Alcohol-Enhanced Cu-Mediated Radiofluorination

Article abstract of DOI:10.1002/chem.201604633

The potential of many ¹⁸F-labeled (hetero)aromatics for applications in positron emission tomography remains underexplored because convenient procedures for their radiosynthesis are lacking. Consequently, simple methods to prepare radiofluorinated (hetero)arenes are highly sought after. Herein, we report the beneficial effect of primary and secondary alcohols on Cu-mediated ¹⁸F-labeling. This observation contradicts the assumption that such alcohols are inappropriate solvents for aromatic fluorination. Therefore, we developed a protocol for rapid radiolabeling of an extraordinarily broad scope of boronic and stannyl substrates under general reaction conditions. Notably, radiofluorinated indoles, phenols, and anilines were synthesized directly from the corresponding unprotected precursors. Furthermore, the novel method enabled the preparation of radiofluorinated tryptophans, [¹⁸F]F-DPA, [¹⁸F]DAA1106, 6-[¹⁸F]FDA, and 6-[¹⁸F]FDOPA.

Full text of DOI:10.1002/chem.201604633

A Journal of
Accepted Article
Title: Alcohol-enhanced Cu-mediated radiofluorination
Authors: Zischler Johannes, Niklas Kolks, Daniel Modemann, Bernd
Neumaier, and Boris Zlatopolskiy
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201604633
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Alcohol-enhanced Cu-mediated radiofluorination
Johannes Zischler,[a,b,c] Niklas Kolks,[b] Daniel Modemann,[a] Bernd Neumaier,*[a,b,c] and Boris D.
Zlatopolskiy[b,c]
Abstract: The potential of many 18F-labeled (hetero)aromatics for
application in positron emission tomography remains underexplored
because convenient procedures for their radiosynthesis are lacking.
Consequently, simple methods to prepare radiofluorinated
(hetero)arenes are highly sought after. Herein, we report the
beneficial effect of primary and secondary alcohols on Cu-mediated
18F-labeling. This observation contradicts the assumption that such
alcohols are inappropriate solvents for aromatic fluorination.
Therefore, we developed a protocol for rapid radiolabeling of an
extraordinarily broad scope of boronic and stannyl substrates under
general reaction conditions. Notably, radiofluorinated indoles,
phenols, and anilines were synthesized directly from the
corresponding unprotected precursors. Furthermore, the novel
method enabled the preparation of radiofluorinated tryptophans,
[18F]F-DPA, [18F]DAA1106, 6-[18F]FDA, and 6-[18F]FDOPA.
allows a simplified preparation of radiotracers that are not easily
accessible by conventional radiochemistry. Azeotropic drying,
base, and other additives are not required. Consequently, only
precursor, [18F]fluoride, and copper catalyst are used (Fig. 2).[5]
In contrast, reported protocols for the Cu-mediated
radiofluorination of pinacolyl arylboronates and arylboronic acids
require azeotropic drying, a base, and additives, such as
3c]
pyridine, 2.2.2-cryptand (K2.2.2), KOTf, and K2C2O4.[3b,
Furthermore, in some cases, unacceptably high losses of 18F-
(up to 40–50%)[6] due to adsorption onto vessel walls occur. To
overcome these shortcomings, we tried to refine the Cu-
mediated radiofluorination of boronic substrates. We found that
the application of primary and secondary alcohols as co-solvents
substantially increased radiolabeling yields. Consequently, this
observation was used to develop a convenient procedure for Cu-
mediated radiofluorination of boronic- and stannyl substrates.
Molecular imaging technologies are indispensable tools in
modern medicine, enabling the noninvasive visualization of
biochemical processes in vivo at a molecular level. Positron
emission tomography (PET) and related hybrid methods (like
PET/CT and PET/MR) are the most important imaging
techniques with unique sensitivities that allow detection of
cellular changes during disease development. PET delineates
the biodistribution of molecular probes labeled with β+-emitting
nuclides by detecting antiparallel γ-photons originated from
positron/electron annihilation. Among β+-emitting nuclides for
PET, fluorine-18 represents the most attractive one because of
the easy accessibility in 'no carrier added' (n.c.a.) form,
convenient half-life (109.8 min), and low β+-energy. However,
the diagnostic potential of many 18F-labeled PET tracers cannot
be fully exploited because simple, efficient procedures for their
preparation are lacking. Recently, several pioneering fluorination
methods have been developed and transferred to PET
chemistry.[1]
Among
them,
transition
metal-mediated
fluorinations,[2] and especially, Cu-mediated ones,[3] are
exceptionally versatile routes to 18F-labeled aromatics,
regardless of their electronic properties (Fig. 1).
