A comparative study on Suzuki-type 11C-methylation of aromatic organoboranes performed in two reaction media

Article abstract of DOI:10.1002/jlcr.3932

The Suzuki-type cross coupling reaction is a palladium-mediated multistep reaction that has been used to synthesize several ¹¹C-labeled tracers for PET. However, the impact of the selected organoborane reagent and reaction medium on the radioch

Full text of DOI:10.1002/jlcr.3932

Received: 21 April 2021
DOI: 10.1002/jlcr.3932
Revised: 13 June 2021
Accepted: 5 July 2021
S H O R T N O T E
A comparative study on Suzuki-type 11C-methylation of
aromatic organoboranes performed in two reaction media
Johanna Rokka1
| Patric Nordeman2,3
| Sara Roslin2,3 | Jonas Eriksson2,3
1Department of Public Health and Caring
Sciences, Molecular Geriatrics, Uppsala
University, Uppsala, Sweden
2Department of Medicinal Chemistry,
Uppsala Biomedical Center, Uppsala
University, Uppsala, Sweden
The Suzuki-type cross coupling reaction is a palladium-mediated multistep
reaction that has been used to synthesize several 11C-labeled tracers for PET.
However, the impact of the selected organoborane reagent and reaction
medium on the radiochemical yield (RCY) has not been thoroughly investi-
gated. To bridge this gap, we studied the synthesis of 1-[11C]methyl-
naphthalene using four different organoborane precursors in reactions
performed in DMF/water and THF/water. In the synthesis of 1-[11C]methyl-
naphthalene, the best radiochemical yields (RCYs), approximately 50%,
were obtained with boronic acid and pinacol ester precursors, whereas
less than 4% RCY was obtained when performing the reaction with the
N-methylimidodiacetic acid boronic ester (MIDA ester) precursor. 1-[11C]
methylnaphthalene was obtained in higher yields in almost all syntheses per-
formed in THF/water as compared to DMF/water. This observation was in line
with previously reported results for [11C]UCB-J, a tracer for the synaptic vesi-
cle glycoprotein 2A (SV2A) receptor, that also was obtained in higher RCY
when synthesized in THF/water. The same trend was observed with [11C]
cetrozole, where the RCY was more than doubled in THF/water compared to
the previously published synthesis performed in DMF. These results suggest
that THF/water could be the preferred reaction medium when producing PET
tracers via the Suzuki-type coupling reaction.
3PET Centre, Uppsala University Hospital,
Uppsala, Sweden
Correspondence
Johanna Rokka, Department of Public
Health and Caring Sciences, Uppsala
University, Dag Hammarskjölds väg
20, 751 85 Uppsala, Sweden.
Email: johanna.rokka@pubcare.uu.se
Funding information
Tor, Joe & Pentti Borg Foundation;
BioArctic AB
K E Y W O R D S
[11C]cetrozole, [11C]UCB-J, 1-[11C]methylnaphthalene, 11C-methylation, organoborane
compounds, positron emission tomography, Suzuki-type coupling
1 | INTRODUCTION
at aromatic and aliphatic structures.
A
recently
developed PET-tracer produced by the Suzuki-type cross
coupling reaction is [11C]UCB-J, a tracer that has been
implemented at several PET-facilities to image the synap-
tic vesicle glycoprotein 2A (SV2A).1–5 The same method-
ology is also used to synthesize for example [11C]ATRA,
[11C]cetrozole, [11C]CIMBI-712, [11C]dehydropravastatin,
Suzuki-type cross coupling reactions utilizing a palla-
dium catalyst at basic conditions is a mild and efficient
way to form carbon-carbon bonds in organic synthesis.
The method has been used in the production of PET
tracers by incorporating carbon-11-labeled methyl groups
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
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© 2021 The Authors. Journal of Labelled Compounds and Radiopharmaceuticals published by John Wiley & Sons Ltd.
J Label Compd Radiopharm. 2021;1–9.
wileyonlinelibrary.com/journal/jlcr
1

2
ROKKA ET AL.
