 5%. c PTC = phase transfer catalyst for [18F]fluoride activation.
precursors, have shown that the use of DMF as solvent and
temperatures above 100 ◦C gave the best radiochemical yields
(RCY).11,12 Table 1 summarizes the results obtained for the
optimization of the labelling conditions for precursor 1a under
conventional heating. Entries 1 to 4 show that an increase of
the base concentration led to higher labelling yields; but also the
formation of an additional new product was evidenced by both
TLC-UV and radio-TLC analyses.
tion mixture creating an inverted temperature gradient compared
to conventional thermal heating.14 Due to these characteristics
microwave heated reactions are faster and in some cases more
selective than those under conventional heating.
Fig. 1 shows the RCY of compounds [18F]1a and 4a in
dependence of the applied microwave power. It can be seen that
the total RCY increases with power, however, at about 50 W the
undesired diastereomer 4a starts to appear and its yield increases
also with elevated power.
In order to identify the side product a cold experiment was
carried out and the new compound was isolated and analyzed by
1
NMR. The H spectrum revealed that the new species was the
diastereomer 4a (see Scheme 2), resulting from epimerization in
position 5 of the imidazolidinone system. As a further evidence of
this statement, the D-enantiomer of [18F]3a could be identified
at the end of the synthetic procedure via comparison of the
authentic standard compound using chiral HPLC. The increase
◦
of the temperature to 150 C did not provide better RCY but a
diastereomeric 1 : 1 mixture of the compounds [18F]1a and 4a after
10 min. Routine 18F-labeling conditions using Kryptofix2.2.213
provides the undesired diastereomer 4a even as major product.
Fig. 1 Dependence of the RCY of [18F]1a and 4a as function of the
microwave power. 15 mmol 1a, TBAHCO3 5.1 mmol, 1 mL DMF, 1 min.
Table 2 compares the optimized results obtained with the
synthesis of [18F]1a and [18F]1b under conventional and microwave
heating. It can be noticed that either conventional or microwave
heating produce a similar RCY. The main difference is the reaction
time, where the microwave heated reaction is ten times faster than
that with heating by oil bath. The RCY of the compounds [18F]1
are limited due to the occurrence of the diastereomers 4.
Scheme 2 Epimerization of 1a,b during the isotopic exchange reaction.
Based on these results, the conditions described in entry 2 of
Table 1 were selected in further experiments for the labelling of
precursor 1a under conventional heating.
Similarly, the labelling reaction with precursor 1b generates the
products [18F]1b and 4b following the trends previously described
for the compound 1a, i.e. the fluorine exchange yield increases
with the increase of both, the concentration of the base and of the
temperature, in detriment of the radiochemical purity. The best
RCY of [18F]1b was 59% while that of 4b was 4%. These results
were obtained using 15 mmol of precursor, 6.4 mmol of TBAHCO3
and 1 mL of DMF at 130 ◦C for 10 min.
In an attempt to improve the isotopic exchange process the
reaction was performed using microwave heating. Microwave
irradiation produces efficient internal heating by direct coupling of
microwave energy with the molecules that are present in the reac-
Table 2 Optimized RCY of labelling of 1a,b by isotopic exchange using
both conventional and microwave heatinga
Entry
Precursor
Heatingb
Time/min
[18F]1 (%)
4 (%)
1
2
3
4
1a
1a
1b
1b
CH
MH
CH
MH
10
1
10
1
51
42
59
53
6
5
4
4
a SD = 5% (CH), 1% (MH). b CH: conventional heating (oil bath), MH:
microwave heating.
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Table 3 Solvent effect on the RCY of the decarbonylation reaction on
Decarbonylation
[18F]1aa,b
The removal of the activating formyl group was performed
with Rh(PPh3)3Cl (Wilkinson’s catalyst). Using this reagent for
decarbonylation, however, a stoichiometric reaction is required
due to the formation of stable Rh(PPh3)2(CO)Cl as secondary
product. Optimization studies were carried out using compound
[18F]1a as starting material under similar conditions as those
described by Plenevaux and co-workers for the decarbonylation
of [18F]fluorobenzaldehydes.15 Dioxane was used as solvent and
the reaction◦solution was magnetically stirred for 20 min in an oil
bath at 150 C. Since the labeled compound [18F]1a is chemically
indistinguishable from the precursor 1a they can not be separated
and the amount of the Rh complex was calculated as the equivalent
molar quantity of 1a.
Fig. 2 graphically depicts the obtained results. Using equimolar
amounts of starting material and organometallic reagent 64 5%
of the desired compound 2a was observed in the radio-HPLC
analysis (System A) as well as 21 7% of the starting material
[18F]1a and 15 3% of an unknown compound. Increasing the
amount of Wilkinson’s catalyst to 1.5 eq improved the conversion
of the starting material to 99% and a RCY of 85 8% of the
desired compound 2a. Further increase of the amount of catalyst
did not cause any improvement.
