Convenient synthesis of diaryliodonium salts for the production of [18F]F-DOPA

Article abstract of DOI:10.1002/ejoc.201403378

[¹⁸F]F-DOPA is an important radiotracer that is used in the diagnosis of Parkinson's disease and neuroendocrine tumours. We describe a simple synthesis for a number of diaryliodonium salt precursors that are suitable for the production of [¹⁸F]F-DOPA through reaction with no carrier added (n.c.a.) nucleophilic [¹⁸F]fluoride. The simple procedure gives bench-stable, complex iodonium precursors in good yields without the need for laborious anhydrous conditions. Further alteration to the precursor counterion can be readily achieved for a range of halides and pseudo halides by a simple modification of the workup. Preliminary "hot" and "cold" fluorination results show the suitability of the compounds for the production of [¹⁸F]F-DOPA.

Full text of DOI:10.1002/ejoc.201403378

FULL PAPER
DOI: 10.1002/ejoc.201403378
Convenient Synthesis of Diaryliodonium Salts for the Production of
[18F]F-DOPA
Richard Edwards,[a] Andrew D. Westwell,[b] Stephen Daniels,[c] and Thomas Wirth*[a]
Keywords: Analytical methods / Isotopic labeling / Imaging agents / Fluorination / PET / Radiochemistry
[
18F]F-DOPA is an important radiotracer that is used in the
yields without the need for laborious anhydrous conditions.
Further alteration to the precursor counterion can be readily
achieved for a range of halides and pseudo halides by a sim-
ple modification of the workup. Preliminary “hot” and “cold”
fluorination results show the suitability of the compounds for
the production of [18F]F-DOPA.
diagnosis of Parkinson’s disease and neuroendocrine tu-
mours. We describe a simple synthesis for a number of diaryl-
iodonium salt precursors that are suitable for the production
of [18F]F-DOPA through reaction with no carrier added
(n.c.a.) nucleophilic
[
18F]fluoride. The simple procedure
gives bench-stable, complex iodonium precursors in good
specific activity (SA) of no carrier added (n.c.a.) [18F]fluor-
ide. Traditional nucleophilic routes for labelling aromatic
compounds with [18F]fluoride include Balz–Schiemann and
Wallach reactions.[5] Unfortunately, these transformations
use harsh conditions and suffer from poor radiochemical
yields (RCYs) and a narrow substrate scope. Aromatic nu-
cleophilic substitution of halides and other leaving groups
(notably NO2 and N+Me3) can be used but, in general,
these reactions are limited to aromatic compounds bearing
electron-withdrawing groups and regioselectivity remains a
significant issue. With these limitations, extending such
methodologies to complex systems can be difficult and
often requires multistep synthesis.
For more electron-rich aryl moieties, the use of electro-
philic fluorine is traditionally more common, utilising [18F]-
fluorine gas or reagents produced from this source of the
18F nuclide. However, these methods are avoided if possible
because of their numerous disadvantages including low SA
and generally poor RCYs. The use of fluorine gas as the
source of radioactivity also suffers from handling difficult-
ies and a much reduced availability compared with that of
n.c.a. [18F]fluoride.
Recently, iodonium salts have generated much interest as
precursors for the nucleophilic incorporation of [18F]fluor-
ide into electron-rich target molecules. The properties of di-
aryliodonium salts make them ideal precursors for aromatic
radiotracer synthesis using nucleophilic fluorination. A
quick, selective reaction is crucial for short reaction and
purification times to increase RCY. This is achieved by the
high reactivity of the salts, which is attributed to the “hy-
perleaving group ability” of the PhI group, being approxi-
mately 106 times that of a triflate.[6]
Introduction
The synthesis of radiolabelled compounds is currently an
area of great interest, primarily due to their application in
positron emission tomography (PET). This highly sensitive
and versatile imaging technique allows for the pharmacoki-
netic and biodistribution of positron emitters to be studied
in vivo, and is crucial to diagnosis and evaluation of dis-
eases, including cancers[1] and neurodegenerative diseases
such as Parkinson’s disease.[2]
[18F]Fluorine is a commonly used radioisotope in the
production of such radiotracers. This popularity is due to
a number of advantages; it has a relatively long half-life
(109.8 min) compared with that of 11C (20.4 min) and 13N
(9.98 min), allowing multistep reactions, complex purifica-
tions, and even transportation before unacceptable loss of
radioactivity. In addition, it is also possible to produce
[18F]fluorine in multi-Curie levels with low energy.[3] The
strength of the carbon–fluorine bond means that such com-
pounds generally show good metabolic stability in vivo.
