Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers in a mixed organic solvent system

Article abstract of DOI:10.1016/j.tetlet.2018.06.033

Efficient aliphatic radiofluorination in a mixed organic solvent system was investigated. This method obviates the time-consuming [¹⁸F]fluoride drying step routinely required in the preparation of most fluorine-18 positron emission tomography (

Full text of DOI:10.1016/j.tetlet.2018.06.033

Accepted Manuscript
Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers
in a mixed organic solvent system
Young-Do Kwon, Jeongmin Son, Mijin Yun, Joong-Hyun Chun
PII:
S0040-4039(18)30775-5
https://doi.org/10.1016/j.tetlet.2018.06.033
TETL 50071
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
24 April 2018
4 June 2018
11 June 2018
Please cite this article as: Kwon, Y-D., Son, J., Yun, M., Chun, J-H., Azeotropic drying-free aliphatic
radiofluorination to produce PET radiotracers in a mixed organic solvent system, Tetrahedron Letters (2018), doi:
https://doi.org/10.1016/j.tetlet.2018.06.033
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Azeotropic drying-free aliphatic radiofluorination to produce PET
radiotracers in a mixed organic solvent system
Young-Do Kwona , Jeongmin Sonb , Mijin Yuna,b and Joong-Hyun Chuna 
a Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722,
Republic of Korea
b Department of Nuclear Medicine, Severance Hospital, Yonsei University Health System,
Seoul 03722, Republic of Korea
ABSTRACT
Efficient aliphatic radiofluorination in a mixed organic solvent system was investigated. This
method obviates the time-consuming [18F]fluoride drying step routinely required in the
preparation of most fluorine-18 positron emission tomography (PET) radiotracers. The
[18F]fluoride ions eluted from a QMA (quaternary ammonium anion exchange) cartridge with
phase transfer agents were directly mixed in various organic solvents for subsequent
radiofluorination. Herein, we report the azeotropic drying-free radiofluorination of aliphatic
substrates and demonstrate the viability of hydrated [18F]fluoride ions in a mixed organic
solvent system for obtaining useful radiochemical yields (RCYs). This practical and simple
method has demonstrated general applicability to the production of established PET tracers as
well as to the rapid assessment and chemical optimization of early-stage potential radiotracers.
Keywords: PET, fluorine-18, radiofluorination, PET radiotracer, automation
 Corresponding author. Joong-Hyun Chun, Tel.: +82-2-2228-2348; fax: +82-2-312-0578; e-mail: jchun@yuhs.ac

Positron emission tomography (PET) is a molecular imaging technique used to study
the dynamics and metabolism of radiotracer distribution in living subjects.1 The widespread
availability of affordable cyclotrons in hospitals allows this technology to be used to diagnose
various diseases in their early stages, thus improving overall clinical outcomes. Among the
many radionuclides produced by cyclotrons, fluorine-18 is the species of choice as it provides
ideal imaging characteristics and a desirable decay pattern.2 Considering the short half-life
(t1/2 = 110 min) of fluorine-18, a short radiolabeling time requires reliable PET radiotracer
production to introduce fluorine-18 to the target molecule for subsequent imaging studies.
The hydration of [18F]fluoride ions is known to have a detrimental effect on the
nucleophilicity of fluorine-18, leading to poor overall labeling. In general, cyclotron-
produced [18F]fluoride ions are generated by the 18O(p,n)18F nuclear reaction and delivered in
their fully hydrated states in [18O]H2O water. Azeotropic evaporation for the removal of
water from cyclotron-produced [18F]fluoride ions is considered to be a crucial step in many
18F-radiotracer preparation procedures. It is, however, both laborious and time-consuming.3
Excluding this drying step can be advantageous for extensive radiochemistry optimization by
allowing the rapid screening of vast chemical libraries against desired target molecules.
Significant progress has been made to relieve the burden of this time-consuming process
during radiolabeling. Recent efforts have focused on improving radiolabeling efficiency
either by varying the [18F]fluoride elution method or by modulating the [18F]fluoride drying
process using tetraalkylammonium salts,4 polymeric solid supports,5 modulation of bases,6
ionic liquids,7 and the addition of protic solvents to the reaction medium.8 These efforts have
been moderately effective in either improving the radiochemical yield (RCY) or enhancing
operational convenience; however, some limitations to the application of these methods in
commercial modules for complete automation remain, such as elution from QMA in the
reverse direction or multiple elutions.4–7 Although radiofluorination in aqueous medium has

