Cu-Mediated Radiofluorination of Aryl Pinacolboronate Esters: Alcohols as Solvents with Application to 6-L-[18F]FDOPA Synthesis

Article abstract of DOI:10.1002/ejoc.202001198

Cu-mediated radiofluorination of arylboronic acid pinacol esters (ArylBPin) using Cu(OTf)₂(Py)₄ complex is a useful approach for the introduction of [¹⁸F]fluorine into non-activated arenes and heteroarenes. Owing to the co

Full text of DOI:10.1002/ejoc.202001198

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Cu-mediated radiofluorination of aryl pinacolboronate esters:
alcohols as solvents with application to 6-L-[18F]FDOPA
synthesis
Authors: Viktoriya Orlovskaya, Olga Fedorova, Olga Kuznetsova, and
Raisa Krasikova
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001198
Link to VoR: https://doi.org/10.1002/ejoc.202001198
01/2020

10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
Cu-mediated radiofluorination of aryl pinacolboronate esters:
alcohols as solvents with application to 6-L-[18F]FDOPA
synthesis.
Viktoriya Orlovskaya, Dr. Olga Fedorova, Olga Kuznetsova and Dr. Raisa Krasikova*
N.P. Bechtereva Institute of the Human Brain, Russian Academy of Sciences
197376, 9, Pavlova street, Saint-Petersburg, Russia
E-mail: raisa@ihb.spb.ru
Supporting information for this article is given via a link at the end of the document.
Abstract: Cu-mediated radiofluorination of arylboronic acid pinacol
esters (ArylBPin) using Cu(OTf)2(Py)4 complex is a useful approach
for the introduction [18F]fluorine into non-activated arenes and
heteroarenes. Due to complexity of the mechanism and wide variation
in substrate reactivity the choice of reaction conditions must be made
individually for every precursor. Careful selection of phase-transfer
catalysts also plays a role, as Cu-catalyst and ArylBPin precursors are
known to be unstable in basic conditions. Using tetrabuthylammonium
triflate alcohol solution for elution of [18F]fluoride from ion-exchange
cartridge and employing same alcohol as a co-solvent in the following
labelling step, we have developed a general protocol resulting in
>80% fluorination efficiency of ArylBPin precursors for 4-[18F]fluoro-
D,L-phenylalanine and 6-L-[18F]FDOPA. Radiofuorination in neat
alcohol was particularly effective for the synthesis of 6-L-[18F]FDOPA,
allowing for substantial increase of yield and decrease of synthesis
time compared to current methods (activity yield 14.5 ± 0.5%, 70 min
synthesis time).
appropriate leaving group. In the past few years several
innovative 18F-labeling approaches have been introduced,
allowing for “late-stage radiofluorination” of non-activated
(electron-rich) aromatic structures using, for example, iodonium
salts, spirocyclic hypervalent iodine (III) complexes,
organoborons, and stannanes. [2] Among methods reported, Cu-
catalyzed radiofluorination of pinacol esters of arylboronic acids
[3a]
(ArylBPin) (Figure 1) introduced by the Gouverneur’s group
following chemistry developed by Sanford’s group [3b] is one of the
more promising synthetic avenues for the preparation of a range
of radiotracers that cannot be readily accessed through
conventional approaches. Based on copper-promoted Chan-Lam
[4]
type C-F cross-coupling reaction adapted to radiofluorinations
in the presence of commercially available Cu(OTf)2(Py)4, this
approach was found to be effective for introducing fluorine-18 into
[1a, 1d]
electron-rich , -neutral and -poor arenes.
In the follow-up
[5a]
studies Cu-mediated radiofluorination of organoborons
and
[5b]
(hetero)aryl organostannanes
was developed, employing
catalyst generated in-situ from copper triflate and pyridine [5a,b] or
[5c,d]
pre-formed Cu(OTf)2(Py)4 complex
. However, copper-
Introduction
promoted radiofluorination of ArylBPin precursors is, to date, the
most versatile method [2d] applied to the preparation of various 18F-
fluorinated amino acids [6] as well as a number of other clinically
significant tracers. [7] The value of the method was confirmed by
the application for radiolabeling of a large variety of drug-like
molecules [8] for preclinical and biomedical research.
Positron emission tomography (PET) serves as a highly sensitive
routine diagnostic tool for the diagnosis of cancer, cardiovascular
and neurological disorders. It has also become an important tool
in drug discovery and development. Fluorine-18 is currently the
predominant PET radionuclide due to its useful nuclear imaging
properties and broad availability in multi-GBq quantities from
commercial cyclotrons. The relatively long half-life and well-
developed chemistry enable access to a great variety of 18F-
labelled radiopharmaceuticals. Significant number of them
(fluorinated amino acids, drug-like molecules etc.) contain Ar-F
group with a metabolically stable C-F bond. While methods for the
introduction of fluorine-18 into aromatic functionality via
electrophilic radiofluorination using [18F]F2 are well-established,
they suffer from several limitations such as difficulties in handling
radionuclide in a gaseous form and unavoidable introduction of
unlabeled carrier lowering the molar activity (Am). Due to this,
labelling starting from fluoride-18 in aqueous solution offers
multiple benefits, including easier handling and greater availability
of no-carrier-added nucleophilic [18F]fluoride from water targets,
while also affording significantly higher Am compared to
electrophilic methods. [1]
Nevertheless, despite of the success of Cu-mediated
radiofluorination in a small-scale synthesis using small aliquots of
aqueous [18F]F-, attempts to implement this method into full-batch
clinical production usually reveals several problems, including
modest or fluctuating radiochemical yields, long synthesis times
and problematic protocols that not always prove to be adaptable
to automation. Also, amounts of ArylBPin precursors employed
can pose a number of practical challenges at purification step(s).