This is especially true of aryl carbon–fluorine bonds, with
some aliphatic carbon–fluorine bonds being prone to enzy-
matic cleavage.[4]
Numerous methods exist for the incorporation of fluor-
ine into molecules at an aryl position with both electro-
philic and nucleophilic reagents. Nucleophilic incorporation
of [18F]fluoride is the preferred route because of the high
[a] School of Chemistry, Cardiff University
Park Place, Main Building, Cardiff CF10 3AT, UK
E-mail: wirth@cf.ac.uk
http://www.cf.ac.uk/chemy/wirth
[b] School of Pharmacy and Pharmaceutical Sciences
Cardiff University, Cardiff CF10 3NB, UK
[c] Wales Research & Diagnostic PET Imaging Centre (PETIC)
School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403378.
The use of diaryliodonium salts for the formation of
[18F]-labelled aromatic compounds was first reported by
Pike et al. using both symmetrical and unsymmetrical di-
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T. Wirth et al.
FULL PAPER
aryliodonium precursors.[7] When an unsymmetrical diaryl- production facilities. An effective [18F]F-DOPA synthesis
iodonium salt is used, the aromatic substituent at which the using a nucleophilic approach would provide a significant
fluorination takes place is dependent on both the electronic improvement to the above synthesis, allowing a more ac-
and steric properties of the two attached aryl moieties. This cessible and facile route to this vital radiopharmaceutical.
allows precursors to be designed for selective fluorination
Recent studies have led to vast improvements in nucleo-
at the desired aromatic position by employing a small, elec- philic methodology for the synthesis of electron-rich aro-
tron-rich aryl group (commonly 2-thienyl and 4-meth- matics such as [18F]F-DOPA. Ritter et al. recently reported
oxyphenyl) as the “non-participating” aryl ring or other the production of protected [18F]F-DOPA and other radio-
non-participating groups such as a [2,2]paracyclophane labelled targets by using a nickel complex in the presence
moiety.[8] The application of spirocyclic iodonium ylide pre- of an oxidant.[12] Scott et al. found that copper-catalysed
cursors for such a regioselective fluorination has also been radiofluorination of mesityl iodonium salts could be used
reported to be of great efficacy by Liang et al.[9]
to access protected [18F]F-DOPA.[13] Gouverneur et al. have
The employment of a diaryliodonium salt precursor for recently shown the utility of boronic esters as precursors for
the synthesis of a practical PET tracer was first reported by nucleophilic [18F]fluorination also in the presence of a cop-
Suzuki et al. for the synthesis of [18F]DAA1106, a tracer per catalyst.[14] This method allows access to high SA elec-
used for imaging peripheral-type benzodiazepine receptor tron-rich targets including [18F]F-DOPA.
in the brain.[10] The utility of such diaryliodonium salt pre-
Drawbacks to these advancements in nucleophilic [18F]-
cursors offers a selective and widely applicable methodol- fluorination include the use of metals in all cases and the
ogy for the introduction of [18F]fluoride into a large employment of air-sensitive reagents in those reported by
number of functionalised arenes. Nevertheless, the use of Scott and Ritter.