17-[11C]HAD, [11C]MENET, [11C]M-MTEB, N-(4-[11C]
ethylphenyl)propionamide, [11C]palmitate, [11C]PSPA-4,
and [11C]toluene derivatives (Figure 1A,B).6–15
mixture containing sodium and benzophenone just before
use to remove water and peroxides. Aqueous solution of
TFA (1%) was prepared by dilution with MilliQ water.
Ammonium formate (AMF) buffer solution (50mM,
pH 3.5) was purchased from Bio-Hospital (Kopparberg,
Sweden). AMF buffer solution (pH 10) was prepared by
mixing ammonia solution (40 ml, 37%) and AMF solution
(2000 ml, 50mM, pH 3.5). The 11C-methylation reactions
were performed in disposable conical glass vials (crimp
neck, 0.9 ml) with septa (11 mm aluminum crimp cap
with 1.3 mm butyl/PTFE seal), purchased from VWR
(Karlskoga, Sweden).
Several organic chemistry publications have shown
that Suzuki-type coupling reactions may benefit from the
use of THF/water as reaction medium.16–18 Still, most
11C-labeled tracers have been synthesized from pinacol
ester precursors in DMF or DMF/water medium while
the use of THF solvent has only been reported for com-
pounds labeled in aliphatic positions (Figure 1A,B).
Recently, we showed that the radiochemical yield (RCY)
of [11C]UCB-J was improved by changing the reaction
medium to THF/water. In the current work, we wanted
to investigate if THF/water medium would improve the
[11C]methylation also for other aromatic structures. Sev-
eral different organoborane precursors, for example,
pinacol esters, trifluoroborates, and boronic acids, have
been used in 11C-methylation of tracers, but we found
that the selection of organoborane species and their
impact on the radiochemical yield (RCY) has not been
investigated systematically.
For
the
1-[11C]methylnaphthalene
syntheses,
naphthalene-1-boronic acid, 1-naphthylboronic acid
MIDA ester, naphthalene-1-boronic acid pinacol ester
and the reference 1-methylnaphthalene were bought
from Sigma Aldrich (Stockholm, Sweden). Potassium
1-naphthalenetrifluoroborate was from Fisher Scientific
(Göteborg, Sweden). For [11C]UCB-J synthesis, the pre-
cursor (R)-3-(difluoroboranyl)-4-((2-oxo-4-(3,4,5-trifluoro-
phenylpyrrolidin-1-yl)methyl)-pyridin-1-ium
fluoride
The aim of the current study was to investigate how
the organoborane precursor and reaction medium affect
the RCY. For this, 1-[11C]methylnaphthalene was
selected as model compound and it was synthesized
from commercially available organoborane precursors;
naphthalene-1-boronic acid, 1-naphthylboronic acid N-
methylimidodiacetic acid boronic ester (1-naphthylboronic
acid MIDA ester), naphthalene-1-boronic acid pinacol
ester, and potassium 1-naphthalenetrifluoroborate. The
reactions were performed in DMF/water and in THF/water
reaction media. We compared the results from 1-[11C]
methylnaphthalene synthesis to structurally complex com-
pounds [11C]UCB-J synthesized from trifluoroborate pre-
cursor and [11C]cetrozole synthesized from pinacol
precursor, to see if the trends observed for 1-[11C]methyl-
naphthalene would have general implications (Figure 1C).
(BF3-Dm-UCB-J) and the reference compound (4R)-
1-[(3-methyl-4-pyridyl)methyl]-4-(3,4,5-trifluorophenyl)
pyrrolidin-2-one (UCB-J), were purchased from
Pharmasynth (Tartu, Estonia). For [11C]cetrozole
synthesis the precursor MD-298 and the cetrozole refer-
ence 4-((4-methylbenzyl)(4H-1,2,4-triazol-4-yl)amino)
benzonitrile) were from RIKEN Center for Biosystems
Dynamics Research (Kobe, Japan).
