Base/Cryptand/Metal-Free Automated Nucleophilic Radiofluorination of [18F]FDOPA from Iodonium Salts: Importance of Hydrogen Carbonate Counterion

Article abstract of DOI:10.1002/ejoc.201801608

As evidenced by the number of publications and patents published in the last years, the radiosynthesis of 6-[¹⁸F]fluoro-3,4-dihydroxy-L-phenylalanine ([¹⁸F]FDOPA) using the nucleophilic [¹⁸F]F- process remains currently a challenge for the radiochemists scientific community even if promising methods for the radiofluorination of electron-rich aromatic structures were recently developed from arylboronate, arylstannane or iodonium salt precursors. In such context, based on the use of an iodonium triflate salt precursor, we optimized a fast and efficient radiofluorination route fully automated and free from any base, cryptand or metal catalyst for the radiosynthesis of [¹⁸F]FDOPA. Using this method, this clinically relevant radiotracer was produced in 64 min, 27–38 % RCY d.c. (n = 5), >99 % RCP, >99 % ee., and high Am 170–230 GBq/μmol. In addition, this optimization study clearly highlighted the important role of a triflate-hydrogen carbonate counterion exchange during the radiolabeling process to achieve high fluorine-18 incorporation yields.

Full text of DOI:10.1002/ejoc.201801608

A Journal of
Accepted Article
Title: Base/cryptand/metal-free automated nucleophilic radiofluorination
of [18F]FDOPA from iodonium salts: importance of hydrogen
carbonate counterion
Authors: Aurélie Maisonial-Besset, Audrey Serre, Ali Ouadi, Sébastien
Schmitt, Damien Canitrot, Fernand Léal, Elisabeth Miot-
Noirault, David Brasse, Patrice Marchand, and Jean-Michel
Chezal
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801608
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801608
Supported by

10.1002/ejoc.201801608
European Journal of Organic Chemistry
FULL PAPER
Base/cryptand/metal-free
automated
nucleophilic
radiofluorination of [18F]FDOPA from iodonium salts: importance
of hydrogen carbonate counter ion.
Aurélie Maisonial-Besset,*,§,[a] Audrey Serre,§,[a] Ali Ouadi,[b] Sébastien Schmitt,[a] Damien Canitrot,[a]
Fernand Léal,[a] Elisabeth Miot-Noirault,[a] David Brasse,[b] Patrice Marchand,[b] and Jean-Michel
Chezal[a]
Abstract: As evidenced by the number of publications and patents
published in the last years, the radiosynthesis of 6-[18F]fluoro-3,4-
dihydroxy-L-phenylalanine ([18F]FDOPA) using nucleophilic [18F]F-
and deliver [18F]FDOPA. In addition to the difficulty of handling a
radioactive gas, the use of carrier added radioactive F2 which
displays low molar activity (Am, 0.1-0.6 GBq/µmol) was also
problematic for the radiosynthesis of [18F]FDOPA due to the
concomitant formation of non-radioactive [19F]FDOPA presenting
potential pharmacological effects.[5] During the last decade,
significant efforts have been deployed to access to [18F]FDOPA,
from the widely available and no-carrier-added (n.c.a.)
[18F]fluoride ions.[6] However, radiofluorination of such electron-
rich aromatic structure via nucleophilic substitution remains a
highly challenging task. The radiosynthesis of [18F]FDOPA is
also hampered by the presence of an oxygen-sensitive catechol
function and a chiral center requiring a careful control of the
enantiomeric excess (e.e.). The most recent and marked
examples of nucleophilic approaches overcoming these
challenges are depicted in Figure 1. The fully automated multi-
step radiosynthesis (Figure 1, method A) described by Lemaire
process remains currently
a challenge for the radiochemists
scientific community even if promising methods for the
radiofluorination of electron-rich aromatic structures were recently
developed from arylboronate, arylstannane or iodoniums salts
precursors. In such context, based on the use of an iodonium triflate
salt precursor, we optimized a fast and efficient radiofluorination
route fully automated and free from any base, cryptand or metal
catalyst for the radiosynthesis of [18F]FDOPA. Using this method,
this clinically relevant radiotracer was produced in 64 min, 27-38%
RCY d.c. (n = 5), >99% RCP, >99% e.e., and high Am 170-230
GBq/µmol. In addition, this optimisation study clearly highlighted the
important role of a triflate-hydrogen carbonate counterion exchange
during the radiolabelling process to achieve high fluorine-18
incorporation yields.
