2-Bromo-6-[18F]fluoropyridine: Two-step fluorine-18 radiolabelling via transition metal-mediated chemistry

Article abstract of DOI:10.1002/jlcr.3147

Novel radiolabelling methods are important for the development of new tracers for positron emission tomography. Direct nucleophilic fluorination of aromatic rings with [¹⁸F]fluoride is limited to activated substrates, restricting the application of this approach. Inspired by transition metal-mediated transformations, a fluorine-18 synthon was prepared to supplement the radiolabelling methods available for molecules unsuitable for direct labelling. 2-Bromo-6-[¹⁸F]fluoropyridine (denoted [¹⁸F]1) was prepared in high yield, and palladium-mediated cross-coupling reactions were exemplified. High incorporation of fluoride and efficient cross-coupling reactions demonstrate that compound [¹⁸F]1 holds promise as a new synthon for construction of fluorine-18-labelled molecules via transition metal-mediated reactions.

Full text of DOI:10.1002/jlcr.3147

Special Issue Article
Received 30 June 2013,
Accepted 29 October 2013
Published online 18 December 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3147
18
2-Bromo-6-[ F]fluoropyridine: two-step
fluorine-18 radiolabelling via transition metal-
mediated chemistry†
a,d,e
Helen M. Bettsa,b,c and Edward G. Robins
*
Novel radiolabelling methods are important for the development of new tracers for positron emission tomography. Direct
nucleophilic fluorination of aromatic rings with [18F]fluoride is limited to activated substrates, restricting the application of this
approach. Inspired by transition metal-mediated transformations, a fluorine-18 synthon was prepared to supplement the
radiolabelling methods available for molecules unsuitable for direct labelling. 2-Bromo-6-[18F]fluoropyridine (denoted [18F]1)
was prepared in high yield, and palladium-mediated cross-coupling reactions were exemplified. High incorporation of fluoride
and efficient cross-coupling reactions demonstrate that compound [18F]1 holds promise as a new synthon for construction of
fluorine-18-labelled molecules via transition metal-mediated reactions.
Keywords: PET; fluorine-18; synthon; 2-Fluoropyridine; palladium; cross-coupling
reported, but these synthons have not been widely adopted as
Introduction
they are either prepared in moderate yield from the symmetrical
Positron emission tomography (PET) is a valuable imaging
dihalobenzene or from iodonium salts, which require complex
precursor syntheses, and can be prone to side reactions.4–6
technique for monitoring physiological processes in vivo in a
[18F]Fluorinated heteroaromatics such as [18F]fluoropyridines
non-invasive manner, using concentrations of radiolabelled
compounds that do not cause a pharmacological response.1
have become more prevalent as the heteroatom can be used
The most widely available isotope for PET imaging is fluorine-
to tune a potential PET tracer’s pharmacokinetic profile. In some
18, which has a half life of 109.7 min and is readily produced as
cases, heteroaromatics are more amenable to
a direct
aqueous fluoride from a cyclotron. Although the moderate half
life is ideal for patient scanning without excessive radiation
burden, it presents a challenge for the radiochemist to prepare
and purify [18F]fluorine-labelled imaging agents within a short
window.
radiolabelling approach, although the presence of electron
withdrawing groups is preferred.7
Molecules of interest for PET imaging commonly feature the
fluorine radiolabel as a fluoroaromatic group. Direct nucleophilic
[18F]fluorination of aromatic ring systems requires the presence
of electron withdrawing substituents, and harsh reaction
conditions are employed for efficient incorporation.2 Multistage
synthon approaches provide an alternative in which an activated
precursor is radiolabelled and subsequently incorporated into
the molecule of interest. Popular synthons include 4-[18F]
fluorobenzaldehyde and N-succinimidyl-4-[18F]fluorobenzoate.
However, these synthons are limited to labelling molecules with
a reactive nucleophile for conjugation, and their purification
from by-products can be difficult.3 Novel methods of
radiolabelling aromatic systems with [18F]fluoride are therefore
of interest.
This article describes the synthesis and transition metal-
mediated reactions of the novel synthon 2-bromo-6-[18F]
fluoropyridine. Transition metal-mediated approaches have
often been reported in carbon-11 radiosyntheses (t1/2 = 20 min,
β+) to selectively assemble reaction components in good yield;
however, relatively few examples exist for [18F]fluorine
radiolabelling.1 Notably, palladium-mediated reactions of [18F]
fluorobromo benzene and [18F]fluoroiodobenzene have been
aGE Healthcare Discovery, Medical Diagnostics, Cyclotron Building,
Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
bGE Healthcare Discovery, Medical Diagnostics, The Grove Centre, White Lion
Road, Amersham, Bucks, HP7 9LL, UK
cNottingham University Hospitals NHS Trust, PET/CT Centre, Nottingham City
Hospital, Nottingham, NG5 1PB, UK
dSingapore Bioimaging Consortium (SBIC) Agency for Science, Technology and
Research (A*STAR) 11 Biopolis Way, Helios Building, Singapore 138667
eClinical Imaging Research Centre (CIRC), Yong Loo Lin School of Medicine,
Centre for Translational Medicine, National University of Singapore, 14 Medical
Drive, Singapore, 117599
*Correspondence to: Helen M. Betts, Nottingham University Hospitals NHS Trust,
PET/CT Centre, Nottingham City Hospital, Nottingham, NG5 1PB, UK.
E-mail: helen.betts@nottingham.ac.uk
† This article is published in the Journal of Labelled Compounds and
Radiopharmaceuticals as a special issue on ‘Current Developments in PET and
SPECT Imaging’, edited by Jonathan R. Dilworth, University of Oxford and Sofia
I. Pascu, University of Bath.
J. Label Compd. Radiopharm 2014, 57 215–218
Copyright © 2013 John Wiley & Sons, Ltd.