One of the problems associated with low radiochemical yield
(RCY) at the radiofluorination step has been the sensitivity of Cu-
mediated process to basic conditions [9] that are realized when
using classical [18F]KF/K222 approach with K2CO3 as base [3a]. The
improvement in radiofluorination efficiency was achieved using
less basic K2C2O4/K2CO3 combination [7] or substantially reducing
[9]
both base and kryptofix amounts
(“low-base protocol”). Also,
use of less basic phase transfer catalysts (PTC)
-
[5c]
tetraethylammonium hydrocarbonate (Et4NHCO3),
tetrabutyl
Nucleophilic SN2 radiofluorination has been applied for
decades in the synthesis of a number of PET radiotracers. As for
nucleophilic aromatic substitution (SNAr), it was generally limited
to introducing 18F into aromatic structures containing electron-
withdrawing groups in the para- or ortho-positions to the
ammonium triflate (Bu4NOTf) [6d,e] and pyridinium sulphonates [10]
was found to be effective for this radiolabeling approach. In
addition to improving radiofluorination efficiency, using organic
[5c, 6d, 10b, 10c]
solutions of PTCs
to elute [18F]F- from the anion-
1
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10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
exchange cartridge allowed to simplify automation and shorten
synthesis time by omitting time-consuming azeotropic drying step.
[1]
reports on Cu-catalyzed radiofluorination of ArylBPin substrates
in neat alcohols have been published to date. Based on these
findings, the synthesis of 6-L-[18F]FDOPA, a widely-used PET
radiotracer for diagnosis of Parkinson disease, neuroendocrine
tumors and gliomas, was fully automated on a modified TracerLab
FX C-Pro platform implementing our new approach. The product
was obtained in the activity yield (isolated, not decay-corrected)
of 14.5±0.5% (n=3) with 70 min average synthesis time. The
substrate selectivity in the Cu-mediated radiofluorination in neat
2-PrOH could be due to many factors related to the specific
features of the radiolabeling substrate: coordination of
heteroatoms in the molecule with copper complex, specific
solubility and solvation in 2-PrOH and so on, however, lack of
specific mechanistic evidence leaves this open to speculation and
further studies would be required to fully elucidate the mechanism
of this reaction.
Results and Discussion
Nucleophilic 18F-fluorination reactions traditionally include
the steps of [18F]fluoride adsorbtion/elution on the anion-
exchange cartridge followed by an azeotropic drying with
acetonitrile. However, the time-consuming azeotropic drying step
is associated with radioactivity losses due to decay, absorption on
the walls of the reactor and often difficulties in automation. As of
late, several adsorbtion/elution protocols have been proposed to
shorten 18F-recovery step and, which is more important, to provide
less basic and milder 18F-fluorination conditions. For kryptofix-
mediated radiofluorinations using К222/K2CO3 the standard
amount of base required for efficient elution of [18F]F- retained on
the anion-exchange cartridge is too high (2.0-3.5 mg; 14-25 μmol)
for base sensitive reactions such as Cu-mediated
radiofluorination of ArylBPin precursors to proceed efficiently. To
address this problem a reversed loading/elution procedure (the
Figure 1. Cu-mediated 18F-fluorination of ArylBPin precursors.
As copper-mediated radiofluorination approach has been
taken up for the labeling of ArylBPin precursors, [2a,d] a number of
other factors, in addition to the base sensitivity of the Cu-complex
and ArylBPin substrates, have been shown to have an impact on
the outcome of this complex catalytic process.
solvents, in particular, have a profound effect, [5c, 6a, 8e, 8f] as well as
[11]
Reaction
the amount of labelling precursor used and the stoichiometry of
[5c, 10,12a]
the precursor to the copper complex.
Radiolabeling is
commonly carried out in DMF or DMA, however, following several
studies that have revealed the enhancing effects of alcohols as
co-solvents with DMA [5c] successful radiofluorinations of various
ArylBPin substrates were performed using DMA/1-BuOH system
with Et4NHCO3 as the PTC. [6c,6g, 8d,12b]
[9]
so-called “back-flushing protocol”) has been suggested
allowing for a substantial reduction in the amounts of К222/K2CO3
or other PTCs, such as Et4NHCO3, used. The work-up procedure
includes loading of an aqueous [18F]fluoride onto an anion-
exchange cartridge from the male side, flushing with MeOH from
the same side, followed by elution of [18F]F- from the female side
using solution of the PTC in an appropriate solvent. A further
refinement to the Cu-mediated radiofluorination procedure was
introduced later [5c], eliminating azeotropic drying and evaporation
steps which is advantageous for automation. As has been
described, the [18F]F– is eluted directly with an alcohol (usually 1-
BuOH) solution of a suitable salt, like Et4NHCO3, into a DMA or
DMF solution of an appropriate precursor and Cu(OTf)2Py4 for the
fluorination reaction. The presence of alcohol as co-solvent in Cu-
mediated process has a beneficial effect on the radiofluorination
It should be emphasized that numerous attempts to
optimize Cu-catalyzed reaction have been undertaken using
simple model compounds; yet the results obtained often cannot
be directly translated to 18F-labeling of complex molecules. A
recent review on the radiofluorination screening of a large series
[13]
of heteroaryl boronic acid esters
has shed considerable light
on the importance the structure of the labeling substrate plays, in
particular, the presence of specific functional groups and
substituents that can influence or even prevent 18F-fluorination in
certain circumstances. In this study we put forward two effective
protocols for catalytic radiofluorination of arylBPin substrates
using Bu4NOTf as a neutral PTC and 2-PrOH both as an elution
solvent for 18F-fluoride and also the labelling reaction solvent/co-
solvent. The methods proposed remove the need for conventional
azeotropic drying steps or any process of solvent removal
preceding the fluorination reaction. When carrying out the
reaction in DMA/2-PrOH, high radiochemical conversions rates
(>80%) were obtained for model arylpinacol boronates and
ArylBPin precursors for 4-[18F]fluoro-D,L-phenylalanine and 6-L-
[18F]FDOPA, demonstrating versatility and efficiency of this
procedure. In addition, radiofluorination in neat 2-PrOH was
observed as well, but in a substrate-specific manner, being
efficient only for the preparation of 6-L-[18F]FDOPA, but not for
other substrates under study. To the best of our knowledge, no
efficiency [5c] leading to substantial increases in the radiochemical
[6c,6g; 8d,12b]
yield (RCY) for various ArylBPin substrates.