In
particular,
Cu-mediated
radiofluorination
of
(aryl)(mesityl)iodonium salts under “minimalist” conditions[4]
Figure 1: Copper-mediated 18F-labeling of diaryliodonium salts (A), pinacolyl
arylboronates (B), and boronic acids (C).
[a]
J. Zischler, D. Modemann, Prof. Dr. B. Neumaier*
Institute of Neuroscience and Medicine, INM-5: Nuclear Chemistry
Forschungszentrum Jülich GmbH
Initially, to obviate azeotropic drying, we tested the elution of 18F–
from an anion exchange resin (QMA cartridge) using a solution
of K2CO3, KOTf, K2.2.2, and pyridine in DMF. Before the elution
the resin was washed with anhydrous DMF and dried with air to
remove residual water after 18F– trapping. Less than 40% of 18F–
was recovered from the QMA cartridge. Possibly, the poor
wettability of the hydrophilic alkyltrimethylammonium phase with
aprotic solvents led to poor 18F– recovery (Fig. S1, Supporting
Information).
52425 Jülich, Germany
E-mail: b.neumaier@fz-juelich.de
[b]
[c]
J. Zischler, N. Kolks, Prof. Dr. B. Neumaier, Dr. B. D. Zlatopolskiy
Institute of Radiochemistry and Experimental Molecular Imaging
University Clinic Cologne
Kerpener Str. 62, 50937 Cologne, Germany
J. Zischler, Prof. Dr. B. Neumaier, Dr. B. D. Zlatopolskiy
Max Planck Institute for Metabolism Research
Gleueler Str. 50, 50931 Cologne, Germany
Supporting information for this article is given via a link at the end of
the document
In order to prevent resin collapse, we used hexane instead of
DMF. Consequently, the resin was washed with hexane and
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10.1002/chem.201604633
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dried with air before the elution step. Because hexane is
immiscible with water, water in the pores of the hydrophilic
stationary phase was not displaced. Indeed, if the cartridge was
rinsed with hexane, the elution efficacy increased to 80%. We
applied the resulting eluate for the Cu-mediated radiofluorination
of pinacolyl phenylboronate
RCC. These radiolabeling experiments were carried out
according to Zlatopolskiy et al.[5b] and Preshlock et al.[3c]
Intrigued, we studied the influence of different alcohols on Cu-
mediated radiofluorination systematically. 18F– was eluted from
the anion exchange resin with a solution of Et4NHCO3 (2.7 mg)
in the corresponding alcohol (0.4 mL; see Table 1) into a vial
containing a solution of PhBPin and Cu(py)4(OTf)2 (60 and
26.5 µmol, respectively) in DMA (0.8 mL; final concentration of
alcohol 33%). Subsequently, the resulting solutions were directly
heated at 110 C for 20 min under air atmosphere. For practical
reasons
we
changed
from
the
elution
with
K2CO3/K2.2.2/KOTf/Py to the elution with Et4NHCO3 since
solutions of K2CO3/K2.2.2/KOTf/Py have only very limited shelf-
life and are relatively cumbersome to prepare. At the same time
the elution efficacy and RCCs of the radiofluorination step with
Et4NHCO3 was comparable or even better as those with
K2CO3/K2.2.2/KOTf/Py.
Figure 2: Copper-mediated 18F-labeling of diaryliodonium salts under
“minimalist” conditions.
(PhBPin). However, only traces of [18F]fluorobenzene ([18F]1)
were observed in the reaction mixture, demonstrating the high
sensitivity of the reaction towards water.
