Enhanced copper-mediated 18F-fluorination of aryl boronic esters provides eight radiotracers for PET applications

Article abstract of DOI:10.1039/c6cc03295h

[¹⁸F]FMTEB, [¹⁸F]FPEB, [¹⁸F]flumazenil, [¹⁸F]DAA1106, [¹⁸F]MFBG, [¹⁸F]FDOPA, [¹⁸F]FMT and [¹⁸F]FDA are prepared from the corresponding arylboronic esters and [^18<

Full text of DOI:10.1039/c6cc03295h

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Enhanced copper-mediated F-fluorination of
aryl boronic esters provides eight radiotracers for
PET applications†
Cite this:DOI: 10.1039/c6cc03295h
Sean Preshlock,a Samuel Calderwood,‡a Stefan Verhoog,‡a Matthew Tredwell,a
Mickael Huiban,b Antje Hienzsch,c Stefan Gruber,a Thomas C. Wilson,a
Nicholas J. Taylor,a Thomas Cailly,ad Michael Schedler,a Thomas Lee Collier,e
Received 19th April 2016,
Accepted 23rd May 2016
DOI: 10.1039/c6cc03295h
Jan Passchier,b Rene Smits,c Jan Mollitor,c Alexander Hoepping,c Marco Mueller,c
´
Christophe Genicot,f Joel Mercierf and Veronique Gouverneur*a
www.rsc.org/chemcomm
´
¨
[
18F]FMTEB,
[
18F]FPEB,
[
18F]flumazenil,
[
18F]DAA1106,
[
18F]MFBG, Cu-mediated 18F-labeling with 18F-fluoride; one of the distinc-
[
18F]FDOPA, [18F]FMT and [18F]FDA are prepared from the corresponding tive features of this reaction is its compatibility with arylboro-
arylboronic esters and [18F]KF/K222 in the presence of Cu(OTf)2py4. The nates derived from electron rich, neutral and deficient arenes.
method was successfully applied using three radiosynthetic platforms, In this report, we demonstrate that this transformation enables
and up to 26 GBq of non-carrier added starting activity of 18F-fluoride. the preparation of eight radiotracers; [18F]FMTEB, [18F]FPEB,
[18F]flumazenil, [18F]DAA1106, [18F]MFBG, [18F]FDOPA, [18F]FMT,
Positron emission tomography (PET) is a molecular imaging and [18F]FDA (Scheme 1). To achieve this goal, our original reaction
modality with wide-ranging applications in oncology, cardiology, conditions were modified for radiotracers possessing an electron
neurology, as well as fundamental clinical research.1 Despite deficient fluoroarene. This study is significant as, for the first time,
the great success of PET imaging, the development of new a range of radiotracers used in (pre)clinical studies, but difficult to
radiotracers remains a formidable challenge. Among all PET prepare, is within reach applying a single reaction. Selected radio-
radioisotopes, 18F is a widely used clinically relevant radionuclide syntheses were performed on automated platforms and in different
because of its advantageous properties;2 specifically, the half-life laboratories, an advance indicating that the process is robust and
of fluorine-18 (109 min) is long enough to allow remote-site amenable to broad use in PET radiochemistry facilities.
application of radiopharmaceuticals as demonstrated worldwide
by distribution of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG).3,4
A recent upsurge in fluorination chemistry has revealed a number
of novel 18F-labeling methods,5 including the preparation of
18F-fluoroaromatics through aryl iodonium ylides,6 aryl sulfonium
salts,7 preformed PdIV or NiII complexes,8 and aryl boronic pre-
cursors.9 These most recent advances could make an impact in the
clinic if one progresses from proof of concept to the synthesis of
radiotracers and radiopharmaceuticals, and ultimately apply these
new methods for human use. Our group has demonstrated that
arylboronates derived from pinacol are suitable substrates for
a University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road,
OX1 3TA Oxford, UK. E-mail: veronique.gouverneur@chem.ox.ac.uk
b Imanova, Burlington Danes building Imperial College,
London Hammersmith Hospital, Du Cane Road, London W12 0NN, UK
c ABX GmbH Heinrich-Glaeser-Strasse 10-14, D-01454 Radeberg, Germany
d Normandie University, UNICAEN, CERMN, F-14032 Caen, France
e Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, NY 14850, USA
f Global Chemistry, UCB New Medicines, UCB Biopharma sprl,
1420 Braine-L’Alleud, Belgium
Scheme 1 Synthesis of eight radiotracers via Cu-mediated 18F-fluorination
† Electronic supplementary information (ESI) available: Experimental details and
of arylboronic esters. nca (non-carrier added), RCY (radiochemical yield),
RCP (radiochemical purity), SA (specific activity).