The main
drawback of this approach is the need for high amount of the
reactants (up to 60 µmol of precursor and 30 µmol of Cu-catalyst).
Therefore, in the follow-up studies possibility of reduction in the
amount of Et4NHCO3 was investigated using less viscous and
more polar MeOH as eluting solvent; correspondingly the
quantities of precursor/copper catalyst could be reduced to 10-15
[6c,6g]
and 5-10 µmol, respectively.
However, the solvent
evaporation step preceding 18F-fluorination is still required in this
iteration of the method, making this modification of the alcohol-
2
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10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
enhanced radiofluorination less attractive for automation and
implementation into routine production.
under air. In regards to radiofluorination efficiency, the highest
RCY (96%) in radiofluorination of 1 (Figure 2) was obtained using
Sep-Pak QMA light (130 mg) cartridge (Table 1, entry 1).
Therefore, this type of the cartridge, incidentally the most
commonly used in automated synthesizers, was selected for all
the further experiments in semi-automated and automated
applications.
Based on those findings and our recent experience in the
use of alkylammoinum sulphonates as effective catalysts of the
[14]
aliphatic radiofluorination
we have proposed to replace basic
Et4NHCO3 with a neutral Bu4NOTf in conjunction with 2-PrOH as
the eluting solvent. Preliminary studies have revealed that
Bu4NOTf/2-PrOH is an effective catalyst for the preparation of 6-
[18F]fluoro-L-m-tyrosine via Cu-mediated radiofluorination of
BPin-substituted Ni-BPB-AA complex. [6d] Also, this PTC has been
recently applied for elution of [18F]F- as an aqueous
Bu4NOTf/Cs2CO3 solution to obtain the reactive [18F]fluoride after
removal of water via several cycles of azeotropic drying with
acetonitrile. [6e] In contrast, our protocol based on organic solution
of Bu4NOTf allows not only to avoid the time-consuming
azeotropic
drying step but
bypasses
any solvent
removal/replacement process altogether. The reactive
[18F]fluoride thus obtained can be used “as is” for the
radiofluorination reaction where 2-PrOH serves as co-solvent,
enhancing fluorination efficiency.
As a starting point of method development, the elution
efficiency (EE) of Bu4NOTf solution in 2-PrOH was evaluated for
a series of commercially available cartridges (Table 1).
Table 1. Dependency of 18F-fluoride elution efficiency (EE) and RCY of the
radiofluorination of
1 on the type of anion exchange cartridge. All the
experiments except 3 were performed in triplicate.
Entery
1
Cartridge
Сounterion
EE (%)
80
RCY (%)
96±2
Sep-Pak QMA
light (130 mg)
Сl-
Figure 2.
precursors via Cu-mediated radiofluorination in DMA/2-PrOH using Bu4NOTf as
neutral PTC; here and elsewhere RCY radiochemical yield of the
radiofluorination step as calculated from radioTLC data.
[
18F]fluoroarenes prepared from the corresponding arylBPin
a
-
-
2
3
4
PS-HCO3 (46
mg)
HCO3
53
33
88
91±3
84
Compared
with
the
original
“alcohol-enhanced”
Oasis WAX 3cc
(30 mg)
-
radiofluorination protocol using Bu4NOTf as a neutral PTC, high
18F-fluorination efficiency was achieved while substantially
reducing ArylBPin precursor and Cu-catalyst amounts [5c] (15/7.5
μmol vs 60/30 μmol respectively). Further reduction in reactant
amounts to 5/3 μmol has resulted in a dramatic decrease in yield
(Table 2, entry 1). Attempts to replace DMA with acetonitrile as a
more convenient reaction solvent failed in achieving reasonable
radiofluorination efficacy (Table 2, entry 3). Poor fluorination rate
was accompanied by losses of radioactivity on the inner surfaces
of the reaction vessel (up to 30-50% of total radioactivity). Overall,
the 15/7.5 µmol ratio of precursor to catalyst was found to be
optimal for fluorinations in DMA/2-PrOH. It also afforded high RCY
in the preparation of simple [18F]fluoroarenes [18F]1a-5a as well
as protected 4-[18F]-D,L-fluorophenylalanine ([18F]7a) (Figure 2).
However for poorly fluorinated substrate [18F]6a (RCY of
radiofluorination of 8±2 % reported by Gouverneur’ group [13]) our
protocol was also not efficient providing RCY of 12±1 %.
2-
Sep-Pak QMA
light carb (46
mg)
CO3
76±1
5
Vac QMA 1cc
(100 mg)
Cl-
95
96±2
Prior to use, all the cartridges, except Oasis WAX 3cc, were
rinsed with NaHCO3 (0.05 M) solution followed by water. As
shown in Table 1, the type of anion exchange cartridge
substantially influenced the efficacy of 18F-elution and especially
the subsequent radiolabeling step. The highest recovery rate (EE
95%) was obtained with Sep-Pak Vac QMA 1cc (100 mg) followed
by Sep-Pak QMA light carb (46 mg) and Sep-Pak QMA light (130
mg) cartridges (88 and 80%, respectively). As a side-note, when
using barrel-type Vac QMA cartridge in the automated synthesis
module the problem was encountered with complete removal of
the residual water drops from the inner surface of the cartridge.
The “back-flushing” protocol [5c] was used for loading/elution of the
[18F]F- using 5 mg (12.7 µmol) of Bu4NOTf in 0.6-0.8 ml of 2-PrOH.
The [18F]Bu4NOF thus obtained was reacted with a model
Table 2. Optimization of the Cu-mediated radiofluorination of 1 with Bu4NOTf;
reaction conditions from Figure 2.