2.2 | Synthesis equipment
All syntheses were performed using the fully automated
Tracer Production System (TPS) developed in-house
(Uppsala University Hospital PET Centre, Sweden). The
TPS device contains 10 modules, including a robotic liq-
uid handler, a gripper with a shaker function, heating/
cooling for reaction vials, injection port for semi-
preparative HPLC, fraction collector, vortex evaporator,
SPE reformulation system, sterile dispenser and a control
software that allows independent tasks to run concur-
rently. Preparative HPLC purification were done using
semi preparative HPLC (Agilent 1260 Infinity II).
The effluent was monitored with a Bioscan Flow-Count
PMT radioactivity detector and UV detector (Agilent
1260 Infinity II) set at 254 nm.
2 | EXPERIMENTAL
2.1 | Materials
Tris (dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3), tri
(o-tolyl)-phosphine (P(o-tol)3), anhydrous potassium
carbonate (K2CO3), N,N-dimethylformamide (DMF),
acetonitrile (ACN), 37% ammonia solution, phosphorous
pentoxide (Sicapent), Ascarite, hydroiodic acid (57%),
trifluoroacetic acid (TFA) and tetrahydrofuran (THF, for
DNA and peptide synthesis, max. 0.005% H₂O) were pur-
chased from Sigma Aldrich (Stockholm, Sweden). Lithium
aluminum hydride in THF (0.1 M, LAH) was purchased
from ABX (Radeberg, Germany). THF was distilled from a
2.3 | Synthesis
Tris (dibenzylideneacetone)-dipalladium(0), tri(o-tolyl)-
phosphine, potassium carbonate, and 1 mg organoborane

ROKKA ET AL.
3
FIGURE 1 Suzuki-type coupling reaction schemes. (A) 11C-labeled tracers synthesized using DMF or DMF/water as reaction medium.
(B) 11C-labeled tracers synthesized using THF or THF/water as reaction medium. (C) Reaction conditions investigated in current study,
synthesizing 1-[11C]methylnaphthalene, [11C]cetrozole and [11C]UCB-J. For references, see the text

4
ROKKA ET AL.
precursor were weighed in a reaction vessel. Exact
amounts of the compounds are listed Table S1. THF or
DMF (350 μl) and MilliQ water (40 μl) was then added,
the vessel was capped and the resulting solution was
degassed with helium and vortexed. Immediately the
THF reaction mixtures appeared homogenous with a
clear dark red color that gradually turned yellowish. The
DMF mixtures appeared as slightly pinkish black opalic
solutions. In the synthesis of [11C]cetrozole in DMF, all
reagents were weighed in the same vessel, DMF was
added, and reaction mixture was filtered and then
degassed yielding a strong yellow solution.19 All solutions
were prepared approximately 30 min before addition of
[11C]methyl iodide.
are found in Figures S1–S6. In all syntheses, the radioac-
tivity of the collected fraction was measured with a dose
calibrator and then a sample was taken for analytical
HPLC analysis.
