Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF

Article abstract of DOI:10.1021/acs.orglett.6b02911

A copper-mediated nucleophilic radiofluorination of aryl- and vinylstannanes with [¹⁸F]KF is described. This method is fast, uses commercially available reagents, and is compatible with both electron-rich and electron-deficient arene substrates. This method has been applied to the manual synthesis of a variety of clinically relevant radiotracers including protected [¹⁸F]F-phenylalanine and [¹⁸F]F-DOPA. In addition, an automated synthesis of [¹⁸F]MPPF is demonstrated that delivers a clinically validated dose of 200 ± 20 mCi with a high specific activity of 2400 ± 900 Ci/mmol.

Full text of DOI:10.1021/acs.orglett.6b02911

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Letter
pubs.acs.org/OrgLett
Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF
Katarina J. Makaravage,† Allen F. Brooks,‡ Andrew V. Mossine,‡ Melanie S. Sanford,*,†
and Peter J. H. Scott*,‡,§
§
†Department of Chemistry and The Interdepartmental Program in Medicinal Chemistry, University of Michigan, 930 North
University Avenue, Ann Arbor, Michigan 48109, United States
‡Department of Radiology, University of Michigan Medical School, 1301 Catherine Street, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: A copper-mediated nucleophilic radiofluorination of
aryl- and vinylstannanes with [18F]KF is described. This method is
fast, uses commercially available reagents, and is compatible with
both electron-rich and electron-deficient arene substrates. This
method has been applied to the manual synthesis of a variety of
clinically relevant radiotracers including protected [18F]F-phenyl-
alanine and [18F]F-DOPA. In addition, an automated synthesis of [18F]MPPF is demonstrated that delivers a clinically validated
dose of 200 20 mCi with a high specific activity of 2400 900 Ci/mmol.
Scheme 1. Radiofluorination of Arylstannanes
ositron emission tomography (PET) imaging is a non-
invasive diagnostic imaging technique that provides in vivo
P
physiochemical information.1−4 Fluorine-18 (18F) is the most
commonly used radionuclide for PET, largely due to its attractive
half-life of 110 min. This half-life enables the sophisticated
synthesis of target molecules, allows distribution of 18F-labeled
tracers to facilities that lack cyclotrons, and facilitates in vivo
pharmacokinetic studies.2 With the increasing number of PET
scans, there is a need for new, practical methods for the late-stage
introduction of 18F into bioactive molecules. Methods that enable
the nucleophilic radiofluorination of readily accessible and stable
precursorsareinparticularlyhighdemandduetotheavailabilityof
[18F]fluoride from small medical cyclotrons.5,6
Arylstannanes are appealing precursors for PET radiolabeling
for a number of reasons. First, they can be easily prepared from
inexpensive starting materials,7,8 and important examples are
already known intermediates and/or commercially available (i.e.,
TriBoc-L-DOPA methyl ester).9 Second, the Sn−C bond is stable
to most functional group manipulations,10,11 which enables
flexible and modular syntheses of complex precursors that can
then undergo selective late-stage radiofluorination. Third,
arylstannanes have already been validated as precursors to
radiopharmaceuticals for human clinical trials,12−15 thereby
mitigating concerns about toxicity and the feasibility of Sn
removal. However, to date, the major limitation in this field is that
existing methods for the fluorination16,17 and radiofluorina-
tion18,19 of arylstannanes require electrophilic fluorine sources
(e.g., F2, N-fluoropyridinium salts, N-fluorobenzenesulfonimide,
Selectfluor) (Scheme 1a).20 These reagents are much more
expensive and less available than fluoride (particularly in the 18F
form). Furthermore, electrophilic radiofluorination methods
result in products with dramatically lower specific activity (ratio
of 18F/19F), which greatly reduces imaging sensitivity.3
from our group6e,21 and others6c,f demonstrating a related Cu-
mediated (radio)fluorination of arylboron precursors. In addition
to the generally attractive features of arylstannane precursors
discussed above, we anticipated that they would be particularly
well suited for Cu-mediated radiofluorination. Specifically, a key
fundamentalstepoftheCu-mediatedprocess,thetransmetalation
of the aryl group to Cu, is expected to proceed significantly faster
from tin versus boron, which should result in faster reaction rates
(crucial for radiolabeling applications) as well as fewer side
reactions and higher yields.22,23 We report herein the develop-
ment, optimization, and scope of the Cu-mediated radio-
fluorination of arylstannanes with [18F]KF. This transformation
exhibits high functional group tolerance and has been applied to
thelate-stageradiofluorinationofanumberofcomplexmolecules.