NMR spectra. See DOI: 10.1039/c6cc03295h
‡ These authors contributed equally to this study.
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Table
18F]flumazenil [18F]1c from 2a, 2b and 2c, respectively, starting with
4.0–10.0 GBq of 18F-fluoride
1
Radiosynthesis of [ [ [ [
18F]FMTEB 18F]1a, 18F]FPEB 18F]1b and
Our original protocol consists of treating the aryl boronic
ester with [18F]KF/K222 and Cu(OTf)2py4 in DMF at 110 1C. Under
these reaction conditions, the copper-mediated 18F-fluorination
of aryl boronic esters is most effective for the 18F-labeling of
electron rich arenes. We therefore anticipated that the level of
optimization required for the synthesis of [18F]FMTEB [18F]1a,
[18F]FPEB [18F]1b, [18F]flumazenil [18F]1c, [18F]DAA1106 [18F]1d,
[18F]MFBG [18F]1e, [18F]FDOPA [18F]1f, [18F]FMT [18F]1g and
[18F]FDA [18F]1h from their respective arylboronate precursors
2a–h would vary. This validation study was performed with a
NanoTek platform applying a semi-automated protocol.10 All
radiochemical conversions (RCCs) reported in the present study
are corrected for decay and radiochemical yields (RCYs) are non-
decay corrected.
[
Entry
Radiotracer
Eluent
RCYa [%]
1
2
[
[
[
[
[
18F]1a
18F]1b
18F]1c
18F]1c
18F]1c
K2C2O4
K2C2O4
K2C2O4
Cu(OTf)2py4
K2C2O4
29 Æ 6 (n = 2)
13 Æ 5 (n = 2)
35 Æ 7 (n = 3)
16 (n = 1)
3
4b
5b,c
17 (n = 1)
Radiosynthesis of electron deficient fluoroarenes: [18F]FMTEB
[18F]1a, [18F]FPEB [18F]1b and [18F]flumazenil [18F]1c. 3-[18F]Fluoro-
5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]benzonitrile ([18F]FMTEB) and
3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl]benzo-nitrile ([18F]FPEB) are
radioligands developed for PET imaging of metabotropic glutamate
receptor subtype 5 (mGlu5) in the central nervous system.11,12
Reaction conditions: 0.03 mmol substrate, 0.04 mmol Cu(OTf)2py4, air,
DMA 400 mL, 120 1C, 20 min. a RCY of isolated product. b DMF : pyridine 9 : 1
was used as reaction solvent. c Cu(OTf )2 was used instead of Cu(OTf )2py4.
BPin = boronic pinacol ester.
[18F]Flumazenil is a suitable radioligand for PET assessment of used in combination with pyridine is employed as an alternative
central benzodiazepine receptors (BZR).13 Applying the reaction to the preformed complex Cu(OTf)2py4 (Table 1, entry 5).
conditions outlined in our original report for small scale reaction,
[18F]FMTEB was obtained from the corresponding arylboronic ester
Radiosynthesis of electron rich fluoroarenes: [18F]DAA1106
[
18F]1d, [18F]MFBG [18F]1e, [18F]FDOPA [18F]1f, [18F]FMT [18F]1g
2a in 3% Æ 1% RCC (n = 4). This reaction employed 20 MBq of and [18F]FDA [18F]1h. Initial studies employing 20 to 30 MBq of
[18F]KF/K222, 0.06 mmol of 2a and 0.0053 mmol of Cu(OTf)2py4 in starting [18F]fluoride and the model electron rich arylboronic ester,
DMF (300 mL) at 110 1C for 20 minutes. This result was not 2-(3,4-dimethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,
unexpected as arenes with electron withdrawing substituents were indicated that the reaction solvent DMA was superior to DMF,
among the most challenging precursors for 18F-labeling using this and that the higher copper loading, found beneficial for the
methodology. Reevaluation of the reaction stoichiometry and 18F-labeling of electron deficient arene, was detrimental for
the reaction solvent led to significant improvements. Reversing reaction efficacy. Experiments with 2.4 to 7.4 GBq of starting
the substrate : Cu ratio from 10 : 1 to 1 : 1.5, and replacing DMF [18F]fluoride were conducted on precursors 2d–h in either DMF
(N,N-dimethylformamide) with DMA (N,N-dimethylacetamide) and DMA (Scheme 2). Full batch isolation experiments using a