2.4 | Radiochemical and chemical
purity, identity, and molar activity
The radiochemical purity (RCP) and identity of the 11C-
labeled product was assessed by analytical HPLC
(Agilent 1290 Infinity II pump) using a Phenomenex
Kinetex 5 μm C18 100 Å (100 Â 3.0 mm) column with
an eluent flow of 0.7 ml/min. The effluent was moni-
tored with a radioactivity detector (a Flow-Count PMT)
and a UV detector set at 254 nm (Agilent 1290 Infinity
II). The eluents used were acetonitrile in AMF buffer
(pH 3.5) (50/50) for [11C]methylnaphthalene, acetonitrile
in AMF buffer (pH 3.5) (85/15) for [11C]cetrozole and
acetonitrile in AMF buffer (pH 3.5) (30/70) for [11C]
UCB-J. For [11C]cetrozole synthesized in DMF,
the eluents used were acetonitrile in 8.1mM ammonium
Carbon-11 was obtained as [11C]CO2 was produced
through the 14N(p,α)11C nuclear reaction by 17 MeV
proton irradiation with the beam current 45 μA
(Scanditronix MC-17 cyclotron) on nitrogen gas (AGA,
Nitrogen 6.0) containing 0.05% oxygen (AGA, Oxygen
4.6). Typical irradiation time was 30 min, which gave
approximately 30 GBq [11C]CO2 at the end of bombard-
ment (EOB). The [11C]CO2 was converted to [11C]methyl
iodide by the “wet method” where first, [11C]CO2 was
transferred to a reactor using helium gas (160 ml/min)
and trapped in LAH (300 μl, 0.1 M in THF). The mixture
was evaporated to dryness at 80ꢀC under a stream of
nitrogen gas (150 ml/min) during 2 min. Hydroiodic acid
(600 μl, 57%) was added to the reactor and mixture was
heated at 130ꢀC for 70 s and then cooled to 80ꢀC. The
formed [11C]methyl iodide was then transferred in a
stream of nitrogen gas (10 ml/min) to the reaction vessel
via a phosphorous pentoxide/ascarite column to remove
moist and acidic vapors. [11C]Methyl iodide was trapped
in the reaction mixture at room temperature. After trap-
ping, the reaction solution was mixed by a vigorous shake
of the vial and then heated at 70ꢀC for 4 min. The mixing
was repeated after 1 min of heating.
The reaction mixture was diluted with 300 μl water
and the 11C-labeled product was purified by semi-
preparative HPLC. 1-[11C]methylnaphthalene and [11C]
cetrozole, synthesized in THF/water solutions, were puri-
fied using an ACE C18, 5 μm, 10 Â 150 mm column. The
eluent used for 1-[11C]methylnaphthalene was acetoni-
trile in 50 mM AMF pH 3.5 (70/30). The eluent used for
[11C]cetrozole purification was acetonitrile in 50 mM
AMF pH 3.5 (40/60). [11C]Cetrozole synthesized in DMF
solution was purified using ACE 5 SuperC18 5 μm
(10 Â 150 mm) with acetonitrile in 8.1 mM ammonium
carbonate solution (40/60) as eluent.19 [11C]UCB-J was
purified using a Phenomenex Gemini 5 μm NX-C18
(250 Â 10 mm) column eluted with acetonitrile in AMF
buffer (pH 10) (40/60). The preparative UV and radioac-
tivity chromatograms of all the 11C-labeled compounds
carbonate (40/60) on
a Gemini NX 5 μm C18
(100 Â 4.6 mm) column. The analytical UV and radioac-
tivity chromatograms of all the 11C-labeled compounds
are found in Figures S1–S6.
3 | RESULTS AND DISCUSSION
Three compounds, 1-[11C]methylnaphthalene, [11C]
cetrozole, and [11C]UCB-J were synthesized from [11C]
methyl iodide and organoborane precursors by the
Suzuki type coupling reaction performed in THF/water,
DMF or DMF/water (Figure 1C). The radioactivity yields
for the isolated products in GBq (HPLC fraction), RCYs,
RCPs and molar activities are listed in Table 1. The pres-
ented RCYs are decay corrected and based on the amount
of trapped [11C]methyl iodide in the reaction vial and the
amount of radioactivity in the collected preparative
HPLC fraction. By basing the RCYs on trapped amount
of [11C]methyl iodide in reaction vial, the events before
the 11C-methylation reaction were excluded. We did not
observe any significant differences in the trapping effi-
ciency of [11C]methyl iodide depending on the solvents.
For example, the trapped amount of [11C]methyl iodide
was 17.8 4.5 GBq (n = 10) in the synthesis of 1-[11C]
methylnaphthalene performed in DMF/water, while
when performed in THF/water the trapped activity was
19.6 2.2 GBq (n = 10). Analysis of residual palladium
in the isolated product was not performed but it can be
noted that our previous studies have only showed
extremely low amounts.5,19

ROKKA ET AL.