et al.[7] was based on
a classical aromatic nucleophilic
substitution of an ortho-activated trimethylammonium triflate
precursor with [18F]fluoride ([18F]F-), followed by solid supported
reduction and halogenation of the aldehyde function into benzyl
iodide. The enantioselective introduction of the amino-acid part
was achieved by alkylation with the tert-butyl glycinate-
benzophenone Schiff base in the presence of a chiral phase-
transfer catalyst. Final deprotection with concentrated hydroiodic
acid afforded [18F]FDOPA on the curie level with high
radiochemical yield (RCY), Am, enantiomeric excess (e.e.) and
extraordinary short time of 65 min for such complex multi-step
radiosynthesis procedure. Taking advantage of the most recent
advances in radiofluorination of electron-rich aromatic rings,
[18F]FDOPA has also been obtained with high RCY and e.e. by
copper promoted carbon-fluorine coupling reaction on an
arylboronate precursor[8,9] (Figure 1, methods B1 and B2). The
Introduction
6-[18F]Fluoro-3,4-dihydroxy-L-phenylalanine
([18F]FDOPA)
positron emission tomography (PET) imaging has been used for
more than 30 years for a broad range of clinical applications[1]
including diagnosis and follow up of neurodegenerative
disorders,[2] brain tumours[3] and other malignant diseases.[4]
Despite its obvious clinical utility, [18F]FDOPA was underused
primarily due to a lack of availability. Until a few years ago, the
electrophilic substitution of the corresponding stannylated
precursor with gaseous carrier added radioactive F2 was the only
available radiosynthesis for this radiotracer, thus limiting to a few
number of radiopharmaceutical centres the capacity to produce
protected [18F]FDOPA was also obtained with
a
high
radiolabelling efficiency by copper promoted carbon-fluorine
reaction starting from an arylstannane precursor[10] (Figure 1,
method C) but the following deprotection step to afford
[18F]FDOPA was not reported in this case. Finally, [18F]FDOPA
was produced by [18F]F- nucleophilic substitution of an
asymmetrical diaryliodonium salt[11] (Figure 1, method D)
followed by removal of the protecting groups.
Despite later stage incorporation of fluorine-18, moderate decay-
corrected (d.c.) RCY were obtained for strategies depicted in
methods B1 and D (<15% or even less than 10% for copper-
mediated radiosynthesis when applied on a Synthra platform).
[a]
Dr. A. Maisonial-Besset,* Dr. A. Serre, Dr. S. Schmitt, D. Canitrot, F.
Léal, Dr. E. Miot-Noirault, Prof. Dr. J. M. Chezal
Université Clermont Auvergne, INSERM U1240, Imagerie
Moléculaire et Stratégies Théranostiques, BP 184, 58 rue
Montalembert, F-63000, Clermont Ferrand, France.
*E-mail: aurelie.maisonial@uca.fr
Homepage: https://www.uca.fr/recherche/structures-de-
recherche/laboratoires/imagerie-moleculaire-et-strategies-
theranostiques-781.kjsp
[b]
Dr. A. Ouadi, Dr. D. Brasse, Dr. P. Marchand
Université de Strasbourg, CNRS, IPHC, UMR 7178, 23 rue du
Loess BP 28, F-67000 Strasbourg, France.
§ Both authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801608
European Journal of Organic Chemistry
FULL PAPER
from any base, cryptand and metal catalyst. We also highlight in
this manuscript that the success of such radiofluorination
reaction is highly dependent of the nature on the iodonium
precursor counter ion: herein a HCO3- anion.
Results and Discussion
Synthesis of diaryliodonium salt precursors
According to slight modifications of the procedure previously
published,[11] the target diaryl iodonium salt precursor 6b was
obtained in five steps from commercially available L-DOPA.
Briefly, 1 was produced by esterification and NH-Boc protection
of starting material (Scheme 1). Then, catechol hydroxy groups
were selectively protected as ethoxymethyl ethers to give
compound 2. Regioselective monoiodination with the
combination of iodine and bis(trifluoroacetoxy)phenyl-λ3-
iodane[14] provided 3 in 74% yield (the use of fleshly prepared
bis(trifluoro)phenyl-λ3-iodane[15] is recommended to obtain
reproducible and consistent yields). Compound 3 was converted
into the bis-Boc protected derivative
4
to circumvent
intramolecular interaction during the radiosynthesis between the
iodine (III) center and the NH-Boc function.[16] The fully protected
compound 4 was converted into triflate diaryliodonium salt 6b
using a multistep one-pot procedure via the key intermediate
(diacetoxyiodo)arene 5. The latter was prepared in situ by
treatment of aryl iodine 4 with F-TEDA-2BF4 (Selectfluor©) and
TMSOAc.
methoxyphenyl)trifluoroborate
Treatment
of
5
and
with
TMSTFA
potassium
gave
(4-
the
corresponding diaryliodonium trifluoroacetate salt. The
trifluoroacetate counterion was then successively exchanged
with acetate, hexafluorophosphate and finally triflate to give
radiolabelling precursor 6b.
Figure 1. n.c.a. radiosyntheses of [18F]FDOPA according to Lemaire et al.[7]
(method A), Tredwell et al.[8a] (method B1), Zischler et al.[8b] (method B2),
Makavarage et al.[10] (method C) and Kuik et al.[11] (method D).
Among other limitations, high amount of precursor was required
for method B2 (i.e. 40 mg) while non-radioactive metal
contamination, particularly copper, in the final solutions must be
carefully assessed before human use for methods B and C.