18F-Incorporation yields of 90–99% were observed using n-
BuOH and iso-BuOH, whereas n-PrOH and 2-BuOH delivered
RCCs of > 80%. Noteworthy, n-BuOH enabled the most efficient
elution of 18F− [radioactivity recovery amounted to 80–95% (n >
100)].[7]
Next, the application of alcohols for water removal was
investigated.[7] Alcohols are protic solvents and are capable to
completely displace H2O from the resin pores and at the same
time prevent resin collapse. By using alcohols, we achieved a
moderate 18F– recovery (up to 55%).[8] Direct heating of the
eluates containing traces of alcohols with PhBPin and
Cu(py)4(OTf)2 afforded [18F]1 in unexpectedly high radiochemical
conversions (RCCs)[9] of up to 70–80%. For comparison, use of
pure DMA or DMF as reaction solvent afforded [18F]1 in ≤ 65%
Next, we evaluated the alcohol-enhanced, Cu-mediated 18F-
fluorination of PhB(OH)2 as a model arylboronic acid (Fig. 5).
Incorporation yields of  85% for most alcohols were observed.
Only MeOH and tert-BuOH afforded [18F]1 in lower RCCs of 67
and 46%, respectively. In the absence of alcohols DMA or DMF
afforded
RCCs
of
only
≤
12%.
Table 1: 18F-Recovery and 18F-incorporation (RCC) using different alcohols as co-solvents.[10]
RCC±SD from
PhBPin
RCC±SD from
PhB(OH)2
18F recovery
[%] (n≥3)
[%] (n≥3)
[%] (n≥3)
H2O
99±1
0
0
MeOH
EtOH
97±1
91±2
70±4
71±2
80–95*
84±6
35±4
43±5
46±3
40±3
59±2
82±3
62±4
94±2
89±4
29±3
82±1
50±5
82±5
67±3
90±4
96±2
86±2
98±4
93±3
46±4
85±5
90±4
13±2
n-PrOH
iso-PrOH
n-BuOH
iso-BuOH
tert-BuOH
2-BuOH
1-OctOH
DMA w/o alcohol
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Interestingly, our results contradict previous observations
concerning the deleterious effect of protic solvents, including
alcohols, on SNAr fluorination, usually explained by extensive
hydrogen bonding, which reduces the nucleophilicity of
fluoride.[11] Unsurprisingly, to date, no transition metal-catalyzed
fluorinations in alcoholic media have been reported. Hence, we
studied the tolerance of the radiofluorination reaction with
respect to the alcohol content (Fig. 3).
EtOH still afforded [18F]1 in a RCC of 45%. The kind of aprotic
solvent had a significant influence on RCCs. Thus, using
pinacolyl 4-methoxyphenylboronate as a model substrate, DMA
and NMP afforded the highest RCCs of 4-[18F]fluoroanisole
([18F]2) of 87 and 77%, respectively.[7] DMF and sulfolane
yielded radiolabeled arenes in moderate RCCs of 50%. 18F-
Incorporation in DMSO and acetonitrile was rather low (11 and
3%, respectively).
Additionally, radiolabeling kinetics was studied. At 110 °C
incorporation yields of > 80% and > 90% were observed already
after 5 and, 10 min, respectively.[10]
Figure 3: Dependency of RCC on alcohol content.[10]
To demonstrate the versatility of the procedure, we
radiofluorinated a series of (hetero)arylboronic substrates (Fig.