Entry
1,
μmol
Cu(OTf)2(Рy)4,
Radiofluorination
Solvent
RCY, %
µmol
substrate
-
2-(3,4-dimethoxyloxyphenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (1, 15 μmol) - bearing BPin leaving group in
a non-activated position (Figure 2) together with 7.5 μmol
Cu(OTf)2(Py)4 dissolved in 0.3 ml of DMA at 110 C for 20 min
1
2
5
5
3
DMA/2-propanol
DMA/2-propanol
59±8
o
7.5
96±2 (n≥10)
3
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10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
solvent (Table 3). The suggested use of the neutral Bu4NOTf as
phase-transfer catalyst and 2-PrOH as reaction co-solvent (Table
3, entry 4) appears to be optimal, affording high efficacy of the
fluorination of 1 while using substantially lower amounts of
precursor and catalyst. The ease of generating reactive 18F-
species makes this protocol attractive for the implementation into
automated production routine.
3
15
7.5
AcN/2-propanol
18±1
As mentioned above, the outcome of radiofluorination of
ArylBpin precursors depends upon several key parameters like
PTC/base combination, main reactant amounts and reaction
Table 3. The results of Cu-mediated radiofluorination of 1 using different PTC and reactants amounts (110 0C, 20 min, under air).
Entry
1,
μmol
Cu-catalyst,
Eluent
ЕЕ, %
Reaction
solvent
RCY, %
Refs
μmol
PTC, μmol
Solvent
1
2
3
4
60
20
60
15
5.3
40
К222/ К2СО3
AcN /
H2O
≥ 95
95
DMF
DMA
54
68
83
[3a]
[7]
К222/К2С2О4/ К2СО3
AcN /
H2O
26.5
7.5
Et4NHCO3
14.1
1-ВuОН
80-95
80-94
1-ВuОН
/DMA
[5c]
Bu4NOTf
12.7
2-PrOH
2-PrOH
/DMA
96±2
(n≥1)
This
work
1 and 2 - “aliquot labelling”; 3 and 4: no azeotropic drying, no solvent evaporation
Our next step was implementing our new methodology into the
Figure 3. Radiosynthesis of 6-L-[18F]FDOPA via сopper-mediated
radiofluorination of 3,4-OMOM-6-(BPin)DOPA(Boc)2-OtBu (8) using Bu4NOTf
as the PTC.
automated
synthesis
of
6-L-[18F]fluoro-3,4-
dihydroxyphenylalanine (6-L-[18F]FDOPA), a common radiotracer
used for evaluating progression of Parkinson’s disease, as well
[15]
as detection of gliomas and neuroendocrine tumors.
The
While the optimal conditions are chosen based on the
consideration of results from semi-automated syntheses, it is
often impossible to apply those methods directly to fully-
automated productions. In regards to the prospects for
automation the limitation of our protocol has been the high boiling
radiosynthesis of 6-L-[18F]FDOPA using nucleophilic [18F]F-
process has been
radiochemists.
a
long-standing challenge for PET
The applicability of Cu-mediated
[16]
radiofluorination of ArylBPin precursors for 6-L-[18F]FDOPA with
different protecting groups on the catechol and amino acid
moieties was previously evaluated by several groups in manual
(“aliquot labeling”), semi-automated and fully automated
point of DMA
- complete removal of the solvent after
radiofluorination was found to be a critical point for ensuring high
efficiency of the deprotection step following the radiolabelling
(Figure 3). An attempt to replace DMA with acetonitrile led to a
substantial reduction in radiolabelling efficiency (Table 4, entry 2)
even when using 15/7 μmol ratio of precursor to catalyst. Varying
the amounts of the reactants (Table 4, entries 4-6) we were able
to slightly increase the RCY, however the values were far below
those obtained with DMA/2-PrOH mixture.
Somewhat unexpectedly, the radiofluorination of 8 in neat
2-PrOH proceeded well, resulting in high RCY (Table 4, entries 7
and 8). Using same solvent in fluorination reaction as in the 18F-
fluoride elution step provides additional benefits cutting the need
for any solvent removal steps. The fluorination in 2-PrOH
proceeded well only when stoichiometry of reactants was
reversed (16 - 20 μmol of Cu(OTf)2(Py4) to 10 μmol of 8 (Table 4,
entries 7 and 8). To the best of our knowledge, no reports
supporting the use of neat alcohols as the reaction solvents in
copper-mediated radiofluorinations ArylBPin precursors have
been published previously. In contrast, the replacement of
DMA/1-butanol mixture with neat 1-butanol has resulted in a
[3a, 5c, 6e, 7a]
procedures, resulting low-to-moderate activity yields.
For our work we have chosen 3,4-OMOM-6-(BPin)DOPA(Boc)2-
OtBu (8, Figure 3) for the precursor as it was commercially
available and MOM- and Boc-protecting groups can be removed
easily in acidic conditions. Considering high cost of the precursor
and limits on copper for iv administration in pharmaceuticals the
amounts of 8 and Cu-catalyst were reduced to 8 и 5 µmol,
respectively; even with those amounts the radiofluorination in
DMA/2-propanol proceeded without any drop in the 18F-
fluorination efficiency (Table 4, entry 1).
4
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10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
dramatic decrease of efficiency in the radiofluorination of
phenylboronic acid pinacol ester from 99 to 8%. [5c]
coordination of heteroatoms in the molecule with copper complex,
specific solubility and solvation in 2-PrOH, for the proof of which
more extensive studies are required.
Table 4. Optimization of Cu-mediated radiofluorination of 8 under various
protocols (semi-automated module, under air).