Among the aforementioned strategies and considering that
reducing the overall radiosynthesis time remains a commonly
used solution to enhance RCY with such short half-life
radionuclide, we speculated that the relatively long reaction time
of the iodonium salt procedure (i.e. 117 min, Figure 1, method
D) could be shortened. We proposed to directly elute [18F]F- from
the anion exchange QMA cartridge with an alcoholic solution of
iodonium salts as previously described.[12] This strategy would
also take advantage of eliminating base and cryptand of the
reaction media in order to circumvent any decomposition of the
reactive iodonium salt precursor under the harsh conditions
used for radiolabelling of such structures.[13] Following these
assumptions, we report here the development of a new fully
automatic fast nucleophilic radiosynthesis of [18F]FDOPA free
Scheme 1. Preparation of diaryliodonium salts 6a-e. Reagents and conditions:
(a) i) MeOH, SOCl2, 0 °C then reflux, 16 h; ii) (Boc)2O, THF, sat. aq. NaHCO3,
RT, 2 h, 95%; (b) C2H5OCH2Cl, DIPEA, THF, 0 °C then 40 °C, 15 h, 99%; (c)
I2, K2CO3, PhI(OCOCF3)2, CH2Cl2, RT, 2.5 h, 74%; (d) NEt3, DMAP, (Boc)2O,
MeCN, RT, 29 h, 86%; (e) Selectfluor, TMSOAc, MeCN, RT, 6.5 h; (f) i)
TMSOCOCF3, p-MeOPhBF3K, MeCN, RT, 10 min; ii) 0.5 M aq. NaOAc/AcOH
buffer (pH 5); iii) aq. NaPF6, MeCN, RT; iv) IRA-400 (TfO-) ion-exchange resin,
36%; (g) Sn2Me6, Pd(PPh3)4, 1,4-dioxane, reflux, 1.5 h, 91%; (h) i) p-
MeOPh(IOAc)2, CH2Cl2, -40 °C, 1 h; ii) TFA, -40 °C then RT, 5 h, 74%; (i) 1 M
aq. NaOTf, CH2Cl2, RT, 85%; (j) 1 M aq. NaOTf, NaBF4, NaCl or NaClO4,
CH2Cl2, RT, 87-95%. EOM: ethoxymethyl.
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Several modifications of the final synthesis step have been
made. First, the use of a N2 charged glove-box necessary for the
formation of a highly instable (difluoroiodo)arene intermediate,
1/ Elution of [18F]F- from the QMA cartridge
In order to prevent the decomposition of the precursor under
basic conditions and avoid the time consuming drying procedure
mandatory when using K2CO3/crypt-222, a direct elution of
QMA-loaded [18F]F- with the diaryliodonium salt 6b was
assessed. Based on the work of Richarz et al.[12b] describing a
comparable minimalist approach, we compared different
solvents or mixture of solvents for the elution of [18F]F- (Figure 2).
Consistent with their findings, only protic solvents afforded
suitable elution yields (62 to 97%) with a concentration of 13
µmol / 750 µL of 6b while decreasing the volume of eluent, with
the same amount of precursor, led to decreased elution yields
(data not shown). Furthermore, any attempts to use an aprotic
solvent such as acetonitrile, typically used in fluorine-18
radiochemistry processes, or mixture of aprotic and protic
solvents decreased dramatically the elution yield (<16%). Finally,
we found that a solution of precursor 6b (13 µmol) in a minimum
of 750 µL of methanol revealed to be the most effective
combination to elute [18F]F- initially trapped on the anion
exchange cartridge (97 ± 0.03%, n = 41).
was substituted by
a benchtop procedure under argon
atmosphere. Moreover, the final isolation and purification of 6b
by precipitation in MTBE was not successful and was replaced
by silica gel column chromatography purification. These
modifications could explain the lower yield obtained (36%)
compared to the reported procedure (63%). Alternatively, to this
time-consuming and relatively complex one-pot reaction, we
turned our attention to the recent development described by
Wirth and co-workers[17] for solid-supported synthesis of
iodonium salts. This strategy required the synthesis of
trimethylstannane
7 from aryl iodine derivative 4 using
hexamethylditin and Pd(PPh3)4 as catalyst. Ligand exchange
with (diacetoxyiodo)anisole[18] in the presence of TFA, added in
a
sequential manner at -40 °C, gave diaryliodonium
trifluoroacetate 6a. Complete CF3CO2- to CF3SO3 exchange was
then easily achieved by repeated washes of a solution of 6a in
dichloromethane with an aqueous solution of NaOTf. According
to this protocol, compound 6b was obtained over two steps in
53% yield, comparable to the one described by Kuik et al.[11]
(63%). Regardless to the methods used for the synthesis of 6b,
the structural determinations were fully in agreement with the
previously reported data (see supporting information).
-
Radiofluorination of diaryliodonium salts
We first tested as benchmark the previously reported
radiofluorination method for [18F]FDOPA production via iodonium
salt precursor 6b.[11] The radiosynthesis was performed on a
SynChrom R&D Raytest EVOII platform using 935 to 4470 MBq
of azeotropically dried K[18F]F-crypt-222-carbonate complex and
11.2 ± 0.5 mg (13 µmol) of 6b in anhydrous diglyme at 140 °C
for 5 min. In these conditions, only 8.7 ± 2.3% (n = 3) of the
protected radiofluorinated FDOPA derivative was obtained after
solid phase C18 cartridge extraction. To increase the yield of
incorporation of [18F]F- and try to reproduce the results of Kuik et
al.[11] (i.e. RCY = 14% after deprotection), we increased the
reaction time up to 15 min but without success. It should be
noted that similar values (i.e. 4.5±1.3% RCY) were recently
reported by Collins et al.[19] In the radiolabelling conditions
described above, TLC-monitoring of the reaction mixture
evidenced that no iodonium salt precursor can be detected by
UV revelation of TLC plates already after 2 min at 140 °C
highlighting the high instability of this compound under basic
conditions (K2CO3/crypt-222). In addition, we clearly noticed that
the sensitive precursor had to be freshly prepared, carefully
stored under anhydrous argon atmosphere and protected from
heat, light and moisture.