5). Different electron-rich, electron-deficient, and electron-neutral
18F-labeled arenes were prepared in RCCs exceeding or
averaging 80% (Fig. 4). The introduction of O- and N-containing
substituents into the ortho-position ([18F]4, [18F]10) resulted in
lower RCCs, presumably due to unfavorable interactions with
the leaving groups, impeding transmetalation. Remarkably,
radiofluorinated phenols ([18F]8, [18F]9) could be directly
prepared from the corresponding unprotected boronic substrates
in 80–97% RCCs. For comparison, without alcohol, RCCs of
In 20–60% n-BuOH in DMA, a near quantitative (>96%)
formation of [18F]1 from PhBPin occurred. Even in 70–80% n-
BuOH, RCCs of > 80% were observed. However, in pure n-
BuOH, 18F-incorporation did not exceed 8%. Radiolabeling of
PhB(OH)2 was even more tolerant towards alcohols. With this
substrate we tested environmentally benign EtOH, which
furnished RCCs of > 90% at 10–50% alcohol content. A further
increase of the alcohol content resulted in a decrease of 18F-
incorporation to 75, 70 and 66% in 60, 80 and 90% ethanolic
solutions, respectively. Nevertheless, radiolabeling even in pure
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3d, 3e]
only 7–15% were achieved.[3b,
afforded 2- and 3-
Furthermore, n-BuOH
tumors.[15] To date, [18F]F-DPA (17) is accessible only via
electrophilic radiofluorination.[16] Preparation of this probe via
conventional nucleophilic 18F-fluorination of the respective
iodonium, trimethylammonium, and nitro precursors resulted in a
maximum 18F-incorporation of 3%.[17] In contrast, using n-BuOH-
enhanced Cu-mediated fluorination, [18F]F-DPA was obtained in
85% RCC. Afterwards, we produced 6-[18F]fluoro-3,4-
dihydroxyphenethylamine (6-[18F]FDA) and 6-[18F]fluoro-L-3,4-
dihydroxyphenylalanine (6-[18F]FDOPA). 6-[18F]FDA is widely
used to image chromaffin tumors.[18] 6-[18F]FDOPA is the most
popular PET tracer for visualizing the central dopaminergic
system and is also used for diagnosis of neuroendocrine
tumors.[19] For N,N,O,O-Tetra-Boc-protected substrates 18b and
21b 18F-incorporation amounted to 87 and 68%, respectively.
Surprisingly, in the case of mono-N-Boc-protected precursors
the acceptable 18F-incorporation of 78 and 30% for 18a and 21a,
respectively, was achieved. (Fig. 5). During 18F-incorporation,
almost complete (> 80%) cleavage of one of the N-Boc
protection groups and partial cleavage of one of the O-Boc
groups (overall > 35%) occurred. Surprisingly, mono-N-Boc-
protected precursors also yielded the desired radiolabeled
products in reasonable RCCs (78 and 30% for [18F]19 and
[18F]22, respectively). If radiolabeling of mono-N-protected 6-
[18F]FDOPA and 6-[18F]fluoro-m-tyrosine (6-[18F]FMT) precursors
was carried out in pure aprotic solvents only ≤ 5% of the
radiofluorinated amino acids were observed in the reaction
mixture, possibly due to concurrent intramolecular Chan-Lam
Figure 4: Substrate scope for the n-BuOH-enhanced copper-mediated
radiofluorination of pinacolyl boronates and boronic acids. [c]Et4NHCO3 was
used for elution of 18F–.[10] RCC±SD [%].
[18F]fluoroanilines ([18F]10, [18F]11) from the corresponding
unprotected precursors, albeit in lower RCCs of up to 10 and
21%, respectively.[12] In the presence of n-BuOH, highly electron
rich unprotected 4-, 5-, and 6-indole boronic acids and pinacolyl
boronates ([18F]12–14) underwent near-quantitative (> 96%)
radiofluorination. Radiolabeling of indoles is of significant
interest given their importance as cycloxygenase-2, cannabinoid
receptor type 2, -adrenoreceptor and 5-hydroxytryptamine
receptor type 3 ligands.[12] The metabolism of tryptophan, a
proteinogenic amino acid with an indole ring in the side chain, is
significantly altered in numerous neurological disorders and
tumors.[13] The applicability of our method to prepare
radiofluorinated tryptophans was confirmed by the preparation of
protected radiolabeled 4- and 6-fluorotryptophans ([18F]15,
[18F]16) in RCCs of 92 and 99%, respectively.[14]
The method was also used to prepare clinically relevant PET
tracers. F-DPA is a very potent agonist at the 18 kDa
mitochondrial translocator protein (TSPO), a biomarker of brain
inflammation and reactive gliosis, characteristic of some
neurodegenerative and psychiatric diseases, stroke and brain
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coupling, i.e., formation of the respective indolines instead of
[18F]19 were detected. We assumed that the minor product peak
in HPLC chromatogram should correspond to partially
deprotected intermediates (N,3-O-diBoc and N,4-O-di-Boc-
protected dopamines). After the subsequent treatment with HCl
only [18F]fluoride and 6-[18F]FDA could be detected in the crude
reaction mixture strongly supporting our assumption. Similarly,
during 18F-labeling of 21a and 21b the formation of the two
3e]
fluorination.[3d,
In alcoholic media, this side reaction was
efficiently suppressed. During radiofluorination of 18a and 18b
we observed the formation of two identical radioactive products.