With optimized conditions for the fluorination of 8 developed,
we have applied them to the automated synthesis of 6-L-
[18F]FDOPA using TRACERlab FX C Pro (GE Healthcare)
synthesis module. This two-reactor automated module was
originally designed for the preparation of 11C-labelled compounds
and was later adapted to 18F-fluorination use as well. Despite
efficient radiofluorination of 8 in 2-PrOH, the poor solubility of
Cu(OTf)2(Py)4 in this solvent at room temperature was associated
with difficulties in the automated mode. The catalyst had to be
placed directly into the reaction vessel necessitating its
disconnection from the holder before performing each run, if neat
2-propanol was used as reaction solvent. Given greater solubility
of Cu-catalyst in acetone (which was a good solvent for 8 as well)
the reagents were dissolved in acetone, which was then used as
co-solvent together with 2-PrOH in radiofluorination. Introduction
of acetone into the reaction had not had any negative impacts on
the RCYs (Table 3, entries 9, 10) resulting in values similar to
those obtained with neat alcohol. Additionally, acetone was used
for flushing QMA cartridge to remove any residual water before
elution of the [18F]fluoride. An additional benefits of our novel
protocol was that there was no need to provide the access to the
Entry
8,
μmol
Cu(OTf)2(Рy)4,
Radiofluorination
Solvent
RCY
18F]8a, %
µmol
[
radioTLC
1
2
8
5
7
DMA/2-propanol
84±4 (n=3)
30
15
AcN /
2-propanol
3
4
5
6
15
10
10
10
30
10
20
50
AcN /
2-propanol
49±1 (n=2)
AcN /
2-propanol
37
64
65
AcN /
2-propanol
AcN /
2-propanol
7
8
9
10
10
10
16
20
16
2-propanol
2-propanol
79±2 (n=2)
87±2 (n=3)
82±5 (n=3)
atmospheric oxygen usually required for Cham-Lam coupling-like
[3a]
oxidation cycle.
This is an important issue as the standard
acetone/
automated modules for PET radiochemistry are flushed and
operated with the inert gas and the introduction of the atmospheric
oxygen can be difficult.
2-propanol
10
10
20
acetone/
85±3 (n=2)
2-propanol
Briefly, the automated synthesis of 6-L-[18F]FDOPA started
from the preparation of reactive [18F]fluoride using Bu4NOTf (12.5
µmol in 0.9 ml of 2-PrOH) using back-flushing protocol approach.
Executing this step in the automated mode improved 18F-recovery
rate from 80% obtained in semi-automated regime (Table 1, Entry
1) to 91-96%. Reactive [18F]F- was collected into the round-bottom
reaction vessel (2 ml volume) pre-filled with solution of 10 µmol of
8 and 16 µmol of Cu(OTf)2(Py)4 in 0.3 ml of acetone and the
reaction mixture was heated to 90°C for 20 min under N2 while
stirred. At the deprotection step, in the original approach the
removal of the catechol protective groups has been always
associated with difficulties - the common methodology for removal
In addition to 2-PrOH, we have screened a series of
alcohols by using the alcohol as the elution solvent for [18F]F- and
allowing reactive species thus generated to react with 10 µmol of
8 and 16 µmol of Cu(OTf)2(Py)4 in 0.3 ml of the alcohol (100 - 105
o C, 20 min) using a semi-automated module. As expected, 18F-
recovery was highest for methanol (96%) while poor
radiofluorination efficiency (< 30%) was associated with its use as
reaction solvent. Ethanol was moderately effective in terms of
both elution (75%) and fluorination yield (60%). 1-propanol and 2-
propanol produced similar results within margin of error in terms
of elution efficiency (c.a. 80-90%) and labelling yield (c.a. 85%).
Encouraging results obtained for fluorination of 8 in neat 2-
PrOH prompted further studies investigating the applicability of
this “pure alcohol radiofluorination” for a series of other substrates.
However, use of neat 2-PrOH as a radiofluorination reaction
solvent was found to be beneficial only for the synthesis of [18F]8a.
Under similar conditions [18F]1a, [18F]2a, [18F]3a, [18F]4a, [18F]5a,
[18F]6a and [18F]7a, were obtained in 8±1, 12±2, 41±1, 10±1,
34±2, 7±2 and 31±13% RCY, respectively (n=3). This result was
not entirely unexpected considering the recent study
demonstrating dependence of the Cu-catalyzed process outcome
on the structure of substrate molecule, with presence of functional
groups often impairing labelling efficiency. [13] In our limited series
of substrates the key structural difference between 8 and the
simple model substrates 1 - 6 is the presence of the amino acid
moiety. Precursor 8 for 6-L-[18F]FDOPA contains catechol motif
with MOM-protection; the protection of carboxyl group in 7 and 8
are also different (OMe and OtBu). Possibly, high reactivity of 8 in
the copper-mediated radiofluorination in 2-PrOH is a result of
many factors related to the specific features of this substrate:
of 4,5-methylenedioxy or 4,5-bis-methoxy groups employs 57%
o
aq. HI and high temperatures (180-200
C), which is not
compatible with most synthesis modules. However, the precursor
8 was designed with methoxymethyl ether (MOM) and OtBu
protective groups that can be removed using aqueous HCl
solution. 6 N HCl was inefficient in removal of the protecting
groups, however, using a combination of 6 N HCl (0.4 ml), MeOH
(0.3 ml) and 0.25 M ascorbic aсid (0.2 ml in water) with heating to
110 °C for 5 min resulted in near-100% deprotection reaction
efficiency. The ascorbic acid was added as it was known to
[6e]
prevent decomposition of 6-L-[18F]FDOPA,
while methanol
increased solubility of the liphophilic intermediate [18F]8a. Notably,
for performing this step successfully removal of the fluorination
solvent was essential and easily achieved in case of acetone/2-
PrOH. 6-L-[18F]FDOPA was isolated from the reaction mixture by
semi preparative reverse phase HPLC using an aqueous 0.1%
CH3COOH (pH 4) as a mobile phase at 4 ml/min flow rate on a
Ascentis RP-AMIDE (5 µm, 250×10 mm) column. The product
fraction (Rt 12-13 min, 4-5 ml volume, Figure S6) corresponding
to pure 6-L-[18F]FDOPA was collected into a vented sterile vial
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
pre-filled with 5 ml of normal saline following on-line sterilization
through the 0.22 μm filter.