Figure 2. Percentages (%, ratio between values of activity measured in the
eluate and initially loaded onto the QMA cartridge, n = 2 except for MeOH: n =
-
41) of [18F]F- elution from QMA-HCO3 cartridges depending on the solvent
used for dissolution of the iodonium salt 6b (13 µmol in 750 µL); Mixture 1:
MeCN/3-methylpentan-3-ol, 25/75, v/v; Mixture 2: MeCN/H2O, 90/10, v/v.
Then, we intended to study the influence of the counterion of the
iodonium precursor for the recovery of [18F]F- from the QMA
cartridge. To this end, the five iodonium salts 6a-e (Scheme 1)
-
-
-
-
with Cl-, ClO4 , BF4 , CF3SO3 or CF3CO2 counterions were
-
compared (Figure 3). When using classical QMA-HCO3
cartridges (SepPak Accell Plus QMA Plus Light cartridges,
Waters, 130 mg, preconditioned with K2CO3), moderate elution
-
-
yields were obtained for the BF4 and CF3CO2 iodonium salts.
The best results were observed with iodonium salts bearing Cl-,
We then turned our attention to the direct elution of [18F]F- from
the anion exchange QMA cartridge with an alcoholic solution of
iodonium salt 6b. Our optimisation study was divided in three
parts: 1) elution of [18F]F- from the QMA cartridge, 2)
incorporation of fluorine-18 on the protected structure, and 3)
deprotection step leading to [18F]FDOPA.
-
-
ClO4 , or CF3SO3 counterions (91, 86 and 97% respectively).
We noted that the elution efficiency seemed to be correlated
with pKb values of the corresponding counteranions tested.
Indeed, the stronger the basicity of counterions is, the worse the
elution of [18F]F- gets. As we suspected that all anions present in
the reaction mixture could enter in competition with [18F]F- during
the radiofluorination reaction, we also tried QMA cartridges
-
preconditioned with the corresponding counterion (i.e. Cl-, ClO4 ,
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10.1002/ejoc.201801608
European Journal of Organic Chemistry
FULL PAPER
-
-
-
BF4 , CF3SO3 or CF3CO2 ). In all cases, this preconditioning
strategy did not affect the trapping of [18F]F- on the anion
exchange resin (always higher than 90%). However, for most of
the evaluated anions, the elution yields were lower compared to
commercially available anisole in 43% yield (see supporting
information). For the exchange study, a solution of iodonium salt
8 in CD3OD (750 µL) was passed through a QMA-HCO3
-
cartridge (beforehand washed with 1 mL of methanol and dried
over an argon flow for one min). The percentage of counterion
exchange was then assessed by 1H NMR in CD3OD. After
elution a mixture of iodonium salts was observed. Nearly
complete counterion exchange was obtained using less than 10
µmol of the iodonium salt 8 for the elution (Figure S3,
supplementary information). All signals corresponding to the
former tosylate counteranion could not be detected, confirming
the complete exchange expected.
QMA-HCO3 cartridges (49% for Cl-, 14% for BF4 , 32% for
CF3SO3 and 19% for CF3CO2 ). Interestingly, only the ClO4
iodonium salt 6e provided comparable elution efficiencies (86%
for the QMA-ClO4 vs. 85% for the QMA-HCO3 ). These
experiments highlighted that the HCO3 anions present on the
exchange resin seem to play a key role in the elution process of
the [18F]F-. To clarify this phenomenon, we tried to determine
more precisely the chemical composition of the QMA-HCO3
-
-
-
-
-
-
-
-
-
cartridge eluates. For this study, we used the same
preconditioned QMA-HCO3 cartridges described above and a
All attempts to purify the eluted iodonium salt by column
chromatography or crystallization remained unsuccessful and
led to the complete decomposition of the eluted structure. This
could be explained by the relatively low stability of iodonium
hydrogen carbonate derivatives, which moreover are rarely
-
methanolic solution of iodonium salt 6b which proved to be the
most efficient media to elute [18F]F- (Figure 3). A solution of
precursor 6b in methanol (13 µmol, 750 µL) was then passed
through the cartridge and the alcohol was evaporated under
reduced pressure (we noticed by TLC that the temperature of
the bath had to be lower than 40 °C to prevent the thermal
decomposition of 6b). First, a reduced quantity of precursor
(<70%) was recovered from the QMA cartridge after evaporation
of the eluate. Surprisingly, 1H NMR analysis of the residue in
CD3OD (see Figure S1, supplementary information) indicated no
significant modification of the structure of 6b while only 8% of
the latter could still be detected in the eluate by 19F NMR (see
Figure S2, supporting information). Keeping in mind that the
counterions of diaryliodonium salts can be readily exchanged
with numerous organic or mineral (di)anions,[20] we assumed that
the eluted compound was the diaryliodonium hydrogen
-
found in the literature.[21] In fact, only the presence of the HCO3
counterion was evidenced on crude residue by IR analyses with
a broad vibration band clearly visible at 1351 cm-1 (C=O) (see
Figure S4, supplementary information). To confirm the nature of
the eluted counterion, we tried to visualize the sp2 carbon of the
-
HCO3 anion by NMR 13C analyses. Unfortunately, this signal
could never be detected even with optimisation of the acquisition
parameters. We then decided to use an enriched aqueous
-
[13C]K2CO3 solution to equilibrate the QMA-HCO3 cartridge.