H. M. Betts and E. G. Robins
Inspired by the range of transformations possible using and Suzuki coupling, (Scheme 2). The coupling efficiency for
transition metal cross-coupling, we developed 2-bromo-6-[18F] each reaction using [18F]1 after silica cartridge purification is
fluoropyridine and here report its synthesis and characterisation. displayed in Table 2. Radiolabelled products were verified by
co-injection of a conventionally characterised [19F] standard,
(see Supplementary Information).
Synthon
Buchwald–Hartwig amination was successfully used to
2-Bromo-6-[18F]fluoropyridine, [18F]1, was prepared from 2,6- prepare electron-rich [18F]fluoropyridyl compounds. Reaction of
dibromopyridine 2 by nucleophilic aromatic fluorination with [18F]1, [Pd2dba3], BINAP and sodium t-butoxide with
[18F]fluoride dried in the presence of the phase transfer agent benzylamine or N-benzylpiperazine yielded N-benzyl-6-[18F]
Kryptofix-222 and potassium carbonate. (Scheme 1). 2,6- fluoropyridin-2-amine (denoted [18F]3) and 1-benzyl-4-(6-[18F]
Dibromopyridine 2 is appropriate for both fluoride substitution fluoropyridin-2-yl) piperazine (denoted [18F]4), respectively,
and oxidative addition reactions, and the symmetrical precursor (Table 2 and Scheme 2). Preliminary experiments showed that
was selected to avoid potential mixtures of products. pre-mixing the [Pd2dba3] and BINAP prior to addition to [18F]1,
Furthermore, 2 is commercially available as a crystalline solid purging of the reaction headspace with N2, as well as keeping
and has no special storage requirements.
solvent volume to a minimum were all beneficial to the rate of
Various solvents and reaction conditions were screened, and reaction. The use of a great excess of the amine (~100-fold, with
the resulting [18F]1 was purified by semi-preparative HPLC, respect to [Pd2dba3]) was critical to drive conversion to the
(Table 1). All reactions were performed manually using starting desired product.
[18F]fluoride activity of 74–222 MBq. Crude reaction mixtures
Various solvents were tested to establish the optimum
were analysed by HPLC with UV and radio-detection. Under all conditions for the Buchwald–Hartwig reaction. In anhydrous
conditions tested, only two radioactive species were present, MeCN, compound [18F]3 was formed with a 60% conversion from
identified as [18F]fluoride and [18F]1 as verified by co-injection [18F]1 after 15 min at 100 °C. Under the same conditions, the
of [19F]1 standard. After HPLC purification, non-decay-corrected coupling reaction to form [18F]4 showed 49% conversion after
isolated yields of [18F]1 of up to 53% (79% corrected for decay) 25 min; presumably, steric effects around the nitrogen hindered
were obtained. Complete removal of 2 was observed after HPLC the formation of the [18F]FPy-Pd(II)-amine complex in the