Furthermore, ithasbeenscaledtoanautomatedsynthesismodule
andusedtoprepare aclinicallyvalidatedhighspecificactivitydose
of the radiotracer 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-
fluorobenzamidoethylpiperazine ([18F]MPPF).
Our initial investigations focused on the Cu(OTf)2-mediated
fluorination of 1-SnBu3 with KF under conditions analogous to
thosedemonstratedforaryltrifluoroboratesubstrates.21 After18h
We sought to address this limitation through the development
ofamethodfortheCu-mediatednucleophilicradiofluorinationof
arylstannanes (Scheme 1b). This work builds on recent reports
Received: September 27, 2016
© XXXX American Chemical Society
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Table 1. Cu-Mediated Nucleophilic Fluorination of
Arylstannanes in Acetonitrile with Excess Fluoride
Table 2. Cu-Mediated Nucleophilic Fluorination of 3-SnBu3
a
a
with [18F]KF
entry
R
R1
time (h)
additive
none
KF (equiv) yield (%)
b
entry
solvent
temp (°C)
pyridine (equiv)
RCC (%)
1
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Me
Bu
Me
Bu
Me
F
F
F
F
F
F
18
4
42
55
42
53
51
15
23
24
34
64
57
65
1
2
3
4
5
6
7
CH3CN
CH3CN
DMF
60
60
0
50
50
50
50
15
15
15
15
nd
nd
nd
2
18
18-crown-6
none
4
3
2
4
60
4
2
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
4
DMF
110
110
110
140
140
140
22
51
53
2
1
1
5
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
4
b
DMA
DMA
DMA
DMA
DMA
6
0.5
4
7
MeO
MeO
Ph
55 10
8
4
c
8
65
44
2
1
9
4
d
9
10
11
12
Ph
4
a
Ac
4
General conditions: 3-SnBu3 (0.01 mmol, 1 equiv), Cu(OTf)2 (2
equiv), pyridine (15 equiv), [18F]KF, DMA (0.01 M), 140 °C, 30 min.
Ac
4
b
a
RCC determined by radio-TLC (n ≥ 2). nd = no product detected by
radio-TLC or HPLC. Reaction time = 5 min. 3-SnMe3 used as
General conditions: Arylstannane (0.025 mmol, 1 equiv), Cu(OTf)2
(4 equiv), KF, 18-crown-6 (4 equiv), CH3CN (0.083 M), 60 °C. Yield
determined by 19F NMR spectroscopic analysis of the crude reaction
c
d
substrate.
b
mixture using 1,2-difluorobenzene as an internal standard. Yield
based on KF.
the dramatic change in fluoride stoichiometry (from 0.3 M with
KF to approximately 1 nM with [18F]KF).26 Three modifications
were found to be critical for achieving radiofluorination in this
system: (1) changing from CH3CN to an amide-based solvent
(DMF or DMA); (2) the addition of pyridine (which was also an
important additive in related radiofluorinations of arylborons);6e
and (3) increasing the reaction temperature to between 110 and
140 °C. The optimal radiofluorination conditions for 3-SnBu3
wereasfollows:2equivofCu(OTf)2,15equivofpyridinein0.1M
DMA at 140 °C. This afforded [18F]3 in 65 2% radiochemical
conversion (RCC) within just 5 min (entry 8).
The optimal conditions were applied to a series of aryl-,
heteroaryl-, and vinylstannane precursors. As summarized in
Figure 1, this method is compatible with aromatic substrates
bearing electron-neutral (3), electron-withdrawing (4, 13), and
electron-donating substituents (2, 5−10) as well as hetero-
at 60 °C with 4 equiv of KF in CH3CN, the fluorinated product 1
was obtained in 42% yield as determined by 19F NMR
spectroscopy (Table 1, entry 1). While this yield is lower than
that reported with 1-BF3K under closely analogous conditions
(70%,20h),theadditionof18-crown-6asaphase-transfercatalyst
could be used to boost the yield with 1-SnBu3 to 55% (entry 2).
Furthermore, as predicted, the fluorination of 1-SnBu3 is
significantly faster than that of 1-BF3K. For example, 1-SnBu3
affords 51% yield after just 15 min under these conditions. In
contrast, the analogousreactionof 1-BF3Krequires morethan2h
toafford50%yield.Thefasterratewith1-SnBu3 ishighlydesirable
for PET applications. We also examined the sensitivity of this
reaction to the stoichiometry of fluoride. This is another key
consideration for translation because [18F]fluoride is typically the
limiting reagent during radiofluorination. We were encouraged to
see that this reaction still proceeds (albeit in reduced yield) with
KF as the limiting reagent (Table 1, entry 6).