Under these conditions, NMR 13C analysis of the eluate clearly
highlighted the characteristic signal corresponding to the sp2
-
carbon of the HCO3 anion at 161.5 ppm (Figure 4).
-
-
carbonate salt resulting from
exchange.
a supported CF3SO3 /HCO3
Figure 3. Percentages (%, ratio between values of activity measured in the
eluate and initially loaded onto the QMA cartridge, n = 2, except for QMA-
-
-
-
HCO3 , X = CF3SO3 : n = 41) of [18F]F- elution from QMA-HCO3 or QMA
cartridges preconditioned with corresponding anions depending on the
counterion of the iodonium salt used (13 µmol in 750 µL of methanol).
Figure 4. Comparison of 13C NMR spectra of starting iodonium salt 8 and
-
eluate obtained after elution of a 13C-enriched QMA-HCO3 cartridge with 5
In order to evaluate the exact amount of iodonium salt required
µmol of 8 showing the complete conversion of the tosylate derivative into its
to achieve a complete conversion of the counterion on the QMA-
HCO3- analogue.
-
HCO3
cartridges,
bis(4-methoxyphenyl)iodonium-4-
methylbenzenesulfonate (8) was used as a surrogate model.
This iodonium salt was synthesised in one step from
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10.1002/ejoc.201801608
European Journal of Organic Chemistry
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2/ Radiofluorination reaction
mineral bases in the reactor before the radiofluorination reaction
led to a significant decrease of the fixed activity on the glass. To
prevent any side reaction and limit the number of competitive
anions in the reaction mixture, we chose bases containing bulky
cations and carbonate or hydrogen carbonate counterions (i.e.
Cs2CO3, CsHCO3, Bu4NHCO3, etc). Unfortunately, all these
attempts also led to a decrease of the fluorine-18 incorporation
on the iodonium structure compared to the optimized conditions
described above (no additive conditions, Figure 5C).
-
In the next step, we evaluated the influence of such HCO3
exchanges on the radiosynthesis of [18F]FDOPA on a Raytest
SynChrom R&D EVOII bireactor automate. [18F]F- was eluted
-
from the QMA-HCO3 cartridge using 13 µmol of 6b in 750 µL of
anhydrous methanol (elution yield: 97 ± 0.03%, n = 41; %
-
exchange to HCO3 counterion: 92% evaluated by 19F NMR). The
obtained eluate was evaporated under vacuum at 30 °C to
prevent any thermal decomposition of the precursor. Then, 750
µL of diglyme was added to the reactor and heated at 140 °C.
For all time points checked, only around 3% of the desired
fluorine-18 labelled intermediate [18F]9 was observed.
Interestingly, no increase over time could be detected. Also,
variations of the temperature (90 °C, 110 °C, 140 °C, or 160 °C)
did not increase the radiolabelling efficiency. When the amount
-
of precursor used for the elution of the QMA-HCO3 cartridge
was reduced (<13 µmol) to achieve a complete conversion of the
counterion, no incorporation of the [18F]F- could be observed.
Considering the loss of iodonium salt previously observed on the
-
QMA-HCO3 cartridges, we assume that the quantity of precursor
present in the reactor was definitely too low to allow any [18F]F-
incorporation. We then decided to investigate the influence of
the precursor concentration, temperature and solvent used for
the radiofluorination step. As highlighted in Figure 5A, increasing
the concentration of the precursor 6b in diglyme while
decreasing the temperature to 110 °C led to a significantly
higher labelling efficiency (16% in 100 µL diglyme at 110 °C vs
<3% in 750 µL diglyme at 140 °C). Using the optimized
concentration and temperature conditions, we tried to change
the reaction solvent. The use of the aprotic polar solvents (DMF
or DMSO) dramatically impacted the labelling efficiency which
was lower than 3% for all attempts performed (data not shown).
-
To reduce [18F]F-/HCO3 counteranion competition during the
heating process, toluene was then tested as non-polar solvent
and compared to diglyme. When using 200 µL of toluene at
110 °C for 10 min, the labelling efficiency was significantly
higher (Figure 5B, 23 ± 4%, n = 6). Further modifications of the
temperature or reaction time did not improve the percentage of
incorporation of radioactive fluorides.
-
-
In order to evaluate the impact of the CF3SO3 /HCO3 counterion
exchange on the radiofluorination reaction, we used these
optimized radiofluorination conditions on evaporated eluates
obtained from QMA cartridges preconditioned with the same
Figure 5. Influence of: (i) the temperature, concentration (13 µmol of 6b in
various volumes of solvent) and reaction time on the radiolabelling efficiency in
diglyme (A) or toluene (B) and (ii) the addition of traces of mineral or organic
bases in the reactor (C), % were calculated based on the starting [18F]F-
activity; purity of the eluted compound was controlled by radio-TLC (>98%).
-
-
CF3SO3 counterion. In the absence of HCO3 , the reaction
mixture rapidly turned black at 90-100 °C and less than 1% of
the desired radiofluorinated product [18F]9 was detected. The
same observation was made when using ClO4- derivative 6e and
-
ClO4 -preconditioned QMA-cartridge. These findings further
3/ Deprotection step
-
confirmed the importance of the HCO3 counterion to ensure the
Finally, we turned our attention to the deprotection of the
radiofluorinated intermediate [18F]9 obtained after solid phase
extraction. The loss of activity on the solid phase C18 cartridge
was negligible (1.78 ± 0.02%, n = 67). Surprisingly, after
concentration of the ethanolic eluate and final deprotection using
a 3M aqueous H2SO4 solution at 140 °C for 5 min (reported by
Kulk et al.[11]) radio-HPLC analysis of the reaction mixture
revealed that only 16% of the total activity detected accounted
for [18F]FDOPA. The other main radioactive component of the
success of the radiofluorination step.