purification. As an alternative purification method, [18F]1 was reaction cycle. For both amine substrates (after dilution with
passed through a silica Sep-Pak cartridge. Using cartridge H2O for HPLC analysis), the balance of the radioactivity was found
purification, compound 2 was not separated from [18F]1, but this at the solvent front, with no [18F]1 remaining. Attempts to
was not detrimental to the subsequent coupling reaction. increase the conversion by using the higher boiling solvents
Cartridge purification was therefore pursued to minimise the NMP, DMF or toluene did not improve the reaction yields,
total reaction time.
although the rate of consumption of [18F]1 was increased; after
5 min in MeCN/NMP, all [18F]1 was consumed, and [18F]3 was
formed in 53%. No desired product was observed when the
reaction was attempted in DMF. As expected, omission of the
palladium catalyst resulted in the displacement of [18F]fluoride from
[18F]1, and all radioactivity was found at the solvent front by
analytical HPLC.
Coupling reactions
Cross-coupling reactions
With [18F]1 in hand, palladium-mediated cross-coupling
reactions were exemplified by the Buchwald–Hartwig amination
The Suzuki reaction was used to prepare a further model
electron-rich [18F]fluoropyridine. [18F]1, and p-tolylboronic acid
reacted in the presence of sodium carbonate and [Pd(PPh3)4] in
MeCN/H2O. Excellent conversion to 2-[18F]fluoro-6-( p-tolyl)
pyridine [18F]5 of 98% was found after 5 min. Unlike the
Buchwald–Hartwig aminations, this reaction was relatively
insensitive to volume; comparable yields of 98% and 95% were
recorded with total reaction volumes of 0.35 mL and 0.65 mL,
respectively. Product [18F]5 was isolated to assess the end of
synthesis yield from [18F]fluoride. The reaction was diluted in
H2O and passed through a filter before loading to a semi-
preparative HPLC system. Use of aqueous-miscible MeCN as
the reaction medium facilitated the purification by standard
reverse-phase HPLC on C18 stationary phase, using a MeCN/
H2O gradient method. The major UV-active components
(including 2-bromo-6-(p-tolyl)pyridine) were easily separated
from [18F]5, which was isolated in 22 6% (n = 4) non-decay-
corrected yield from starting [18F]fluoride activity. The total
Scheme 1. Preparation of 2-bromo-6-[18F]fluoropyridine, [18F]1.
Table 1. Summary of radiolabelling conditions for [18F]1
Mass of Solvent
Temp
°C*
Yield (decay
corrected) %
Synthesis
time (min)
2 (mg)
(0.2 mL)
5.0
2.0
2.0
2.0
2.0
2.0
1.0
DMF
DMF
MeCN
NMP
DMF
THF
120
120
100
100
100
100
100
42(68)
42(64)
43(67)
18(28)
53(79)
5(7)
74
65
70
74
64
68
67
MeCN
40(60)
*Each reaction was heated for 10 min. Yields given are of
HPLC purified, isolated [18F]1 calculated from aqueous [18F]
fluoride. Decay corrected yields are given in brackets.
Scheme 2. Cross-coupling reactions of [18F]1.
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 215–218