gave [18F]FMTEB in 71% RCC (n = 5). Under similar conditions 1 : 1 molar ratio of 2d : Cu in DMF afforded [18F]DAA1186 [18F]1d,
(ratio 2b : Cu = 1 : 1.3, ratio 2c : Cu = 1 : 1.3), [18F]FPEB [18F]1b a radioligand for the translocator protein 18 kDA (TSPO), in
and [18F]flumazenil [18F]1c were obtained in 66% (n = 2) and 16 Æ 2% RCY; significant improvement with a RCY of 39% was
75% (n = 2) RCC, respectively. These encouraging results observed in DMA.15 The radiotracer [18F]MFBG [18F]1e was obtained
prompted further studies investigating how an increase of in a one pot two steps sequence from the tetraboc-protected aryl
starting activity of non-carrier added (nca) 18F-fluoride influ- boronate 2e in 7 Æ 3% RCY using the same 2e :Cu molar ratio of
ences efficacy. The Oxford-based radiochemistry laboratory 1 : 1. For this radiosynthesis, the 18F-fluorination step was followed
handles a maximum of 10 GBq of starting nca [18F]fluoride, by deprotection with 57% HI at 120 1C for 10 min. Similarly to
so the ‘‘scale-up’’ experiments were performed with 2.4–10 GBq [18F]DAA1186, DMA proved to be a superior solvent allowing for
of 18F-fluoride. When using a full batch of [18F]fluoride on a [18F]1e to be isolated in 25 Æ 2% RCY. [18F]MFBG is a promising
single reaction, rather than subdividing into multiple aliquots, agent for imaging NET-expressing neuroblastomas.16 When the
the amount of K2CO3 employed to elute the [18F]fluoride from reaction was performed in DMF, 6-[18F]fluoro-L-dopa ([18F]FDOPA)
the QMA cartridge became problematic for 18F-labeling. A study
[
18F]1f, 6-[18F]fluoro-L-m-tyrosine ([18F]FMT) [18F]1g and 6-[18F]-
investigating how the nature of the inorganic base affects fluorodopamine ([18F]FDA) [18F]1h were isolated in 22%, 15%
efficacy and facilitates elution of trapped 18F-fluoride from the and 20% RCYs, respectively applying a one-pot 18F-fluorination-
QMA cartridge identified K2C2O4 with minimal amounts of K2CO3 deprotection sequence similar to the one applied for [18F]1e.
as the most suitable conditions.14 With this modified protocol, The use of DMA as an alternative solvent was beneficial only for the
[18F]FMTEB [18F]1a, [18F]FPEB [18F]1b and [18F]flumazenil [18F]1c synthesis of [18F]1h. Radiotracers [18F]1d–h are used in the clinic for
were obtained in 29%, 13% and 35% RCY, respectively (Table 1, various applications. [18F]FDOPA is used for human brain studies
entries 1–3). When eluting with Cu(OTf)2py4 instead of K2C2O4, a of the dopaminergic system, the evaluation of neuropsychiatric
solution of 10% pyridine in DMF was used as the reaction solvent; disorders, in studies of cognitive behaviour, and in oncology for the
this protocol gave 16% RCY of [18F]flumazenil [18F]1c (Table 1, investigation of neuroendocrine tumors.17 The detection of tumors
entry 4). Finally, [18F]1c is obtained in 17% RCY when Cu(OTf)2 such as pheochromocytomas and para-gangliomas has also been
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Table 2 Radiosynthesis of [18F]FPEB [18F]1b, [18F]flumazenil [18F]1c, [18F]FDOPA
[
18F]1f and [18F]FMT [18F]1g on the SYNTHRA and NEPTIS platforms
Synthra RCY [%] NEPTIS RCY [%]
(n = 1) (n = 10)
Entry Radiotracer
1
2
3
4
[
[
[
[
18F]flumazenil [18F]1c 19a
16 Æ 4c
18F]FPEB [18F]1b
18F]FDOPA [18F]1f
18F]FMT [18F]1g
5a
—
9b
—
—
10b
Reaction conditions. a Radiosynthesis performed on the Synthra platform;
0.03 mmol substrate, 0.04 mmol Cu(OTf )2py4, air, DMA 400 mL, 120 1C,
20 min. b Radiosynthesis performed on the Synthra platform; 0.02 mmol
substrate, 0.02 mmol Cu(OTf )2py4, air, DMF 400 mL, 120 1C, 20 min. c Radio-
synthesis performed on Neptis perform synthesizer; 0.036 mmol substrate,
0.044 mmol Cu(OTf )2py4, air, DMA 1 mL, 130 1C, 10 min.