However, these promising results were counterbalanced by the
loss of activity observed on the reactor vessel. Indeed, working
without any base and cryptand induced typical adsorption of
[18F]F- on the glass wall of the pyrex reactor (50.6 ± 8.4% of the
starting activity, n = 22). To get around this problem, we tried
several pretreatment strategies of the reactor surface (Figure
5C). In most cases, the drying of small amounts of organic or
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European Journal of Organic Chemistry
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mixture was the corresponding methyl ester. An extended
heating time of at least 15 min was necessary to achieve a full
deprotection of the structure. To circumvent this problem and
shorten the reaction time dedicated to the deprotection,
concentrated HBr was used. After concentration of the eluate,
heating at 140 °C for 10 min in 300 µL of concentrated HBr was
then sufficient to achieve the complete deprotection of the
structure and afford [18F]FDOPA without concomitant formation
of radioactive by-products. After dilution of the reaction mixture
with a 1 M aqueous solution of NH4OAc, the crude [18F]FDOPA
was then easily purified by semi-preparative RP-HPLC and
collected to afford [18F]FDOPA in 15.2% RCY, >98% RCP, Am
>150 GBq/µmol (n=3) and e.e. > 99% (chiral HPLC, n=3, see
chromatograms in supplementary information).
efficiencies (29 ± 5%, n = 8). In order to validate the
reproducibility of our radiosynthetic approach, the [18F]FDOPA
was also produced from precursor 18b using a Raytest
SynChrom R&D EVOIII bireactor automate in
a partner
laboratory. While some minor modifications of the protocol were
mandatory to adapt the reaction conditions to this radiosynthesis
module (see supplementary information), the protected
intermediate of [18F]FDOPA was obtained in higher yields (i.e.
46 ± 4%, n = 3). After concentration of the eluate, deprotection
using concentrated HCl at 120 °C for 7 min and purification via
semipreparative RP-HPLC, final [18F]FDOPA was obtained in 64
min, 27-38% RCY d.c. (n = 5), >99% RCP, > 99% e.e., and high
Am 170-230 GBq/µmol (Scheme 3).
To further shorten the overall radiosynthesis time and minimize
the harsh conditions required for the deprotection step, we
investigated the acid-sensitive tert-butyl ester precursor 18b.
The latter was obtained in five steps from the L-DOPA tert-butyl
ester 12 according to the synthetic route described for 6b
(Scheme 2). Precursor 12 was easily produced from
commercially
available
L-tyrosine
using
tert-butyl
acetate/perchloric acid esterification followed by NH-Boc
protection and final oxidation of the aromatic ring into catechol
using freshly prepared 2-iodobenzoic acid.
Scheme 3. A: In house preparation of [18F]FDOPA from 6b following Kuik et
al.[11] protocol compared to our radiosynthetic approach; B: Preparation of
[
18F]FDOPA from tert-butyl ester precursor 18b with our optimized protocol.
Reagents and conditions: (a) [18F]KF-crypt-222-carbonate, diglyme, 140 °C, 5
min; (b) aq. H2SO4 3 M, 140 °C, 5 min; (c) [18F]F-, toluene, 105-110 °C, 10 min;
(d) aq. HBr conc., 140 °C, 10 min; (e) aq. HCl conc., 120 °C, 7 min. EOM:
ethoxymethyl.
Conclusions
We carried out a comprehensive optimization of the nucleophilic
radiosynthetic approach to produce [18F]FDOPA with high molar
activities from iodonium salt precursors. Our experiments clearly
Scheme 2. Preparation of diaryliodonium salt 18b. Reagents and conditions:
(a) tert-butyl acetate, aq. HClO4 (70 wt%), 0 °C then RT, 12 h, 45%; (b) K2CO3,
(Boc)2O, THF/H2O (1/1, v/v), RT, 3 h, 71%; (c) i) 2-iodoxybenzoic acid, DMF,
RT, 30 min; ii) 1 M aq. ascorbic acid, 0 °C, 30 min, 97%; (d) C2H5OCH2Cl,
DIPEA, THF, 0 °C then 40 °C, 24 h, 62%; (e) i) I2, K2CO3, PhI(OCOCF3)2,
CH2Cl2, RT, 4 h, 58%; (f) i) NEt3, DMAP, (Boc)2O, MeCN, 40 °C, 24 h; ii)
(Boc)2O, 40 °C, 23 h, 61%; (g) Sn2Me6, Pd(PPh3)4, 1,4-dioxane, reflux, 1.5 h,
76%; (h) i) p-MeOPh(IOAc)2, CH2Cl2, -40 °C, 1 h, ii) TFA, -40 °C, then RT, 5 h,
67%; (i) 1 M aq. NaOTf, CH2Cl2, RT, 85%. EOM: ethoxymethyl.