been used to produce [18F]fluoroarenes from [18F]fluoride ions, there are few systematic
investigations of aliphatic radiofluorination using hydrated [18F]fluoride ions.9 In this regard,
the exclusion of azeotropic drying boasts several advantages over the conventional full-
drying method in terms of time management and the facile automation of PET tracer
production.
Herein, we report a convenient radiolabeling method without the need for azeotropic
drying through direct use of the [18F]fluoride eluent from QMA in a mixed organic solvent
(Fig. 1). This drying-free radiofluorination method can be applied to the production of many
PET tracers, and to complement existing labeling protocols.
Figure 1. Radiofluorination with [18F]fluoride ions in a mixed organic solvent.

The azeotropic removal of water from cyclotron-produced fluoride ions is a key step
in the preparation of many fluorine-18-based radiotracers. The [18F]fluoride ions generated by
cyclotrons are delivered in their fully hydrated states. Therefore, the radiolabeling medium
inevitably contains water, which may reduce the radiolabeling efficiency. Although
uncommon in established radiofluorination procedures, we used a mixed organic solvent
system to minimize the effect of residual water from QMA elution. The eluted fluoride ion
complex was directly mixed with various organic solvents, including N-methyl-2-pyrolidone
(NMP), 1,4-dioxane, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), and N,N-
dimethylacetamide (DMA), for use over a broad temperature range and to improve substrate
solubility. 3-(Naphthalen-2-yloxy)propyl methanesulfonate (1) has been widely used in the
assessment of aliphatic fluorination efficiency with protic solvents.8,10 Therefore, 1 was
selected as a model compound to explore the feasibility of aqueous aliphatic radiofluorination
in mixed organic solvents with an 18F-/K 2.2.2./K2CO3 eluent. To determine the labeling
efficiency in a mixed organic solvent, model compound 1 was radiofluorinated in different
combinations of solvent with [18F]fluoride eluate directly acquired from the QMA cartridge
(Table 1).

Table 1. Screening of labeling efficiency in a mixed organic system for azeotropic drying-free
radiofluorination.a
18F-/ K 2.2.2./K2CO3
mixed organic solvent
O
OMs
O
18F
100 oC, 10 min
18F]1a
1
[
Entry
Solventb
MeCN
RCY (%)c
1
2
20
39
54
76
71
53
51
71
69
50
50
31
56
30% DMSO/MeCN
50% DMSO/MeCN
70% DMSO/MeCN
90% DMSO/MeCN
70% DMF/MeCN
3
4
5
6
7
90% DMF/MeCN
8
70% DMA/MeCN
90% DMA/MeCN
70% NMP/MeCN
9
10
11
12
13
90% NMP/MeCN
70% 1,4-Dioxane/MeCN
90% 1,4-Dioxane/MeCN
a
Reaction conditions: [18F]Fluoride eluate (200 μL of an eluate from the K 2.2.2./K2CO3 eluent11 (1000 μL)),
precursor 1 (2 mg), 100 oC, 10 min.
b Total reaction volume (2 mL) including the [18F]fluoride eluate (200 μL).
c Determined by radio-TLC (average of two runs).
Radiofluorination was initially performed in a DMSO/MeCN solvent system without
the azeotropic removal of trace water. Note that a [18F]fluoride eluate acquired under these
conditions will inevitably contain a certain amount of water (ca. 20 μL water per 1,000 μL
eluent) from the K 2.2.2./K2CO3 eluent and residual water (ca. 84 μL) from the QMA
cartridge. One fifth of the eluate was used for each reaction in Table 1, so the amount of
water in the reaction medium was as much as 20 μL. Interestingly, aliphatic radiofluorination
proceeded in a 30% DMSO/MeCN solvent mixture at 100 °C for 10 minutes, providing the