Entry Solvent
Rh eq. Temp ◦ Unknown (%) [18F]1a (%) 2a (%)
C
1
2
3
4
Dioxane
Benzonitrile 2.0
Benzonitrile 2.0
1.5
150
150
180
150
14
—
15
62
1
85
60
67
22
40
18
16
DMF
2.0
a SD = 5%. b 15 mmol [18F]1a, 20 min.
yield of the unknown product. The overall best conditions for
decarbonylation, however, were those ones described in entry 1
of the Table 3 with an almost quantitative conversion of [18F]1a
and in total only 15% of other labeled compounds than product
2a. This could be isolated by use of a silica gel column and a
solvent mixture of ethyl acetate in petroleum ether (30%) while the
unknown compound remained attached on the stationary phase.
A microwave heated version of the decarbonylation reaction
was also developed. In this case compound [18F]1b was used for
the optimization procedure and benzonitrile was preferred over
dioxane as solvent since it shows better absorption of microwaves.
The reaction was irradiated with 100 W during 50 s. Figure 3
shows the distribution of radioactivity among products formed as
function of the amount of Wilkinson’s catalyst. In contrast to the
conventionally heated reaction both, the conversion of [18F]1b and
the yield of the desired compound 2b, increased with the amount
of the Rh complex.
Fig. 2 Radioactivity distribution of [18F]1a, 2a and unknown compound
as function of the amount of Rh complex. 15 mmol of [18F]1a, 1 mL of
dioxane, 20 min.
Fig. 3 Radioactivity distribution of [18F]1b, 2b and unknown compound
as function of the amount of Rh complex. 15 mmol of [18F]1b, 1 mL of
benzonitrile, 50 s.
In 2007 Shen and coworkers published
a study deal-
ing with the decarbonylation reaction of poly-substituted
[18F]fluorobenzaldehydes with Rh(PPhe3)3Cl.12 Also there the
formation of an unknown polar compound besides the desired
product was observed. They found a relationship between the
occurrence of the unknown compound and the kind of solvent,
pointing out benzonitrile as the medium of choice for the reaction.
Using benzonitrile as solvent at 150 ◦C the decarbonylation of
[18F]1a provided a mixture of the starting material and the desired
compound 2a in 40 : 60 proportion while the unknown compound
was not detected after 20 min reaction time (Table 3, entry 2). In
orde◦r to improve the conversion, the temperature was raised to
180 C. This time 15% of the unknown compound was detected
while the conversion of [18F]1a was still incomplete (Table 3, entry
3). On the other hand, the use of DMF as solvent produced the
unknown compound as major product (Table 3, entry 4).
When using 4 equivalents of the Rh complex the desired
compounds 2a and 2b were obtained in yields of 83
1%
and 81 1%, respectively. Although neither the yields nor the
selectivity of the microwave heated reactions were better than
those by conventional heating. The reproducibility and specially
the reaction time was again considerably improved by the change
to microwave heating. As with conventional heating again here
an optimal reaction time (50 s) was found, with lower RCY at
shorter times but increased formation of the unknown product
above.
The decarbonylated product was purified using a silica gel
cartridge. Due to the higher boiling point of benzonitrile, the
solvent was not evaporated but the reaction mixture rather diluted
with 5% ethyl acetate in petroleum ether and then passed via
syringe through the column where the reaction products were
In further experiments using dioxane as solvent it was observed
that a reaction time shorter than 20 min decreases the conversion
yields of [18F]1a while a longer reaction time increases the
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retained. A second portion of the same solvent mixture was used
in order to assure the total elution of the benzonitrile. The desired
compound 2b was then eluted with a more polar solvent mixture
as described for the elution of 2a.
Experimental
General
Dry solvents were purchased from Aldrich and Merck, Germany.
All solvents were used without further purification.
Wilkinson’s catalyst was purchased from Aldrich,
Germany. Hydroiodic and hydrobromic acids were acquired
from Merck, Germany. Hydrochloric acid was purchased from
KMF Laborchemie Handels GmbH, Germany. The precursors
Hydrolysis
In previous reports the hydrolysis of imidazolidinones has been
carried out with concentrated HI or HBr and temperatures of
◦
200 ◦C and 150 C, respectively.11,16 The need of such harsh
conditions is due to the high stability of the amide bond.17 In
this work hydrolysis with all typical mineral acids (HI, HBr and
HCl) was performed resulting in quantitative hydrolysis yields at
190 ◦C during 30 min no matter which acid was used. Several
experiments were performed in order to achieve similar results
with diluted acids, e.g. 1.0 to 7.5 N HCl, however they were
unsuccessful. For further experiments concentrated HCl was used
and yielded quantitatively the hydrolyzed products.