5
TABLE 1 The radioactivity of the collected preparative HPLC fraction the RCY, concentration, molar activity (Am), and radiochemical
purity (%) of 1-[11C]methylnaphthalene, [11C]cetrozole, and [11C]UCB-J. All RCYs are decay corrected and based on [11C]methyl iodide. #
Data from Rokka et al.5
HPLC fraction
(GBq)
RCY
(%)
Am
RCP
(%)
Medium
(MBq/nmol)
n
3
[11C]Methylnaphthalene from boronic acid
[11C]Methylnaphthalene from MIDA ester
[11C]Methylnaphthalene from pinacol ester
[11C]Methylnaphthalene from trifluoroborate
[11C]Cetrozole from pinacol ester
THF/water
DMF/water
THF/water
DMF/water
THF/water
DMF/water
THF/water
DMF/water
THF/water
DMF
7.0 0.4
6.2 1.0
0.42
54
45
3,7
2,8
49
52
6
2
550 50
410 60
70
>99.9
>99.9
94.3
3
1
0.30
50
89.6
1
6.1 1.3
6.5 1.4
3.8 1.4
1.4 0.3
9.5 1.5
2.5; 3.9
4
4
400 300
360 180
550 250
210 70
n/a
>99.9
>99.9
>99.4
>94.7
>99.9
>95
3
3
28 10
16
3
5
3
82 11
31; 26
5
150
2
[11C]UCB-J from trifluoroborate
THF/water
DMF/water
2.7 0.5
0.2 0.1
27
8
420 200
n/a
>99.8
>99.9
3#
3#
5.0
3
The Suzuki-type coupling reaction with [11C]methyl
iodide is a multistep process where a 11C-methyl palla-
dium complex is formed by oxidative addition, the com-
plex reacts with the organoborane precursor in a
transmetalation step and finally the 11C-labeled product
is released by reductive elimination (Figure 2A).18,20,21
The organoborane compound enters in transmetallic step
in the form of a boronic acid. Organoboronates can be
hydrolysed to the corresbonding boronic acid either in
situ using base catalyzed hydrolysis or before the
synthesis using either acid or base catalyzed hydrolysis.
However, acidic or basic conditions can promote proto-
deboronation of boronic acid, which causes the precursor
to lose its active site (Figure 2B).18,22,23 Still, anhydrous
conditions are not good either for boronic acids, because
they may create trimeric anhydrides, so called boroxines.
Boroxines are relatively stable at anhydrous conditions
due to their partly aromatic moiety, which may inhibit
the Suzuki-type coupling reaction. Optimal precursor
hydrolysis into boronic acid form is needed when [11C]
methylations are performed, so that the hydrolysis do not
limit the reaction rate.
The processes around transmetalation have been pro-
posed as the reaction rate limiting step.18,20,21,24 There
are two main hypotheses how the organoborone species
enters the catalytic cycle prior the transmetalation step
(Figure 2C). According to computational studies, the low-
est energy pathway is the so-called boronate pathway,
where trihydroxyboronate is generated and then coupled
to the palladium complex. However, experimental studies
have indicated that the so-called oxo-palladium pathway
is kinetically favored. Here the palladium halide reacts
with a hydroxide ion and the formed oxo-palladium com-
plex then reacts with the boronic acid. In case of 11C-
methylation [11C]methyl iodide first has to couple with
palladium complex before [11C]methylation of organ-
oborane precursor can happen In all experiments. the
palladium–(o)tolylphosphine ratio was kept at a 1:2
(Table S1). Theoretically, this ratio of palladium and
ligand can be considered optimal not to sterically hinder
the transmetalation step involving the [11C]methyl-
palladium complex and the organoboronic compound.25
1-[11C]Methylnaphthalene was first synthesized with
standardized reaction conditions using four different
types of organoborane precursors, performed in
THF/water and DMF/water medium. The organoboranes
were used as received and the purity may not be as high
as precursor material manufactured specifically for PET-
tracer synthesis. As the synthesis conditions were stan-
dardized to allow for direct comparison between the
organoboranes, the RCY of 1-[11C]methylnaphthalene
could potentially be further improved but this was not
the scope of this study. As Table 1 shows, the selection of
the organoborane reagent had an impact on the RCY of
1-[11C]methylnaphthalene. Highest RCYs were achieved
using the boronic acid and the pinacol ester precursor
while the trifluoroborate gave moderate yields and the
MIDA ester gave the lowest yields.