H. M. Betts and E. G. Robins
Table 2. Summary of cross-coupling reactions described by Scheme 2
Temp
(°C)
Time
(min)
Yield*
(%)
Substrate
Product
Product
Reagents
Solvent
MeCN
[18F]3
100
15
Pd2dba3 ( )BINAP
NaOtBu
60
[18F]3
[18F]3
100
100
15
15
Pd2dba3 NaOtBu
(No BINAP)
Pd2dba3 BINAP
(No NaOtBu)
NaOtBu
MeCN
MeCN
0
0
[18F]3
[18F]3
100
130
15
5
MeCN
MeCN/NMP
(1:3)
0
53
Pd2dba3 ( )BINAP
NaOtBu
[18F]4
100
25
Pd2dba3 ( )BINAP
NaOtBu
MeCN
49
[18F]4
[18F]4
[18F]5
150
110
100
15
15
5
Pd2dba3 ( )BINAP
NaOtBu
MeCN/
toluene
DMF
45
0
Pd2dba3 ( )BINAP
NaOtBu
Pd(PPh3)4 Na2CO3
MeCN/H2O
(0.35 mL)
98
[18F]5
[18F]6
100
100
5
Pd(PPh3)4 Na2CO3
MeCN/H2O
(0.65 mL)
95
70
30
Pd(II)OAc2 Mo(CO) THF
6 DBU
DBU, diazabicycloundecene.
*Reactions were performed using silica cartridge purified [18F]1. Yield refers to the percentage of product from radio-HPLC
analysis. ‘CO’ source is Mo(CO)6/DBU.
synthesis time was approximately 90 min. Further optimisation after 30 min heating at 100 °C. It is notable that under these
and shortened reaction time may be achieved once translated conditions, the competing Buchwald–Hartwig amination
to an automated platform.
product was absent, indicating efficient insertion of CO in
the reaction cycle.
Multicomponent aminocarbonylation
Conclusions
Multicomponent reactions provide an elegant solution to the
preparation of many carbon-11 radiotracers. Such multicomponent We have successfully demonstrated that the novel synthon
reactions have scarcely been considered for fluorine-18, and the 2-bromo-6-[18F]fluoropyridine [18F]1 can be prepared in high yield
first examples have been reported recently.8 Here, compounds and used in palladium-mediated reactions to prepare electron-rich
[18F]1, benzylamine and CO were selectively assembled to form 2-[18F]fluoropyridines. The possibility of using this synthon in
N-benzyl-6-fluoropicolinamide (denoted [18F]6) using [Pd(OAc)2] multicomponent reactions was also demonstrated. We envisage
as the palladium mediator. Mo(CO)6 was chosen as a convenient that this synthon can widely applied in the wealth of known
solid source of CO, where CO is released when heated after addition transition metal-mediated cross-coupling reactions and provides
of diazabicycloundecene.9 Using silica cartridge purified [18F]1, the a novel method to add to the fluorine-18 radiochemistry toolkit
aminocarbonylation reaction in THF yielded [18F]6 in 70% for the development of new PET imaging agents.
J. Label Compd. Radiopharm 2014, 57 215–218
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

H. M. Betts and E. G. Robins
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Acknowledgments
We would like to acknowledge I. Khan for the contributions in
planning this project and the cyclotron operators at
Hammersmith Imanet for the provision of [18F]fluoride. We
disclose that this work is the subject of a patent application.
Chem. Scand. 1998, 52, 480–489.
[7] F. Dollé, Curr. Pharm. Des. 2005, 11, 3221.
[8] L. Li, M. N. Hopkinson, R. Leuma Yona, R. Bejot, A. D. Gee, V. Gouverneur,
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Conflict of Interest
[9] J. Wannberg, M. Larhed, J. Org. Chem. 2003, 68, 5750.
The authors did not report any conflict of interest.
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www.jlcr.org
Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2014, 57 215–218