We next applied this fluorination to a small set of arylstannanes
(Table1,entries7−12)toestablishtheeffectivenessofour15min
nucleophilic fluorination protocol for electronically diverse
arylstannanes and examine the impact of the alkyl substituents
on tin (R) on the reaction. As shown in Table 1 (entries 7−12),
stannanes bearing electron-donating (p-MeO), electron-neutral
(p-Ph), and electron-withdrawing (p-Ac) substituents react to
form fluorinated products in moderate to good yields within just
15minat60°C. Thep-MeOderivative isparticularly noteworthy,
as the corresponding aryltrifluoroborate is poorly reactive,
affording <5% yield under any of the fluorination conditions
examined.21 Substitution of the alkyl group on the stannane had a
significant impact on yield over this short reaction time, with the
Me-substituted stannanes affording comparable or higher yield
than the Bu derivatives in all cases. This likely reflects a faster rate
of transmetalation from the less hindered tin center.24
We next focused on translating this nucleophilic fluorination to
achieve the 18F-fluorination of 3-SnBu3. As is common in the
radiofluorinationfield,3,25 significantreoptimizationwasrequired,
asthebestcoldfluorinationconditionsaffordednodetectable18F-
labeled product (Table 2, entry 1). This is likely a consequence of
Figure 1. Scope of arylstannane substrates. Conditions: aryltributyltin
substrate(0.01mmol,1equiv), Cu(OTf)2 (2equiv), pyridine(15equiv),
[18F]KF, DMA (0.01 M), 140 °C, 5−30 min. RCC determined by radio-
TLC; (a) 100 °C; (b) 18-crown-6 (0.5 equiv); (c) 30 equiv of pyridine.
B
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aromatic(11)andvinylstannane(12)derivatives. Substratessuch
as 13-SnBu3 include a functional handle that can be used for
further elaboration. Ortho-substitution was well-tolerated, with
theo-MeO substrate 6-SnBu3 affording ayieldcomparable tothat
of the p-MeO substrate 2-SnBu3 (RCC = 57% versus 48%,
respectively). This is in contrast to other metal-mediated
nucleophilic radiofluorinations, which typically afford much
lower yields with ortho-substituted aromatic substrates (see
Table S20). The electron-rich substrates (2, 5−10) are note-
worthy, as they are challenging to radiofluorinate usingtraditional
SNAr.1 Overall, the RCCs are comparable, and in many cases
significantly higher, than those for the state-of-the-art metal-
mediated radiofluorinations of analogous substrates (see Table
S20 for a comparison of metal-mediated nucleophilic radio-
fluorination methods).
Scheme 2. Comparison of Current Methods To Synthesize
[18F]MPPF ([18F]17)36,37
We next applied our method to the preparation of products
currentlybeingevaluatedasradiotracersinclinicaltrialsoralready
FDA approved.27,37 Initial studies were conducted via manual
synthesis, which provided useful RCCs (Figure 2). For instance,
20 mCi dose (13% RCY) after radiolabeling and HPLC
purification.34 ThedosepreparedbythismethodpassedallcGMP
quality control testing necessary for clinical use, as outlined in the
US Pharmacopeia and 21CFR212, including residual Cu and Sn
levels below the allowed limits specific in the ICH Guidelines (see
the Supporting Information for complete information).6g,35 As
shown in Scheme 2, our new method affords nearly double the
RCY and reduces the overall time from end of bombardment
(EOB) to end of purification by one-third relative to the current
commercial synthesis of this tracer.36
In conclusion, this paper discloses a mild, copper-mediated
method for the nucleophilic fluorination and radiofluorination of
arylstannanes. This method represents the first practical
nucleophilic fluorination of stannanes using 18F, is compatible
witharyl,heteroaryl,andvinylstannanes,andfillsanimportantgap
in available late-stage fluorination methods. Furthermore, this
process can be readily automated and scaled on a commercial
radiochemistry synthesis moduleandappliedtoclinicallyrelevant
radiotracers. Finally, we have shown that the method is tolerant of
areasonablenumberoffunctionalgroupscommonindrugtargets.
To expand the utility further, exploration of the compatibility of
this methodwith medicinalchemistryspace isongoingandwill be
reported in due course.
Figure 2. Substrate scope of relevant radiotracers.
this method is effective for the synthesis of protected phenyl-
alaninederivatives([18F]14and[18F]15)forstudyingaminoacid
transport.28 We also targeted 3-[18F]fluoro-5-[(pyridin-3-yl)-
ethynyl]benzonitrile ([18F]F-PEB, [18F]18), whose previous
radiosyntheses suffer from low yields (1−5% RCY, nondecay
corrected).6e,29−31 Our new method, starting from the readily
availableandstablearylstannaneprecursor18-SnBu3, delivers the
product in 11 2% RCC.