Boronic esters are favorable as precursors, being rela-
tively easy to synthesize and offer better stability during
storage compared to boronic acids.18,21,26 In the group of
boronic esters, the pinacol ester has shown to be one
of the most stable forms. In 11C-methylations, pinacol
esters have shown to react in mixtures where no water is

6
ROKKA ET AL.
FIGURE 2 (A) The catalytic cycle of
Suzuki-type reactions. (B) Boronic acids formed
by hydrolysis are active species in Suzuki-type
reaction but could be subjected to
protodeboronation or transformation to
boroxines. (C) The boronate and oxo-palladium
pathways have been proposed to precede
transmetalation of the boronic acid
added as is seen for example in the synthesis of [11C]
cetrozole, suggesting that pinacol esters may react directly
with oxo-palladium complexes or exhibit favorable
hydrolysis rate at semi-dry conditions to form suitable
concentrations of boronic acid in situ.8,13,15,19,27–29 This
may explain why the RCY of 1-[11C]methylnaphthalene
was similar for the pinacol ester and the boronic acid
(Table 1). Being stable in anhydrous conditions, the
MIDA ester needs to hydrolyze to boronic acid before
the Suzuki type coupling reaction can be per-
formed.26,27,30 The slow hydrolysis of MIDA esters are uti-
lized in site specific conjugations, but as shown in our

ROKKA ET AL.
7
study, this may not be beneficial for 11C-chemistry that
requires very short reaction times.
columns when injected on the preparative HPLC. Thus,
THF/water reaction mixture not only improves the RCYs,
possibly by favoring the oxo-palladium route and improv-
ing the hydrolysis of the organoborane precursor, but it
also dissolves the reaction components more efficiently
and thus diminishes the mechanical problems which
may occur with particulates. Because THF/water reaction
mixtures do not contain visible particles, we assume that
the vigorous shaking is not an important mediator for the
reaction and the RCY would remain on the same level
even if the reaction mixture is not shaken during the
reaction, which may be case when commercial available
synthesis devices are used.
Degassing of the reaction mixture is important for
Suzuki type reactions because organoboranes as well as
palladium(0) have tendency towards aerobic oxidation
which decreases the coupling yield.16,21 For that reason,
all reaction mixtures used in this study were carefully
degassed. To further minimize oxidative components in
reaction mixtures, high-grade solvents were used; DMF
was of anhydrous grade and THF was distilled fresh
before use. Furthermore, all lines in the synthesis appara-
tus were flushed with nitrogen gas prior transfer of [11C]
methyl iodide to the reaction vessel to avoid bubbling air
into the reaction mixture. The distillation of THF was not
necessary, when high-grade THF is used from bottle
which has been open less than 1 month as we have previ-
ously shown,5 but these precautions are recommend,
especially if the reagents and devices are not in daily use.
Prior this study we have produced [11C]Cetrozole for
clinical imaging studies and [11C]UCB-J for preclinical
imaging studies using published synthesis protocols.5,19
As already shown, we could increase the RCY of [11C]
UCB-J when trifluoroborate precursor by changing the
reaction medium from DMF/water to THF/water. Here,
we demonstrate that THF/water can also increase the
RCY of [11C]cetrozole synthesized from pinacol ester
precursor.
Potassium organotrifluoroborate salts are stable com-
pounds with long shelf lives, and in synthesis they toler-
ate many common synthetic transformations. In aqueous
and protic solutions, trifluoroborate hydrolyses to boronic
acid. For Suzuki-type couplings, hydrolysis of trifluo-
roborate to boronic acid is essential for the coupling
reaction as intact trifluoroborate cannot react with trans-
metalating species.16–18 Hydrolysis of trifluoroborates is
relatively slow which may be beneficial to avoid
protodeboronation side reactions. Slow hydrolysis could
also explain why the RCYs of 1-[11C]methylnaphthalene
were lower for the trifluoroborate precursor
compared to boronic acid or pinacol ester precursor.