-
pointed out the importance of the HCO3 counterion for the
efficiency of fluorine-18 incorporation on such iodonium
scaffolds. Considering that this new and fast nucleophilic
radiosynthetic process for the automated production of
[18F]FDOPA, free from any base, cryptand and metal catalyst,
was evaluated on different automated systems implemented in
two differents facilities (Clermont Ferrand and Strasbourg,
France), we believe that it could be easily transferable to other
laboratories and could provide an alternative to currently
available [18F]FDOPA radiopharmaceutical production.[7,22]
Finally, we assume that this methodology could be successfully
applied to a broad range of iodonium salt precursors for
radiofluorination of electron-rich aryl derivatives.
We attempted the radiosynthesis of [18F]FDOPA using the
precursor 18b and the optimal conditions described above for 6b.
Direct elution of QMA-loaded [18F]F- was realised using a
solution of 13 µmol of 18b in 750 µL anhydrous methanol
(elution yield: 94.8 ± 3.2%, n = 8). The obtained eluate was
evaporated under vacuum at 30 °C. Then, 200 µL of toluene
were added to the reactor and heated at 110 °C for 10 min.
Surprisingly, compared to the corresponding methyl ester, the
protected radiofluorinated [18F]FDOPA was obtained, after solid
phase C18 cartridge extraction, in higher radiolabelling
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10.1002/ejoc.201801608
European Journal of Organic Chemistry
FULL PAPER
Pak light C18 cartridge (Trap 2, scheme S1). After drying under
He flow (250 mL/min), the cartridge was eluted to the second
reactor using 2 mL of ethanol (SC6, scheme S1). The solvent
was removed under vacuum at 70°C under stirring. Shortly
before complete evaporation, concentrated bromhydric acid (300
µL, SC11, scheme S1) was added to the reaction mixture which
was heated to 140°C for 10 min under stirring. After cooling to
35-40 °C, the dark brown/black reaction mixture was buffered
using a 1 M aqueous solution of ammonium acetate (3 mL, SC7,
scheme S1). The solution containing the crude unprotected
[18F]FDOPA was purified via semi-preparative HPLC. The
collected fraction (Rt = 10.5 min) was diluted in saline and
analyzed by analytic radio-HPLC to determine the radiochemical
purity, enantiomeric excess and specific activity.
Experimental Section
Chemistry
Experimental details, full data, 1H and 13C NMR spectra of
compounds 6a-e, 7, 13-18a,b are available in Supporting
Information.
Radiochemistry
1/ Radiosynthesis of [18F]FDOPA from precursor 6b using a
bi-reactor SynChrom R&D EVOII syntheses module
General experimental information
No-carrier-added fluorine-18 (half-life: 109.8 min) was produced
via the [18O(p, n)18F] nuclear reaction by irradiation of a 2.8 mL
>97%-enriched [18O]H2O target (Bruce Technology) on a CPH14
cyclotron (14 MeV proton beam, Cyclopharma laboratories).
Radio thin layer chromatography (radio-TLC) was performed on
Merck pre-coated silica gel (60 F254) plates with a mixture ethyl
acetate/cyclohexane (2/8, v/v) and measured on an AMBIS 400
(Scanalytics, CSPI, San Diego, CA, USA). Analytical HPLC
measurements were performed on a system consisting of an
Agilent HP series 1100 (Hewlett Packard, Les Ulis, France)
combined with a Flow one A500 Radiomatic detector (Packard,
Canberra, Australia). A Reprosil Chiral-AA 8 µm column (250 x
2/ Radiosynthesis of [18F]FDOPA from precursor 18b using
a bi-reactor SynChrom R&D EVOIII syntheses module
General experimental information
No-carrier-added fluorine-18 (half-life: 109.8 min) was produced
via the [18O(p, n)18F] nuclear reaction by irradiation of a 1 mL
>97%-enriched [18O]H2O target (Huayi isotopes Co) on a TR24
cyclotron (16-24 MeV proton beam, Advanced Cyclotron
Systems Inc, ACSI). Radio thin layer chromatography (radio-
TLC) was performed on Millipore aluminium back-coated silica
gel (60 F254) plates with a mixture of ethyl acetate/cyclohexane
(2/8, v/v) and measured on a MiniGita apparatus (Raytest,
Germany). Analytical HPLC measurements were performed on a
system consisting of a Dionex U3000 HPLC (Thermo scientific,
France) combined with a homemade radio-detector (connected
to an UCI 50 interface, Thermo scientific, France) and a diode
array detector. A Synchronis column (250 x 4.6 mm; 5 µm;
Thermo scientific, France) was used with water/acetonitrile (9/1,
v/v) as isocratic eluent mixture at a flow rate of 0.7 mL/min. Semi
preparative HPLC purifications were performed at λ=254 nm.
Radiochemical syntheses and semi-preparative HPLC
purifications were performed using a bi-reactor SynChrom R&D
EVOIII syntheses module (Raytest). Sep-Pak® Light Accell Plus
QMA Cl- or carbonate cartridges (130 mg) and Sep-Pak® light
C18 cartridges were purchased from Waters. A semi-preparative
VP250/10 Nucleodur C18 HTec column (250 x 10 mm; 5 µm;
Macherey-Nagel) was used with water/ethanol (95/5, v/v)
containing 0.1% trifluoroacetic acid as eluent at a flow rate of 2.5
mL/min.