iodonium salts for the introduction of fluoride cannot be
Herein, we report the synthesis of bench-stable diaryl-
described as general, with a large range of fluorination con- iodonium salts that are suitable for the production of [18F]-
ditions reported for a range of substrates. The production F-DOPA through reaction with n.c.a. nucleophilic [18F]-
and fluorination of more complex biomedically relevant fluoride (Scheme 1b). Multiple strategies for salt formation
iodonium precursors has until recently also been problem- are scrutinised, and preliminary “hot” and “cold” fluorina-
atic. However, as the understanding and experience in this tion results are used to show the suitability of the molecules
methodology grows, the use of iodonium salts as precursors for the production of [18F]F-DOPA.
to form more complex, electron-rich radiotracers have seen
much recent success.[11]
[18F]F-DOPA is a widely used radiotracer most com-
monly employed in the diagnosis of Parkinson’s disease and
neuroendocrine tumours (NETs).[1a,2a] The commonly used
current synthesis of [18F]F-DOPA (Scheme 1a) proceeds
through electrophilic destannylation with [18F]F2 gas. As
Results and Discussion
Iodonium Precursor Formation Using Stannylated Protected
L
-DOPA Ethyl Ester
The reaction of hypervalent iodine(III) reagents of
expected, the reaction suffers from the disadvantages men- Koser-type [ArI(OH)OTs] with arylstannanes to form
tioned above and proceeds with poor RCYs, low SA, and iodonium tosylates is well known and provided the starting
is unavailable to PET centres not equipped with [18F]F2 gas point for our investigation.[9] The formation of 4-meth-
oxyphenyl- and 2-thienyl-substituted Koser-type reagents
was achieved by using reported methods (see the Support-
ing Information).[15] Alternatively, the reaction can be per-
formed with a Koser-type reagent produced in situ from its
corresponding diacetate. (Diacetoxyiodo)arenes were pro-
duced by using reported methods (see the Supporting Infor-
mation).[16] The conditions tested for optimisation of the
salt formation are shown in Table 1.
The use of 2,2,2-trifluoroethanol (TFE) as solvent was
very detrimental to the reaction (Table 1, Entries 1 and 4)
despite being an excellent solvent for the formation of sim-
ple diaryliodonium salts.[17] However, when using a method
adapted from a procedure reported by Chun et al.,[18] it
was found that the reaction proceeded well in a mixture of
chloroform and acetonitrile (Table 1, Entry 2). When ap-
proximately equimolar amounts of the hypervalent iodine
reagent 1 was used, it was found that a significant portion
of the stannane remained unreacted.
By increasing the number of equivalents (1.2 and
1.5 equiv.) of the Koser derivative, higher levels of conver-
sion of stannane into the diaryliodonium salt was observed
Scheme 1. Synthesis of [18F]F-DOPA.
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Diaryliodonium Salts for the Production of [18F]F-DOPA
Table 1. Synthesis of diaryliodonium salts 4.[a]
Entry
Reagent
Reagent [equiv.]
Solvent
Temperatue [°C]
Yield of 4 [%]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
2a
2b
1b
1b
2b
1.02
1.02
1.2
1.2
1.5
1.5
1.2
1.2
1.5
1.5
CH2Cl2/TFE (1:1)
CHCl3/MeCN (5:1)
CHCl3/MeCN (5:1)
MeCN/CH2Cl2/TFE (1:2.5:2.5)
CHCl3/MeCN (5:1)
CHCl3/MeCN (5:1)
CH2Cl2/MeCN (1:1)
CHCl3/MeCN (5:1)
CHCl3/MeCN (5:1)
CHCl3/MeCN (5:1)
0
0
reflux
reflux
reflux
reflux
reflux
r.t.
reflux
50 °C
50 °C
24
37
0
44
24
26
37
60
30
10
[a] Reactions were carried out under ambient conditions; reaction time was 18 h.