The microwave heated version of this reaction gave also quanti-
tative yields while saving reaction time when the temperature/time
control of the device was used in order to keep the temperature at
140 ◦C for 20 min. The application of high power microwaves was
avoided with HCl because of the rapid generation of overpressure
which can lead to the explosion of the reaction vessel.
The conventional heated reactions yielded the desired products
2-[18F]Fphe and 2-[18F]Ftyr in 43% and 49% whereas 34% and 43%
RCYs, respectively, were obtained when microwave heating was
applied. However, 38 min of total preparation time were saved with
the latter. The products were obtained with good enantiomeric
purity of ≥ 94%. The e.e. achieved for 2-[18F]Fphe was 88% while
an e.e of 92% was obtained in the case of 2-[18F]Ftyr.
(2S,5S)-tert-butyl
2-tert-butyl-5-(2-fluoro-5-formylbenzyl)-3-
methyl-4-oxoimidazolidine-1-carboxylate (1a) and (2S,5S)-tert-
butyl 5-(4-(benzyloxy)-2-fluoro-5-formylbenzyl)-2-tert-butyl-3-
methyl-4-oxoimidazolidine-1-carboxylate (1b) were prepared
following a procedure described elsewhere.18
Experiments under microwave heating were performed using a
CEM Discover (Matthews, USA) single-mode microwave reactor
system. Thin layer chromatography (TLC) was performed on
precoated plates of silica gel 60 F254 (Merck, Germany) and the
compounds were detected at 254 nm. Radioactivity on radio-TLC
was detected on a Raytest minigita device (Raytest, Germany).
High-performance liquid chromatography (HPLC) separations
were achieved with a Knauer pump, a Knauer K-2500 UV/VIS
detector, a manual Rheodyne injector (20 mL or 1.0 mL loop), and
a NaI(Tl) well-type scintillation detector (EG&G Ortec; model
276 Photomultiplier Base) with an ACE Mate Amplifier and
BIAS supply (Ortec) for radioactivity detection. Data acquisition
and interpretation were performed with Gina software (Raytest
Germany).
Chromatographic systems
System A. Analytic HPLC of the 18F-labelled compounds
[18F]1 and 2 was performed with a reverse-phase Kromasil 100–5
C18 column (250–4.6 mm; CS Chromatographieservice GmbH).
Elution was performed at a constant flow rate of 1 mL min-1 with
acetonitrile–water (70 : 30).
Specific activity
The specific activity in isotopic exchange procedures obtained is a
function of both, the quantity of labelling precursor and starting
[18F]fluoride activity. Corresponding to the amount of starting
material the maximum amount of carrier that can be found in
2-[18F]Fphe and 2-[18F]Ftyr preparations described in this work is
2.8 mg and 3.0 mg, respectively. Using the electrophilic radioflu-
orination by destannylation it has been reported that batches of
2-[18F]Ftyr can be obtained in activities of 1.41 GBq with a specific
activity of around 74 GBq/mmol,7 which corresponds to a carrier
content of approximately 3.8 mg. This amount is bigger than the
maximum amount of carrier with the isotopic exchange procedure
in development with low starting radioactivity of ca. 300 MBq per
experiment. Thus, in production runs with >10 GBq of n.c.a.
[18F]fluoride, it is expected that the specific activity of the title
compounds will still increase several times as compared to those
achieved by electrophilic procedures.
System B. Analytic HPLC of 2-[18F]Fphe and 2-[18F]Ftyr was
performed with an analytic reverse-phase Synergi 4m Hydro-RP
80A column (250–4.6 mm; Phenomenex). The mobile phase was
aqueous acetic acid (0.1%) used at a flow rate of 1 mL min-1.
System C. Preparative HPLC was carried out with a Synergi
4m Hydro-RP 80A column (250–10 mm; Phenomenex). The
mobile phase was aqueous ethanol (2%), and the flow rate was
4 mL min-1.
System D. The enantiomeric purity of the radiopharmaceu-
ticals was determined by HPLC using a Crownpak CR (1) 5m
column (150–4 mm; Daicel Chemical Industries) and aqueous
HClO4 (0.025 M) as eluent at a flow rate of 1 mL min-1. Peak
recording was achieved by UV detection at 261 nm.
Conclusions
Radiochemistry
A new procedure for the radiosynthesis of 2-[18F]Fphe and 2-
[18F]Ftyr has been developed. The three-step approach can be
performed either under conventional or microwave heating leading
to RCY of over 34% with an enantiomeric excess of >88% for both
compounds. This work is the first example of the radiosynthesis of
18F-labeled aromatic amino acids via a decarbonylation reaction
with Rh(PPh3)3Cl.