solution the radiofluorination reaction can be performed directly
with alcohol as the reaction solvent (or co-solvent with DMA),
offering significant practical benefits through elimination of the
azeotropic drying or solvent removal steps precceding
radiofluorination. Radiofluorination in DMA/2-PrOH was fully
compatible with simple model substrates and ArylBPin precursors
for two aromatic amino acids providing a broadly applicable and
efficient route for 18F-labelling of arenes and heteroarenes with
different functional groups. Radiofuorination in neat alcohol was
substrate-dependent, being particularly effective for the
preparation of 6-L-[18F]FDOPA with activity yield of 14.5 ± 0.5%
(isolated) in a fully automated mode with average synthesis time
of 70 min, which is a significant improvement over currently
employed methods in terms of increased yield and decreased
synthesis time. To the best of our knowledge no reports have
been published previously regarding Cu-mediated fluorination in
neat alcohols, and while our findings are confined to production
of a single, if a very important, radiotracer - 6-L-[18F]FDOPA, it is
also possible that this method could be applied to labeling of other
ArylBPin precursors.
The 6-L-[18F]FDOPA was obtained with the radiochemical
purity above 99%, enantiomeric purity above 95% and molar
activity of 34-61 GBq/µmol (0.9-1.7 Ci/μmol). Activity yield
(isolated radiochemical yield, not decay corrected) was
14.5±0.5 % (n=3) with synthesis time of ca. 70 min. The residual
copper content, measured by ICP/MS, amounted to 0.4±0.2 ppm
and was below any level of concern according to the ICH
[17]
Guideline of Elemental Impurities (Q3D).
The amount of
tetrabutylammonium hydroxide was negligibly small - below
analytical HPLC method limit of detection; no peak with Rt of 5.6
min was detected on the HPLC chromatogram (HPLC system 1,
Figure S8).
Despite the fact that small-scale synthesis of 6-L-
[18F]FDOPA via Cu-mediated radiofluorination of the respective
ArylBPin precursor was already considered in the first publication
[3a]
of Gouveneur’s group,
the automated production of this
radiotracer still remained a challenging task. In the follow-up study
[7]
by the same group
the procedure using Synthra automated
full-batch
synthesis platform has been developed. In
a
preparation the originally used K222/K2CO3 [3a] was replaced with a
less basic K222/K2C2O4/K2CO3 allowing for efficient recovery of
[18F]fluoride retained on the anion-exchange cartridge and better
radiofluorination yield. However, due to long synthesis time (146
min) and the presence of unlabelled impurities co-eluting with the
Experimental Section
General: Unless otherwise stated, reagents and solvents were
commercially available and used without further purification. 2-
(3,4-Dimethoxyloxyphenyl)-4,4,5,5-tetramethyl-1,3,2-
product the method required further optimization. One of the most
[7]
difficult steps in that work
was the hydrolysis/deprotection
o
dioxaborolane (1), 2-(4-biphenylyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (2), indole-4-boronic acid pinacol ester (3), 4-
methoxyphenylboronic acid pinacol ester (4), 9H-carbazole-2-
boronic acid pinacol ester (5), benzooxazole-5-boronic acid
pinacol ester (6), 4-fluorobipheny. Anhydrous ethanol was
prepared in-house using common techniques. Methyl-(S)-2-((di-
tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-phenyl)propanoate (7) and methyl-(S)-2-(2-
((di-tert-butoxycarbonyl)amino)-3-(4-fluorophenyl)propanoate
(precursor and reference for protected 4-[18F]fluoro-D,L-
phenylalanine) were provided by Dr. Chuan-Lin Chen, National
Yang-Ming University, Taiwan. The precursor for 6-L-[18F]FDOPA,
tert-butyl-(S)2-((di-tert-butoxycarbonyl)amino)-3-(2-4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl-4,5-
dimethoxymethylphenyl)propanoate (8) was obtained from WuXi
AppTec Co (China). An authentic reference standard of 6-D,L-
FDOPA was obtained from ABX GmBH (Radeberg, Germany).
Sep-Pak Accell Plus QMA Plus Light Cartridge (130 mg), Sep-
Pak Accell Plus QMA Carbonate Plus Light Cartridge (46 mg),
Sep-Pak Accell Plus QMA 1 cc Vac (100 mg), Oasis Wax 3cc
cartridge were acquired from Waters Corporation, USA.
Chromafix PS-HCO3 cartridge (45 mg) (Product No. 731876) was
purchased from ABX GmBH (Radeberg, Germany). All the
cartridges except Oasis Wax 3 cc were conditioned with 10 mL of
0.05M NaHCO3 followed by 10 mL of water. Oasis Wax 3cc
cartridge was applied as received.
reaction requiring very aggressive conditions (57% HI, 180 C)
leading to a lengthy purification process. While our work was in
progress, the Scott’s group [6e] has published a fully automated
synthesis of 6-L-[18F]FDOPA using the same commercially
available BPin precursor as employed by us. This precursor has
easy-to-cleave MOM protecting groups on the catechol moiety
and tert-butyl ester group protecting the amino acid fragment
allowing for hydrolysis/deprotection step using HCl solution. Even
so, the automated synthesis procedure reported by Scott et al. [6e]
resulted in average synthesis time of 110 min and is relatively
complex. The preparation of the reactive [18F]fluoride using QMA
eluent being an aqueous solution of Bu4NOTf and Cs2CO3
necessitated azeotropic drying step resulting in longer synthesis
time. Radiofluorination of 8 in DMF proceeded in moderate RCY
of 55%; the unavoidable transfer of this solvent to hydrolysis step
required high concentration of HCl (12 N vs 6N in our protocol) for
efficient deptotection reaction. Our efforts were focused on
shortening synthesis and simplifying automation through
implementation of non-aqueous solution of Bu4NOTf for elution of
the [18F]fluoride removing the need for additional drying steps.