(Table 1, Entries 3 and 5). The addition of 1.5 equiv. of 1 Table 2. Synthesis of diaryliodonium salts with different nitrogen
protections and counterions.
was found to be optimal; the addition of larger amounts
led to difficulties in purification.
Interestingly, the reaction proceeded with higher yields
when the stannane was reacted with the Koser reagent pro-
duced in situ (compound 1 and p-toluenesulfonic acid)
rather than preformed Koser reagent (Table 1, Entries 5 vs.
6 and 9 vs. 10).
Conditions reported by Jang et al.[11a] were also investi-
gated, but the combination of dichloromethane and aceto-
nitrile as solvent proved to be less fruitful than the op-
timised conditions (Table 1, Entry 7).
Under the optimised conditions the reaction proceeded
with good yields for both 2-thienyl and 4-methoxyphenyl
Koser reagents, with the highest yields being observed with
the latter derivative (Table 1, Entries 5 and 9).
Significant improvements to the product purity were ob-
served when the solution of the crude salt in dichlorometh-
ane was washed with water before trituration. The use of
the optimised reaction conditions for the formation of di-
aryliodonium salts with different protecting groups is
shown in Table 2.
The formation of diaryliodonium salts 4a and 7a pro-
ceeded in reasonable yields (Table 2, Entries 1 and 2). Yields
could be improved by increasing the number of equivalents
of diacetate 1 and p-toluenesulfonic acid. However, when
the tetra-Boc-protected stannyl precursor was treated with
Entry
Ar
RЈ
RЈЈ
Yield [%]
1
2
3
4
5
6
4a(OTs)
7a(OTs)
8a(OTs)
4b(OTs)
7b(OTs)
8b(OTs)
NHBoc
NBoc2
NPhth
NHBoc
NBoc2
NPhth
Et
Et
Me
Et
Et
Me
44
28
0
60
26
29
more than 1.5 equiv. of p-toluenesulfonic acid, deprotection be isolated. However, the reaction did proceed satisfactorily
of one of the N-Boc groups occurred to yield the tri-Boc- with the 4-methoxyphenyl Koser reagent produced in situ.
protected iodonium salt (4a).
The reasons for this unexpected change in reactivity are not
Surprisingly, reaction of the phthalimide-protected aryl- clear at present.
stannane 6 with the 2-thienyl Koser reagent produced in
When the salt was washed with a saturated aqueous solu-
situ proceeded very poorly, and a pure product could not tion of a potassium salt then a simple counterion exchange
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T. Wirth et al.
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occurred for salts including KI, KOTf and KBr. Yields for
The formation of the fluorinated product was observed
the counterion exchange to the iodonium bromide were in all reactions by 19F NMR and HPLC analyses, except for
quantitative and performed for all compounds shown in the reaction performed in DMSO (Table 3, Entry 1). The
Table 2. Conversion into the iodonium triflate was also formation of the iodonium fluoride intermediate 4(F) was
quantitative, and conversion into the iodonium iodide pro- observed by 19F NMR spectroscopic analysis in all cases
ceeded with 95% yield. These counterion exchange pro- (see the Supporting Information). The thermal decomposi-
cesses were performed with compounds 4a(OTs) and tion of iodonium fluoride 4(F) in DMSO, however, did not
4b(OTs).
proceed to give the fluorinated product (Table 3, Entry 1).
It was found that conversion from the iodonium tosylate It should be noted that no production of 4-fluoroanisole or
into the iodonium perchlorate could not be performed by 2-fluorothiophene was observed in any of these reactions.
using this method but was achieved by using the procedure The reaction proceeds with both the thiophene- and the
reported by Dinkelborg et al.[11c] Thus, the iodonium salt anisole-derived iodonium salts, with neither “non-partici-
was charged on a reverse-phase C-18 cartridge before elut- pating” arene showing a clear advantage over the other,
ing with an aqueous solution of perchloric acid through with all yields (determined by HPLC analysis) being be-
the cartridge. Following this, water was passed through the tween 2 and 5% (Table 3).
cartridge before a gradient of acetonitrile and water was
used to elute the iodonium perchlorate (see the Supporting
Information).