radiofluorinated naphthyl compound [18F]1a in a RCY of 39%. Further variations in the
DMSO volume (30–90% DMSO volume content in the DMSO/MeCN combination)
provided RCYs of 76% and 71% in 70% DMSO and 90% DMSO, respectively. Further
screening in different organic solvents (DMF, DMA, 1,4-dioxane, and NMP) resulted in
moderate to good RCYs ranging from 31% to 71%. In general, reactions performed in the
mixed organic solvents showed higher RCYs than those performed only in MeCN (RCY
20%). From the solvent screening results, 70% DMA/MeCN and 70% DMSO/MeCN
mixtures were chosen as ideal organic solvent systems for radiofluorination.
Next, we investigated the [18F]fluoride elution efficiency associated with the volume
of phase transfer agent (PTA) solution from QMA (see ESI for details). As the total volume
(2 mL) of the reaction solvent can be determined mainly by the portion of eluate volume from
PTA containing the 18F-/K 2.2.2./K2CO3 complex, the optimized volume required to elute the
18F-/K 2.2.2./K2CO3 complex in MeCN/H2O was a key factor in this radiofluorination method.
It is also necessary to use a limited volume of solvent when PET tracers are intended for
18
production on a commercialized module. Due to the inherent water content in the F-/K
2.2.2./K2CO3 eluent, unnecessarily large volumes of PTA should be avoided to minimize the
water content in the reaction medium. Careful measurements revealed that the elution
efficiency of the QMA cartridge with K 2.2.2./K2CO3 in 600 μL of water-MeCN solvent (12
18
μL of water plus 588 μL of MeCN) was 86% F-/K 2.2.2./K2CO3 complex (n = 2), which
was still useful for radiofluorination. The optimal elution efficiency from the QMA cartridge
was not considered in the determination of radiofluorination RCYs.
After establishing the solvent system, other reaction parameters, such as reaction
time and temperature, were explored to optimize the fluorination conditions (Table 2).
Although longer reaction times would provide higher RCYs for some isotope labeling,

reaction times longer than 20 minutes were not considered in the development of our rapid
fluorine-18 radiochemistry model. In addition, temperatures above 150 °C were not
considered to avoid the complications associated with the potential precursor degradation and
side reactions that often occur at elevated temperatures. A total of 600 μL of K 2.2.2./K2CO3
eluent was used for each reaction in Table 2. Consequently, the amount of water in the
reaction medium was ca. 96 μL (volume of water [ca. 12 μL] from the K 2.2.2./K2CO3 eluent
and residual water [ca. 84 μL] from the QMA cartridge). With a higher water content, the
RCYs obtained under otherwise identical reaction conditions were lower (Table 2, entry 1 vs.
Table 1, entry 4 and 8). From radiofluorination in a mixed organic solvent, [18F]1a was
obtained in RCYs of 73% and 76% at 140 °C in 70% DMA/MeCN and 70% DMSO/MeCN,
respectively. These values were comparable to the previously reported RCYs with use of
azeotropically dried [18F]fluoride ions for radiofluorination.7 Furthermore, it was
demonstrated that trace amounts of additional water (0.5–10 volume %) in a mixed organic
system can be tolerated when the reaction is run using the optimal conditions for
radiofluorination (140 °C, 10 min, and 70% DMSO [or DMA]/MeCN) (see ESI for details).
Table 2. Optimization of radiofluorination conditions in DMA/MeCN and DMSO/MeCN mixed systems.a
18F-/K 2.2.2./K2CO3
solvent
O
OMs
O
18F
temp., time
18F]1a
1
[
Solvent (2 mL)
70% DMA/MeCNb
70% DMSO/MeCNb
Temp.
(oC)
Time
(min)
Entry
RCY (%)c
RCY (%)c
1
2
3
4
100
100
120
120
10
20
10
20
19
25
61
64
24
35
55
60

5
6
140
140
10
20
73
72
76
72
a Reaction conditions: [18F]Fluoride eluate from the K 2.2.2./K2CO3 eluent12 (600 μL), precursor 1 (2 mg).
b Total reaction volume (2 mL) including the [18F]fluoride eluate (600 μL).
c RCY was determined by radio-TLC (average of two runs).
Based on these preliminary results, the general applicability of the method was
evaluated with a broader substrate scope (Fig. 2). These labeling precursors were designed to
reflect the structural resemblance often encountered in chemical structures of precursors for
aliphatic radiofluorination (see ESI for details). Using the optimal conditions for [18F]1a,
additional radiofluorination reactions were examined with compounds 2, 3, 4, and 5 to
determine the labeling outcomes (Table 3).
N
N
N
N
N
N
R
R
R = OTs, 2
=
R = OMs, 3
18F, [18F]2a
18F, [18F]2a
=
R
N
N
N
O
R
O
O
R = OTs, 4
18F, [18F]4a
R = OTs, 5
18F, [18F]5a
=
=
Figure 2. Precursors used to evaluate azeotropic drying-free aliphatic radiofluorination.
Compounds 2 and 3, which have an aliphatic fluorination site with tosylate and
mesylate leaving groups, were used as substrates. RCYs of 5–8% and 28–30% were obtained
when compound 2 was radiofluorinated in 70% DMSO/MeCN and 70% DMA/MeCN,