The use of 2-propanol both in the elution stage and in
radiofluorination reaction allowed us to minimize the number of
the intermediate steps and substantially reduce synthesis time (to
70 min) while doubling the yield (14.5±0.5 vs 6±1% [6e]).
Conclusion
Radio-TLC analyses were carried out on silica gel plates (60 F254,
Merck or Sorbfil, Lenchrom, Russia); radioactivity distribution was
determined by radioTLC scanner miniGita (Raytest, Germany).
An aliquot of 2-3 μl of the crude reaction mixture after
radiofluorination reaction and cooling was applied to a TLC plate.
In the present work we have developed two practically applicable
synthetic protocols for Cu-mediated radiofluorination of
arylboronic acid pinacol esters (ArylBPin) employing Bu4NOTf as
a neutral phase-transfer catalyst for the preparation of reactive
[18F]fluoride species. Following elution with Bu4NOTf/2-PrOH
For
3,4-dimethoxy-[18F]fluorobenzene
([18F]1a),
4-
[18F]fluorobiphenyl ([18F]2a) and protected 4-[18F]fluoro-D,L-
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
phenylalanine ([18F]7a) the plates were eluted with CH2Cl2; the Rf
values for [18F]fluoride, [18F]1a, [18F]2a and [18F]7a were 0.05,
0.55, 0.60, 0.47, respectively. For 4-[18F]fluoroindole ([18F]3a), 4-
methoxy-[18F]fluorobenzene ([18F]4a), 2-[18F]fluoro-9H-carbazole
([18F]5a) 5-[18F]fluorobenzooxazole ([18F]6a) the plates were
eluted with ethyl acetate:hexane=1:1; the Rf values for
[18F]fluoride, [18F]3a, [18F]4a, [18F]5a and [18F]6a were 0.05, 0.60,
0.55, 0.50 and 0.56, respectively. In case of radiofluorination of
8 TLC eluent ethyl acetate was used; the Rf values for [18F]fluoride
Cu(OTf)2(Py4), 300 µL DMA. Radiofluorinations were performed
in a sealed vial at 110 0C for 20 min without stirring under
atmosphere air. Radiochemical yield (RCY) of the
radiofluorination step was calculated based on the radioTLC
analysis of reaction mixture.
Preparation of reactive [18F]fluoride for semi-automated
synthesis of [18F]1a - [18F]7a: [18F]Fluoride was produced via
the 18O(p,n)18F nuclear reaction by irradiating [18O]H2O in a silver
target (1.4 mL volume) using 16.4 MeV proton beam on PETtrace
4 cyclotron (GE Healthcare, Sweden). The radionuclide was
transferred from the target by means of helium flow and collected
in the receiving vial. Aqueous [18F]fluoride was loaded onto the
anion exchange cartridge from the male side. Residual water was
removed by rinsing the cartridge with 2 mL of 2-PrOH in the same
direction followed by flushing with compressed air. [18F]Fluoride
was eluted backwards relative to the loading direction using
solution of Bu4NOTf (5 mg) in 0.6-0.8 mL of 2-PrOH; the eluate
was collected into the reaction vessel. Model radiolabeling of the
and [18F]8a
were 0.05 and 0.83, correspondingly. The
radiochemical yield (RCY) of the radiofluorination step was
calculated from radioTLC data as the ratio of the product peak
area to total peaks area on the TLC plate; it was not corrected for
decay.
Analytical HPLC system used, Dionex ISC-5000, consisted of a
gradient pump, Rheodyne-type injector with a 20 μl loop, and
variable wavelength UV absorbance detector (set to 254 nm)
connected in series with a radiodetector model 105-S (Carrol and
Ramsey Associates, USA). HPLC analysis of model compounds
[18F]1a- [18F]7a was conducted on a XBridge® C18 5 µm,
150×4.6 mm reverse phase HPLC column (Waters, USA) using
the following conditions: 5 to 90% gradient (H2O/CH3CN, HPLC
System 1), flow rate 2.0 mL/min:
precursors 1-7 was conducted on the remotely controlled
[1]
synthesis module (in-house development
) with manual
interventions). The module was equipped with a heating block
suitable for 5 mL reaction vessel with a screw cup (Wheaton vial).
0 - 2 min: 5% CH3CN isocratic;
Different
protocols
were applied for
the following
2 - 13 min: 5 - 90% CH3CN linear increase;
13 - 13.5 min: 90 - 5% CH3CN linear decrease;
13.5 - 20 min: 5% CH3CN isocratic
The UV- and radiodetector were connected in series giving delay
of 0.1 min. The Rt values of [18F]1a, [18F]2a, [18F]3a, [18F]4a,
[18F]5a and [18F]6a were 9.0, 9.2, 10.6 and 7.3 min, respectively.
Rt of radiofluorinated [18F]7a was 12.2 min; for partly hydrolyzed
[18F]7a the Rt value was 10.2 min
The same gradient profile were applied for radioHPLC analysis of
6-L-[18F]FDOPA using trifluoroacetic acid (0,1%) instead of water
under flow rate of 2.0 mL/min (TFA 0.1%/CH3CN, 5 to 90%
gradient, same gradient profile, HPLC System 2). The Rt value for
6-L-[18F]FDOPA was 4.0 min, Rt of radiofluorinated intermediate
[18F]8a was 12.9 min.; for partly hydrolyzed [18F]8a the Rt value
was 11.4 min. Residual tetrabutylammonium (TBA) level in the
final product was analyzed using the same system; the Rt for
TBAOH was 5.6 min Enantiomeric purity of 6-L-[18F]FDOPA was
evaluated using Chirobiotic T (Astec) column eluted at 1.0 mL/min
with water/ethanol (60/40) (HPLC System 3). Rt values for L- and
D-isomers of 6-[18F]FDOPA were 4.3 and 5.6 min,
correspondingly. The content of copper in the final formulation
was determined using ICP Optical Emission Spectrometer Varian
725-ES.
radiofluorinations. The RCY was assessed by radioTLC on the
aliquot of the crude mixture. The radioactivity loss on the inner
surface of reaction vessel was evaluated by measuring of the
activity of reaction vessel with reaction mixture and after empting
reaction vessel (the content was sucked out with a syringe).