“Hot” Fluorination Reactions
After the success of the cold fluorinations, further inves-
tigation into the suitability of the precursors for production
of [18F]F-DOPA was carried out. Reactions were performed
with an automated Eckert & Ziegler system in a hot cell.
Reaction of iodonium bromide 4b(Br) with azeotropically
dried [18F]KF·Kryptofix 222·K2CO3 salt gave the 18F-lab-
elled, protected DOPA compound 10 (Scheme 2).
“Cold” Fluorination Reactions
After the successful formation of different iodonium pre-
cursors, it was important to assess their suitability for the
production of F-DOPA. Different conditions for the
fluorination of iodonium salts have been reported.[19] We
started our investigations by performing fluorinations using
tetramethylammonium fluoride (TMAF) in a range of sol-
vents. Acetonitrile, N,N-dimethylformamide DMF) and di-
methyl sulfoxide (DMSO) are commonly used in the
fluorination of iodonium salts, and these were investigated
first. Recent work by DiMagno et al. has shown that non-
polar aprotic solvents such as benzene and toluene can also
be used; they reported that thermal decomposition of the
iodonium fluoride in such solvents can dramatically im-
prove the fluorination yields.[20] Therefore, fluorinations
with TMAF were carried out in acetonitrile, DMF, DMSO
and toluene, as shown in Table 3.
Scheme 2. Synthesis of hot [18F]F-DOPA.
Although the reaction proceeded with poor conversion
of [18F]fluoride into the labelled product, it was found that
Table 3. Fluorinations of diaryliodonium salts 4 with TMAF.
Entry
Ar
Fluorination solvent
Yield [%][a]
1
2
4b(Br)
4b(Br)
4b(Br)
4b(Br)
4a(Br)
4a(Br)
DMSO
DMF
MeCN
toluene
MeCN
toluene
0
2
5
2
3
5
3
4[b]
5
6[b]
[a] Yields were calculated based on HPLC analysis. [b] Iodonium fluoride 4a(F) was produced in acetonitrile before removal of the solvent.
Compound 4a(F) was then redissolved in toluene and passed through a filter into a clean vessel for thermal decomposition to 9.
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Diaryliodonium Salts for the Production of [18F]F-DOPA
form (25 mL). The appropriate protected 6-(trimethylstannyl)-l-
DOPA reagent (0.29 mmol) in chloroform (5 mL) was added drop-
wise. The reaction mixture was heated to 50 °C and stirred for 18 h.
The reaction mixture was cooled to room temperature, and the
solvent was removed under reduced pressure. The residue was dis-
solved in CH2Cl2 (40 mL) and washed with water/saturated KX (X
= Br, I, OTf) solution (3ϫ 40 mL). The organic layer was passed
through a phase separator and concentrated under reduced pres-
sure to give the crude product as a yellow oil. The product was
triturated with hexane from a minimum amount of CH2Cl2 and
diethyl ether (1:1). The precipitate was collected on a Telos phase
separator and washed with hexane. The collected precipitate was
removed from the phase separator with CH2Cl2. The CH2Cl2 was
removed before the product was triturated once more with hexane
from a minimum amount of CH2Cl2 and diethyl ether (1:1). Re-
moval of the solvent under reduced pressure gave the product as a
white solid.
General Procedure for No-Carrier-Added [18F]Fluoride Incorpora-
tion Using Iodonium Salts: [18F]Fluoride delivered from the cyclo-
tron as an aqueous solution was trapped on a pretreated QMA
cartridge to remove the 18O-enriched water. The [18F]fluoride was
eluted with a Kryptofix 2.2.2 carbonate solution (0.6 mL) (0.3 mL
of MeCN, 0.3 mL of H2O, 22.8 mg of Kryptofix 2.2.2, 8.4 mg of
K2CO3) into a 5 mL V-shaped vial. The mixture was dried under
a flow of nitrogen and reduced pressure at 120 °C for 440 s.