Based on its retention time the major product was identified as
N,O,O-tri-Boc protected dopamine [18F]19a
identical radiolabeled products was observed. Additionally, in the
case of radiolabeling of 21b the more hydrophobic product,
presumably, Boc2-6-[18F]FDOPA(Boc)2-OtBu ([18F]22) (12%) was
detected. Also in this case 18F– and 6-[18F]FDOPA were the only
radioactive products observed in the reaction mixture after the
deprotection step. After the radiolabeling step, remaining
pinacolyl boronate precursors were transformed into the
corresponding trifluoroboronates. The latter were separated from
the radiolabeled intermediates, [18F]19 and [18F]22, by solid
phase extraction. Finally, hydrolysis of [18F]19 and [18F]22 with
12 M HCl at 110 C for 5 min, followed by HPLC purification,
afforded 6-[18F]FDA and enantiomerically pure 6-[18F]FDOPA in
a ready-to-use form. The unoptimized, radiochemical yields
were 35 and 40% over the two steps for 6-[18F]FDA and 6-
[18F]FDOPA, respectively. The specific activities were
determined to 39 and 37 GBq/µmol for 6-[18F]FDA (260 MBq)
and 6-[18F]FDOPA (278 MBq), respectively The amounts of Cu
determined in the final solutions by ICP-MS amounted to
6.54±0.08 and 5.92±0.03 µg/preparation for 6-[18F]FDA and 6-
[18F]FDOPA, respectively.[20]
Figure 5: Preparation of 6-[18F]FDA ([18F]20) and 6-[18F]FDOPA ([18F]23).[10]
[a] During radiolabeling of 18b and 21b, concurrent cleavage (>80%) of one of
the N-Boc protection groups and partial cleavage of one of the O-Boc groups
(overall >35%) occurred. Partial deprotection of [18F]19a and [18F]22a was also
Trialkylstannanes are popular substrates for electrophilic
radiofluorination with [18F]F2 and the preparation of
radioiodinated probes. Some of them are commercially available,
e. g., precursors for 6-[18F]FDOPA, 6-[18F]FMT, 2-[18F]fluoro-L-
tyrosine (2-[18F]FTyr), and 5-[I*]iodo-2’-desoxyuridine (5-[*I]IdU).
Quite recently, Mossine et al. reported the Cu-mediated
[18F]fluorination of these substrates with nucleophilic
[18F]fluoride.[21] We examined, whether trialkylstannanes could
be radiolabeled using the novel 18F-fluorination procedure.
observed.
Figure 6: Radiofluorination of SnMe3-substrates.[10]
indicating that a partial deprotection took place. In the case of
radiolabeling of 18b also traces (<1%) of the more hydrophobic
product, presumably, N,N,O,O-tetra-Boc protected intermediate
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PhSnMe3 (24) was efficiently radiolabeled to yield [18F]FPh in
66% RCC (Fig. 6). Moreover, [18F]DAA1106 ([18F]26), a further
promising PET probe for the visualization of TSPO
expression,[5b] was also prepared from the corresponding stannyl
precursor 25 in an unoptimized RCC of 31%.[22] Finally, we
briefly tested the applicability of the method for conventional
fluorination. Tetramethylammonium fluoride as a fluoride source
afforded 12% HPLC yield of 4-fluoroindole from indole-4-boronic
acid under the same reaction conditions applied for 18F-
labeling.[23]
We have demonstrated the efficient application of alcohols as
co-solvents for Cu-mediated 18F-fluorination. Based on this
finding, we developed a procedure for rapid radiolabeling of a
broad range of substrates such as (hetero)arylboronic acids,
pinacolyl boronates, and trialkylstannanes under general
reaction conditions in many cases in yields of 80–99%. This
[5]
a) J. Zischler, P. Krapf, R. Richarz, B. D. Zlatopolskiy, B. Neumaier,
Appl. Radiat. Isot. 2016, 115, 133-137; b) B. D. Zlatopolskiy, J. Zischler,
P. Krapf, F. Zarrad, E. A. Urusova, E. Kordys, H. Endepols, B.
Neumaier, Chem. Eur. J. 2015, 21, 5972-5979.