This method is also effective for the radiofluorination of the
protectedL-DOPAstannane16-SnMe3,affording[18F]16in56
12% yield. This result is noteworthy for several reasons. First,
nucleophilic methods for radiolabeling L-DOPA remain highly
sought after,1,28,32,33 and the obtained RCC is among the best
reported for this type of transformation (see Figure S10 for a
comparison of nucleophilic methods for [18F]F-DOPA deriva-
tives). Second, the precursor 16-SnMe3 is a single step from a
commercial stannane whose derivatives have been used in the
clinical production of [18F]F-DOPA via electrophilic radio-
fluorination.12,13 As such, the successful radiofluorination of 16-
SnMe3 offers the potential for a direct nucleophilic replacement
for this method.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.6b02911.
Experimental procedures, optimization details, radio-
HPLC/TLC traces, and spectral data for all new
compounds (PDF)
Finally, we targeted [18F]MPPF ([18F]17), a serotonin
receptor ligand currently synthesized by SNAr radiofluorination
of the NO2 precursor (Scheme 2a). Our manual Cu-mediated
procedurefromstannane17-SnMe3 delivered[18F]17in33 4%
RCC.The[18F]MPPFsynthesiswasscaledandautomatedusinga
TRACERLab FXFN module (Scheme 2b). The reaction using
1500mCiofinitialactivityaffordedaformulatedandvalidated200
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mssanfor@umich.edu.
*E-mail: pjhscott@umich.edu.
C
DOI: 10.1021/acs.orglett.6b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(16) For examples of metal-catalyzed/mediated electrophilic fluorina-
tion of arylstannanes, see: (a) Furuya, T.; Strom, A. E.; Ritter, T. J. Am.
Chem. Soc. 2009, 131, 1662−1663. (b) Tang, P.; Furuya, T.; Ritter, T. J.
Am. Chem. Soc. 2010, 132, 12150−12154. (c) Ye, Y.; Sanford, M. S. J. Am.
Chem. Soc. 2013, 135, 4648−4651.
(17) For an example of metal-free electrophilic fluorination of
arylstannanes, see: Bryce, M. R.; Chambers, R. D.; Mullins, S. T.;
Parkin, A. J. Chem. Soc., Chem. Commun. 1986, 1623−1624.
(18) For examples of metal-mediated electrophilic radiofluorination of
arylstannanes, see: Teare, H.; Robins, E. G.; Kirjavainen, A.; Forsback, S.;
Sandford, G.; Solin, O.; Luthra, S. K.; Gouverneur, V. Angew. Chem., Int.
Ed. 2010, 49, 6821−6824.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
WeacknowledgetheNIH(R01EB021155toM.S.S.andP.J.H.S.),
US DOE/NIBIB (DE-SC0012484 to P.J.H.S.), and Merck
(M.S.S. and P.J.H.S.) for financial support. We thank Sydonie
D. Schimler (U. of Michigan) for conducting comparative studies
of the fluorination of p-methoxyphenyl trifluoroborate.
(19) For examples of metal-free electrophilic radiofluorination of
arylstannanes, see: (a) Adam, M. J.; Pate, B. D.; Ruth, T. J.; Berry, J. M.;
Hall,L.D.J.Chem.Soc.,Chem.Commun. 1981,733−733.(b)Adam,M.J.;
Ruth, T. J.; Jivan, S.; Pate, B. D. J. Fluorine Chem. 1984, 25, 329−337.
(c) Coenen, H. H.; Moerlein, S. M. J. Fluorine Chem. 1987, 36, 63−75.
(d)Eskola,O.;Gronroos,T.;Bergman,J.;Haaparanta,M.;Marjamaki,P.;
Lehikoinen, P.; Forsback, S.; Langer, O.; Hinnen, F.; Dolle, F.; Halldin,
C.; Solin, O. Nucl. Med. Biol. 2004, 31, 103−110.
(20) We communicated this Cu-mediated fluorination of arylstannanes
in May 2016; see: Mossine, A.; Makaravage, K.; Ichiishi, N.; Brooks, A.;
Miller, J.; Sanford, M.; Scott, P. J. Nucl. Med. 2016, Vol. 57, (Suppl. 2), pp.
2. Following submission of this manuscript in August 2016, a related
copper-mediated fluorination of arylstannanes using K19F was also
disclosed: Gamache, R. F.; Waldmann, C.; Murphy, J. M. Org. Lett. 2016,
18, 4522−4525.
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