In electron deficient aryl trifluoroborates, such as
1-naphthalenetrifluoroborate and the UCB-J precursor,
the hydrolysis rate can be increased for example by per-
forming the reaction in glass vessels and by using an
aqueous biphasic reaction medium.17 An enhanced
hydrolysis rate of the organoborane precursors may
explain the higher RCYs of 1-[11C]methylnaphthalene
and [11C]UCB-J in THF/water reactions compared to the
reactions performed in DMF/water.
Several publications are suggesting that aqueous
biphasic conditions are important for Suzuki type
coupling reactions. Although pure THF and water are
miscible, addition of potassium carbonate makes
water and THF less miscible, yielding a biphasic
medium. A biphasic medium, like the THF/water
reaction solution, could be beneficial as it may
favor the oxo-palladium route that hinders the
formation of trihydroxyboronate.16,18,20,21,23 When reac-
tion medium is changed to DMF/water basic homoge-
nous medium is created which favors the formation of
trihydroxyboronate and the boronate pathway. In our
tests we observed a significant increase in the RCY for
1-[11C]methylnaphthalene (starting with trifluoroborate
precursor), [11C]cetrozole, and [11C]UCB-J, when the
reaction medium was changed from DMF or DMF/water
to THF/water (Table 1). Perhaps, this increase in RCY is
due to enhanced precursor hydrolysis which could also
imply that the oxo-palladium route is prominent in the
11C-methylations of 1-[11C]methylnaphthalene, [11C]
cetrozole, and [11C]UCB-J.
4 | CONCLUSIONS
The impact of organoboronate precursor and reaction
medium selection on Suzuki-type 11C-methylation cou-
pling yields has been studied. For 1-[11C]methylnaphtha-
lene the highest RCY were achieved using boronic acid
and pinacol ester precursors. The reaction media did not
influence on RCY of 1-[11C]methylnaphthalene when
synthesized from pinacol ester precursor, but the aqueous
biphasic conditions created using THF/water as reaction
medium improved the RCY of 1-[11C]methylnaphthalene
synthesized from trifluoroborate and boronic acid precur-
sor. In syntheses of [11C]Cetrozole from pinacol precursor
We also noted in all tests that there were no visible
particles in the THF/water solutions whereas in
DMF/water solutions there were visible particles even
after strong vortexing of the mixtures. Particles will sedi-
ment with time in the mixture, which decreases the avail-
ability of these components in reaction medium and may
hinder the reaction. The second drawback of the visible
particles is that they may clog the capillaries and

8
ROKKA ET AL.
and [11C]UCB-J from trifluoroborate precursor, changing
the reaction medium from DMF or DMF/water to
THF/water gave a significant increase in the RCY. These
results suggest that using a THF/water reaction medium
should be considered when implementing synthesis
protocols for Suzuki-type 11C-methylations.
10. Hostetler ED, Fallis S, McCarthy TJ, Welch MJ,
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ACKNOWLEDGEMENTS
This research received funding from BioArctic AB and
Tor, Joe & Pentti Borg Foundation.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are
available from the corresponding author upon reasonable
request.
ORCID
Johanna Rokka https://orcid.org/0000-0003-3962-696X
Patric Nordeman https://orcid.org/0000-0002-4334-
7368
15. Takahashi K, Hosoya T, Onoe K, et al. 11C-Cetrozole: An
Improved C-11C-Methylated PET Probe for Aromatase Imaging
in the Brain. J Nucl Med. 2014;55(5):852-857.
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pling: the roles of endogenous aryl boronic acid and fluoride.
Angew. Chemie - Int. Ed. 2010;49:5156-5160.
Jonas Eriksson https://orcid.org/0000-0003-0241-092X
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Rokka J, Nordeman P,
Roslin S, Eriksson J. A comparative study on
Suzuki-type 11C-methylation of aromatic
organoboranes performed in two reaction media.
J Label Compd Radiopharm. 2021;1-9. https://doi.
org/10.1002/jlcr.3932