Preparation of TBA18F. N.c.a. [18F]fluoride was produced
via the 18O(p,n)18F nuclear reaction by bombardment of an
isotopically enriched [18O]water target with 17 MeV protons
at the JSW cyclotron BC 1710 (FZ Ju¨lich).19 The produced
[18F]fluoride was isolated from the irradiated water through
electrochemically supported adsorption on a Sigradur-Anode
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(HTW Hochtemperatur-Werkstoffe GmbH) and desorption into
500 mL of pentadistilled water after recovery of the 18O enriched
water.20 An aliquot of the [18F]fluoride solution was added to
17.5–130 mL (2.6–17.0 mmol) of a 0.13 M tetrabutylammonium
bicarbonate solution (TBAHCO3)21 The mixture was diluted with
1.0 mL of dry acetonitrile and transferred via syringe to a reaction
flask. The solvent was evaporated under a stream of nitrogen at
80 ◦C and 650 mbar. The azeotropic evaporation was repeated
twice with 1.0 mL of acetonitrile and afterwards the vial was
evacuated for 5 min at 20–30 mbar.
AcOEt–P.E. After the solvent mixture was evaporated, 250 mL of
hydrochloric acid were added and the reaction mixture was heated
with microwaves to 140 ◦C for 20 min (Ramp: 150 W, 15 s, Hold:
20 min).
Notes and references
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2 H. H. Coenen, P. Kling and G. Sto¨cklin, J. Nucl. Med., 1989, 30, 1367–
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3 (a) K. Wienhard, K. Herholz, H. H. Coenen, J. Rudolf, P. Kling, G.
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5 H. H. Coenen, in PET Studies on Amino Acid Metabolism and Protein
Synthesis, ed. B. M. Mazoyer, W. D. Heiss and D. Comar, Kluwer
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6 H. H. Coenen, K. Franken, P. Kling and G. Sto¨cklin, Int. J. Radiat.
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7 E. Hess, S. Sichler, A. Kluge and H. H. Coenen, Appl. Radiat. Isot.,
2002, 57, 185–191.
8 E. Hess, G. Blessing, H. H. Coenen and S. M. Qaim, Appl. Radiat. Isot.,
2000, 52, 1431–1440.
9 C. Lemaire, S. Gillet and M. Kameda, J. Label. Compd. Radiopharm.,
2001, S857–S859 44(suppl).
General procedure for the radiosynthesis of 2-[18F]Fphe and 2-
[18F]Ftyr under conventional heating. A solution of 10–15 mmol
of the precursor in 1.0 mL DMF was added to the dried residue
◦
of TBA18F. The mixture was heated at 130 C for 10 min. After
labelling, the DMF solution was diluted with water (15 mL), and
passed through a pre-conditioned LiChrolut RP-18e cartridge
(Merck, Germany). The product was eluted from the cartridge
with 2.0 mL acetonitrile and then the solvent evaporated at 80 ◦C
and 650 mbar. A solution of 1.5 eq. of Wilkinson’s catalyst in 1 mL
dioxane was added to the dry residue and the mixture was stirred
for 20 min at 150 ◦C. The dioxane was distilled off, the residue
suspended in 1 mL of a solution of ethyl acetate in petroleum
ether (30% AcOEt/P.E.) and then filtered through a silica gel plug
(650 mg silica gel in a 3 mL polyethylene filtration tube). The
reaction vial was washed with an extra portion of the solution
(1 mL) and the compound was then eluted with 4 mL of the
same mixture. The solvent mixture was evaporated and 250 mL
of hydrochloric acid were added and the reaction was heated to
190 ◦C and stirred for 30 min.
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General procedure for the radiosynthesis of 2-[18F]Fphe and 2-
[18F]Ftyr under microwave heating. A solution of 10–15 mmol of
the precursor in 1.0 mL DMF was added to the dried residue of
TBA18F. The mixture was irradiated with 50 W microwaves during
1 min. The purification of the labelled compound was carried out
using the same procedure described above. A solution of 4.0 eq.
of Wilkinson’s catalyst in 1 mL benzonitrile was added and the
mixture was irradiated with 100 W microwaves during 50 s. The
reaction mixture was diluted with 10 mL of a solution of ethyl
acetate in petroleum ether (5% AcOEt–P.E.) and then passed
through a silica gel column (see above). The desired compound
was then eluted from the column with 5 mL of a solution of 30%
19 S. M. Qaim, J. C. Clark, C. Crouzel, M. Guillaume, H. J. Helmecke,
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