[6]
[7]
[8]
[9]
See Reference [2b], Supporting Information S9-10
Please, see SI for the complete details of optimisation studies.
See Supporting Information, Table 1.
Radiochemical conversion (RCC; 18F-incorporation) refer to the amount
of radiofluoride which is transformed to the desired 18F-labeled
compound, determined by radio-HPLC or TLC. Radiochemical yield
(RCY) refers to the isolated yield of the radiochemically and chemically
pure radiolabeled compound. All RCYs are corrected for decay.
[10] All syntheses were carried out manually.
[11] a) J. H. Clark, Chem. Rev. 1980, 80, 429-452; b) In contrast SN2
radiofluorination in tert-BuOH media is well established. For the recent
review, please, see: Lee, J.-W. et al. Hydrogen-bond promoted
nucleophilic fluorination: concept, mechanism and applications in
positron emission tomography. Chem. Soc. Rev. 45, 4638-4650 (2016).
[12] N. K. Kaushik, N. Kaushik, P. Attri, N. Kumar, C. H. Kim, A. K. Verma,
E. H. Choi, Molecules 2013, 18, 6620-6662.
procedure
substantially
simplifies
the
production
of
[18F]fluorinated arenes by removing the time-consuming
azeotropic drying steps. Furthermore, it allows "last-stage"
access to 18F-fluorinated indoles, phenols, and anilines from
unprotected precursors. The preparation of clinical doses of two
PET-tracers, 6-[18F]FDA and 6-[18F]FDOPA demonstrated the
practicality of the method. The suitability of the protocol for
commercially available synthesis modules is currently under
investigation.
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Acknowledgements
This work was supported by the DFG grant ZL 65/1-1.
[14] We used the novel method for the preparation of 4-, 5-, 6- and 7-
[
18F]fluorotryptophans (RCCs 90–99%). These probes were prepared
Keywords: copper, fluorination, imaging agents, positron
as ready-to-use solutions in 40–50% isolated yields and with specific
activities of 40–60 GBq/µmol (for 1–2.5 GBq of tracer). Their biological
evaluation is under evaluation and will be reported together with details
of their preparation in due course. For recently published synthesis of
6-[18F]fluorotryptophan, see: D. Schäfer, P. Weiß, J. Ermert, J. Castillo
Meleán, F. Zarrad, B. Neumaier, Eur. J. Org. Chem. 2016, 4621-4628.
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J. Fan, N. Akula, G. Groyer, D. Adams, M. Schumacher, Nat. Rev. Drug
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10.1002/chem.201604633
Chemistry - A European Journal
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[20] For comparison, the permitted daily exposure with Cu for parenteral
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the normal copper concentration in blood serum ranges to 70-140
μg/dL. Cited by: Guideline for Elemental Impurities, Q3D, 39-40, ICH
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[22] In preliminary experiments 6-[18F]FDOPA and 3-OMe-6-[18F]FDOPA
were prepared in 20–25% RCYs starting from the corresponding tin
precursors.
[23] No further attempts have been made to optimize this reaction.
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10.1002/chem.201604633
Chemistry - A European Journal
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Entry for the Table of Contents
FULL PAPER
J. Zischler, N. Kolks, D. Modemann, B.
Neumaier, B. D. Zlatopolskiy*
Page No. – Page No.
Alcohol-Enhanced Cu-mediated
radiofluorination
The spirit makes the difference: Alcohol co-solvents enhance the yield of Cu-
mediated radiofluorination. A simple and rapid procedure to prepare 18F-labeled
aromatics was developed, which avoids azeotropic drying and enables the efficient
radiolabeling of an extraordinarily broad scope of (hetero)aryl boronic acids,
pinacolyl boronates, and trialkylstannanes under a unified set of reaction conditions.
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