Radiofluorination
conditions
(optimization
study):
[18F]fluoride trapped on the Sep-Pak Accell Plus QMA Plus Light
Cartridge (130 mg) cartridge was eluted with a solution of
Bu4NOTf (5 mg) in 0.6 mL of 2-PrOH. The eluate was collected
into 5 mL vial pre-filled:
For 1: 5-15 μmol of 1, 3-7.5 μmol Cu(OTf)2(Py4), 300 µL of the
solvent (DMA, CH3CN, 2-PrOH);
For 2-7: 15 μmol of 2-7, 7.5 μmol Cu(OTf)2(Py4), 300 µL of DMA;
For 8: 8-15 μmol of 8, 5-50 μmol Cu(OTf)2(Py4), 300 µL of the
solvent (DMA, CH3CN, 2-PrOH, acetone).
[18F]fluorination was performed in a sealed vial at 100-110 0C for
20 min without stirring under access to the atmospheric air.
Automated radiosynthesis of 6-L-[18F]FDOPA: Radiosynthesis
was performed on the automated synthesis module TRACERlab
FX C Pro (GE Healthcare) equipped with semi-preparative HPLC
(SYCAM S1122 solvent delivery system, UV detector and
radioactivity detector connected in row). The module was
originally designed for the preparation of 11C-labelled compounds
and was adapted to 18F-fluorinations. [18F]Fluoride (2-9 GBq) was
transferred from the target in a water bolus by means of helium
flow and trapped onto the Sep-Pak Accell Plus QMA Plus Light
Cartridge (130 mg) from the male side. Residual water was
removed by rinsing the cartridge with 7 mL of acetone in the same
direction followed by flushing with N2. The radionuclide was eluted
from the cartridge backwards relative to the loading direction with
solution of 12.5 µmol (5.0 mg) of Bu4NOTf in 0.9 mL of 2-PrOH
into the round-bottom reaction vessel (2 mL volume) prefilled with
solution of 10 µmol of 8 and 16 µmol of Cu(OTf)2(Py)4 in 0.3 mL
of acetone. The fluorination was performed at 90°C for 20 min
Anion exchange cartridges screening:
A
series of
commercially available anion exchange cartridges (Table S1)
were evaluated for trapping/elution of [18F]fluoride and the
efficiency of the following radiofluorination of 1. Aqueous
[18F]fluoride was loaded onto the anion exchange cartridge from
the male side. Residual water was removed by rinsing the
cartridge with 2 mL of 2-PrOH in the same direction followed by
flushing with compressed air. [18F]Fluoride was eluted backwards
relative to the loading direction (Fig. S1) using solution of
Bu4NOTf (5 mg) in 0.6 mL of 2-PrOH. The eluate (5 mg of
Bu4NOTf, 0.6 mL of 2-PrOH) was collected into a reaction vessel
pre-filled with 15 μmol of ArylBPin precursor 1, 7.5 μmol
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001198
European Journal of Organic Chemistry
FULL PAPER
3251-3256; d) F. Zarrad, B. Zlatopolskiy, P. Krapf P, J. Zischler, B.
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with stirring under inert atmosphere (N2 gas). The solvent was
evaporated by heating to 50 °C with stirring and the reaction
vessel was cooled down to 40 °C. To the dried residue the mixture
of 6 N HCl (0.4 mL), MeOH (0.3 mL) and 0.25 M ascorbic aсid
(0.2 mL) was added and hydrolysis was carried out for 5 min at
110 °C without stirring. The completeness of hydrolysis was
monitored by analysis of the hydrolysate aliquot using radioHPLC,
System 2. The liquids were evaporated by heating to 120 °C
under nitrogen flow with stirring. After cooling the reaction vessel
to 50 °C, 1.8 mL of HPLC mobile phase (0.1% acetic acid) was
added. The resulting solution (total volume about 1.8-1.9 mL) was
loaded onto the HPLC loop (2 mL) and injected into semi
preparative HPLC column Ascentis RP-AMIDE, 5 µm, 250×10
mm (Supelco). The semi preparative column was equipped with
a guard column to remove residual copper: Security Guard
Cartridge AJO-8327-S in Guard Cartridge Holder KJO-4282
(Phenomenex). The column outlet was connected to an UV
absorbance detector (λ=254 nm) in series with a radioactivity
detector (module TRACERlab FX C Pro (GE Healthcare). After
running HPLC with pure water (0-6 min) the mobile phase was
changed to 0.1% CH3COOH at a flow rate of 4 mL/min giving a
radioactive fraction (4-5 mL volume) corresponding to pure 6-L-
[18F]FDOPA (Rt from 12 to 13 min). The product fraction with pH
4 was collected into a vented sterile vial pre-filled with 5 mL of
sterile normal saline through the 0.22 μm Millipore filter.
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Acknowledgements
This study was supported by the state funding at the N.P.
Bechtereva Institute of Human Brain, Russian Academy of
Sciences. The authors thank Dr. Chuan-Lin Cheng (National
Yang-Ming University, Taipei, Taiwan) for providing precursor and
standard for protected 4-[18F]fluoro-L-phenylalanine.
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Keywords: Radiopharmaceuticals • Arenes • Copper mediated
radiofluorination • Pinacol esters • 6-L-[18F]FDOPA
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10.1002/ejoc.202001198
European Journal of Organic Chemistry
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Entry for the Table of Contents
In this work we demonstrated for the first time the possibility of effective copper-mediated radiofluorination of aryl pinacoloboronate
esters on the example of precursor for 6-L-[18F]FDOPA in a neat alcohol using a neutral phase-transfer catalyst tetrabutyl ammonium
triflate.
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This article is protected by copyright. All rights reserved.