After HPLC purification, [18F]1c was isolated in 16% Æ 4%
(n = 10) RCY (Table 2, entry 1). Three additional radiotracers
were synthesized on the Synthra platform. Using DMA as the
reaction solvent, [18F]FPEB was obtained in 5% RCY with a SA
of 120.8 GBq mmolÀ1 (Table 2, entry 2). The radiosyntheses of
[18F]FDOPA and [18F]FMT performed in DMF gave ndc RCYs of 9%
and 10%, respectively (Table 2, entries 3–4). Both radiotracers were
produced as a single enantiomer (ee 4 95%) with 499% RCP.
In summary, we have prepared eight clinically relevant
radiotracers by applying our recently disclosed Cu-mediated
non-carrier added nucleophilic 18F-fluorination of arylboronic
ester precursors. These precursors are easy to prepare and can
be stored at room temperature under air. The reaction is
reliable and reproducible, and employs commercially available
Cu(OTf)2py4. The demonstration that eight radiotracers can be
produced using a single reaction, some in different laboratories
using different synthetic platforms, suggests that this radiochemistry
could be broadly used in PET radiochemistry facilities. Current
work focused on full automation for the production of radio-
pharmaceuticals that are most needed in the clinic.
Scheme 2 Radiosynthesis of [18F]DAA1186 [18F]1d, [18F]MFBG [18F]1e,
[
18F]FDOPA [18F]1f, [18F]FMT [18F]1g and [18F]FDA [18F]1h starting with
2.4–7.4 GBq of 18F-fluoride. Conditions A: 4–7.4 GBq of [18F]KF/K222, 2d
(0.02 mmol), Cu(OTf)2py4 (0.02 mmol), air, DMF or DMA (400 mL), 120 1C,
20 min; conditions B: 4.9–6.3 GBq of [18F]KF/K222, 2e (0.02 mmol),
Cu(OTf)2py4 (0.02 mmol), air, DMF or DMA (400 mL), 120 1C, 20 min, then
57% HI (300 mL), 120 1C, 10 min; conditions C: 2.4–6.9 GBq of [18F]KF/K222
,
2f–h (0.02 mmol), Cu(OTf)2py4 (0.02 mmol), air, DMF or DMA (400 mL),
120 1C, 20 min, then 57% HI (400 mL), 150 1C, 10 min.
The financial support from UCB (S. P., S. G., M. S., N. T.), the
possible with 6-[18F]FDA.18 6-[18F]FMT is reported to have improved Swiss National Science Foundation (S. G.), the CRUK (M. T., S. V.),
imaging properties compared with the current clinical ‘gold the BBSRC (N. T., M. T.), the MRC (S. C.), Advion (S. C.) and the
standard’ 6-[18F]FDOPA, but its use has been limited possibly EPSRC (S. P., M. T.) is gratefully acknowledged. T. C thanks the
due to the lack of a suitable manufacturing process.19
University of Caen for a one-year visiting stint at the University of
Today, the widespread application of [18F]1a–h in the clinic Oxford. V. G. thanks the Royal Society for a Wolfson Merit Award
is hampered by the paucity of effective production routes from (2013–2018). We thank Dr David R. Turton (Institute of Cancer
[18F]fluoride, a challenge that could be addressed if the methods Research, Royal Cancer Hospital) and Dr Enrico Emer (Chemistry
described herein are amenable to automation on additional Research Laboratory, University of Oxford) for helpful discussions.
synthetic platforms. With these considerations in mind, we
turned our attention to the Synthra and Neptis systems. The
Notes and references
radiosynthesis of [18F]flumazenil [18F]1c was performed on a
Synthra platform starting with 26 GBq of nca 18F-fluoride.
Applying the K2C2O4 elution protocol with DMA as the reaction
solvent, allowed isolation of 5.1 GBq of [18F]1c (19% RCY), in
499% radiochemical purity (RCP) was 499%, and with a
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Flumazenil [18F]1c was also prepared on the Neptis perform
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15 mg of flumazenil precursor 2c and 30 mg of Cu(OTf)2py4
(molar ratio = 1 : 1.2) in DMA with 300 MBq of starting [18F]fluoride.
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