The residue was azeotropically dried twice with the addition of
acetonitrile (2ϫ 1 mL). Distillation was achieved by heating at
120 °C under a flow of nitrogen for 440 s. To the dried [18F]-
KF·Kryptofix 222·K2CO3 salt were added iodonium precursor
(0.03 mmol) and TEMPO (0.021 mmol) in acetonitrile and DMSO
(1.5 mL) (2:1). The reaction mixture was heated at 90 °C for 30 min
before being cooled to room temperature. The reaction mixture was
ejected into a sterile vial, and the activity was measured in a well
counter to calculate the radiochemical recovery (RCR). The reac-
tion mixture was loaded onto the HPLC sample loop. Reverse-
phase purification was performed using a semipreparative Agilent
1200 column [4 mL/min, 70% MeCN in H2O (0.01% formic acid)].
The γ-peak was collected (retention time: 7.5–8.5 min), and the ac-
tivity of the isolated product was measured with a Campitec CRC-
25PET well counter. A 100 μL sample was taken for HPLC analysis
to confirm the product as the protected [18F]F-DOPA.
the reaction performed in a mixture of DMSO and aceto-
nitrile proceeded very cleanly. Interestingly, the reaction did
not proceed in DMSO alone, and reactions in either DMF
or acetonitrile alone proceeded less cleanly, with the forma-
tion of a number of unidentified radiolabelled products. In
all cases, the conversion of fluoride into any products was
low, with Ͻ 1% RCY.
Isolation of the [18F]fluorinated product could be
achieved by using semipreparative HPLC purification to
give the product in Ͼ 95% radiochemical purity.
Alternative protecting strategies for the amine showed no
advantages under the current conditions. No product for-
mation was observed when using the iodonium bromide
8b(Br) (phthalimide protected amine) as the precursor.
Iodonium bromide 7b(Br) (di-Boc-protected amine) gave
the corresponding 18F-labelled, protected DOPA moiety,
but the reaction did not proceed cleanly.
Decay-corrected RCYs were calculated by measurement
of the activity of the isolated [18F]labelled products in a
well counter, because conversions calculated from analytical
HPLC proved to be inaccurate (see the Supporting Infor-
mation). We would thus recommend caution when using
HPLC analysis for monitoring the success of labelling reac-
tions.
To confirm the production of 18F-labelled, protected
DOPA in the successful reactions, the corresponding 19F
compound was co-eluted during HPLC analysis. No chiral
HPLC analysis has yet been performed to assess the chiral
integrity of the product.
Conclusions
Different iodonium salt precursors for the synthesis of
[18F]F-DOPA have been synthesised in reasonable to good
yields by using a robust and facile route with no need for
laborious inert conditions. The complex iodonium precur-
sors are bench-stable molecules. Further exchange of the
precursor counterion can be readily achieved with a range
of halides and pseudo halides by a simple alteration of the
workup. The use of such precursors for the formation of
both 19F- and 18F-protected DOPA has been studied, show-
ing the utility of the iodonium salts as precursors for the
nucleophilic synthesis of this valuable radiotracer. The poor
conversion of [18F]fluoride into the labelled product means
that the current conditions are not suitable for useful pro-
Supporting Information (see footnote on the first page of this arti-
cle): All synthetic methods including spectroscopic data and analyt-
ical data.
Acknowledgments
Support from the Schools of Chemistry, Pharmacy and Medicine
of Cardiff University is gratefully acknowledged. We thank the
duction of [18F]F-DOPA. Hence, further investigations into EPSRC National Mass Spectrometry Facility, Swansea, for mass
spectrometric data.
the “hot” fluorination reaction are ongoing. Investigation
into any possible racemisation during the [18F]labelling re-
action also needs to be undertaken.
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