4.6 mm;
8 µm; CIL Cluzeau; France) was used with
water/acetonitrile (9/1, v/v) as isocratic eluent mixture and a flow
of 0.7 mL/min. Unless otherwise indicated, all HPLC purifications
and analyses were performed at λ=254 nm. Radiochemical
syntheses and semi-preparative HPLC purifications were
performed using a bi-reactor SynChrom R&D EVOII syntheses
module (Raytest). Sep-Pak® Light Accell Plus QMA Cl- or
carbonate cartridges (130 mg) and Sep-Pak® light C18
cartridges were purchased from Waters. Chromafix 30-PS-
-
HCO3 QMA cartridges (46 mg) were purchased from ABX
(Radeberg, Germany). A semi-preparative VP250/10 Nucleodur
C18 HTec column (250 x 10 mm; 8 µm; Macherey-Nagel) was
used with water/ethanol (95/5, v/v) containing 0.1%
trifluoroacetic acid as eluent at a flow of 2.5 mL/min. All
radiolabelled compounds were compared by TLC and/or
analytical HPLC to the authentic non-radioactive material and to
be free of significant chemical and radiochemical impurities.
Radiosynthesis
The aqueous solution of [18F]F- in [18O]H2O obtained from
Cyclopharma Laboratories was passed through an anion
exchange resin (Sep-Pak® Light Accell Plus QMA Cl or
carbonate cartridge, Waters, Trap 1, scheme S1, see supporting
information). The cartridge was rinsed with 1 mL of anhydrous
methanol (SC1, scheme S1) and dried for 2 min under vacuum
and He flow (150 mL/min). Then, the radioactivity was eluted to
the reactor using a solution of the precursor 6b (13 µmol) in
anhydrous methanol (750 µL, SC2, scheme S1). The solvent
was evaporated under reduced pressure at 30 °C under stirring.
When the vacuum in the reactor was stabilized around 30-35
mbar, anhydrous toluene (200 µL) or diglyme (100 µL, SC3,
scheme S1) were added to the reactor. The reaction mixture
was then heated to 110 °C for 10 min under stirring. The reactor
was cooled to 50-60°C before addition of diglyme (500 µL, SC4,
scheme S1) and water (19 mL, SC5, scheme S1) successively
and under stirring. The solution was then passed through a Sep-
The precursor 18b was stored in a desiccator over desiccant in
the fridge (5 °C). After 2 months of storage decreasing yield
were obtained (below 30% RCY decay corrected) and a new
batch of precursor 18b was synthesised for further
radiosyntheses.
Radiosynthesis
The aqueous solution of [18F]F- in [18O]H2O was transferred
under helium pressure to an intermediate vial set in a well
counter inside the hotcell (red dot square on scheme S2, see
supporting information). After counting, the whole solution was
transferred to the reception V-vial of the Raytest module. [18F]F-
in water was trapped on an anion exchange resin (Sep-Pak®
Light Accell Plus QMA carbonate cartridge, Waters, Trap 1,
scheme S2). The cartridge was rinsed with 1 mL of anhydrous
methanol (SC1, scheme S2) and dried under vacuum and argon
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10.1002/ejoc.201801608
European Journal of Organic Chemistry
FULL PAPER
Kema, P. H. Elsinga, W. J. Sluiter, K. Vanghillewe, A. H. Brouwers, P. L.
Jager, E. G. de Vries, J. Clin. Oncol. 2008, 26, 1489–1495.
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flow. The radioactivity was eluted into the reactor using a
solution of the precursor 18b (13 µmol) in anhydrous methanol
(850 µL, SC2, scheme S2). The solvent was evaporated under
reduced pressure at 28 °C under stirring. When the vacuum in
the reactor was stabilized around 50 mbar, anhydrous toluene
(250 µL, SC3, scheme S2) was added to the reactor. The
reaction mixture was then heated to 105 °C for 5 min and 110 °C
for 5 min more under stirring. The reactor was cooled to 50°C
before addition of water (12-13 mL, SC4, scheme S2) under
stirring. The solution was then passed through a Sep-Pak light
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aqueous solution of ammonium acetate (4 mL, SC8, scheme
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transferred to the HPLC loop (5 mL) and purified via semi-
preparative HPLC (95/5, v/v, Water/Ethanol containing 0,1%
TFA). The collected fraction (Rt = 8.5 min) was analyzed by
analytic radio-HPLC to determine the radiochemical purity,
enantiomeric excess and specific activity.
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Entry for the Table of Contents (Please choose one layout)
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[18F]FDOPA challenge:
A
new
Radiofluorination
radiosynthetic route to [18F]FDOPA
was developed and fully automated
Aurélie Maisonial-Besset,*,§,[a] Audrey
Serre,§,[a] Ali Ouadi,[b] Sébastien
Schmitt,[a] Damien Canitrot,[a] Fernand
Léal,[a] Elisabeth Miot-Noirault,[a] David
Brasse,[b] Patrice Marchand,[b] and Jean-
Michel Chezal[a]
from
a key iodonium triflate salt
precursor. This radiotracer was
produced via a “minimalist approach”
(see figure) involving nucleophilic
[18F]F- process, without any use of
base, cryptand or metal catalyst, in 64
min, 27-38% RCY, >99% RCP, > 99%
e.e., and high Am 170-230 GBq.µmol-
1 (n = 5).
Page No. – Page No.
Base/cryptand/metal-free automated
nucleophilic radiofluorination of
[18F]FDOPA from iodonium salts:
importance of hydrogen carbonate
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