respectively. [18F]2a was obtained from 2 with reduced RCY over the temperature range of
120–140 °C in the DMSO mixed system. We later found that the low RCY of [18F]2a could
be ascribed to the instability of 2 in 70% DMSO/MeCN, as verified by HPLC (UV, 254 nm;
data not shown). An alkyl mesylate attached to the triazole ring (3) gave higher RCYs than
the tosylate leaving group. With an alkyl tosylate directly attached to the benzotriazole
nitrogen
heteroatom
(4),
aliphatic
radiofluorination
occurred
to
afford
[18F]fluorobenzotriazole ([18F]4a) in RCYs of 23–32% in the DMSO mixed system and 46–
52% in the DMA mixed system. Compound 5, which has a tetrahydropyranyl (-THP)
protecting group and an alkyl tosylate connected via a glycolic linkage to a naphthalenyl ring,
was selected to assess the applicability of the two-step radiofluorination method. This
chemical structure, which can be found in PET radiotracers such as the tau PET imaging
[18F]THK5351 tracer13 and hypoxia imaging [18F]FMISO PET tracer,14 can be used to
demonstrate the feasibility of the established two-step reaction, including radiofluorination
and deprotection, to afford the [18F]fluorohydrin structure on the PET tracer.
Radiofluorinated [18F]5a was obtained in a RCY of 28% from the reaction in 70%
DMA/MeCN before deprotection. The identity of the protected [18F]5a was confirmed by
comparison with a nonradioactive standard using radio-HPLC.
Table 3. Azeotropic drying-free aliphatic radiofluorination of various substrates in mixed organic solvent.a
[18F]Fluorinated products, RCY (%)c
Temp.
(oC)
Time
(min)
Entry
Solventb
[18F]2a_1d [18F]2a_2e
[18F]4a
[18F]5a
1
2
3
4
5
6
120
120
120
120
140
140
10
10
20
20
10
10
70% DMSO/MeCN
70% DMA/MeCN
70% DMSO/MeCN
70% DMA/MeCN
70% DMSO/MeCN
70% DMA/MeCN
5
28
8
16
38
18
38
20
39
23
16
46
12
32
25
27
5
52
18
26
23
30
49
28
a Reaction conditions: [18F]Fluoride eluate from the K 2.2.2./K2CO3 eluent12 (600 μL), precursor (2 mg).

b Total reaction volume (2 mL) including the [18F]fluoride eluate (600 μL).
c RCY was determined by radio-TLC (average of two runs).
d [18F]2a_1 was produced from compound 2.
e [18F]2a_2 was produced from compound 3.
After establishing the relevance of this method for aliphatic PET radiotracer
production, the method was extended to demonstrate its usefulness in the established
production of clinical PET radiotracers such as [18F]-(E)-PSS232, [18F]FMISO, and
[18F]fallypride (Table 4).

Table 4. Application of azeotropic drying-free radiofluorination to clinical PET tracers.a
70% Organic mixed Solventb
Precursor
amount (mg)
Temp.
(oC)
Time
(min)
DMSO
DMA
Precursor
RCY (%)c
RCY (%)c
120
120
140
140
120
120
140
140
120
120
140
140
10
20
10
10
10
20
10
10
10
20
10
10
13
15
22
36
9
12
16
19
-
1.0
2.0
1.0
2.5
1.0
Mesyl-
PSS232
12
20
22
46
15
16
17
45
46d
25e
12
15
-
Tosyl-
FMISO
16
15
17
-
Tosyl-
Fallypride
2.7
3.0
-
140
10
-
a [18F]Fluoride eluate from the K 2.2.2./K2CO3 eluent12 (600 μL) was utilized.
b Total reaction volume (2 mL) including the [18F]fluoride eluate (600 μL).
c RCY was determined by reverse phase radio-HPLC (average of two runs).
d Reaction was performed with a GE TRACERlab™ FXFN Pro (average of two runs).
e Reaction was performed with a GE TRACERlab™ FXFN (average of two runs) and purified by prep HPLC.
[18F]-(E)-PSS232, a recently developed mGlu5 radiotracer,15 was initially
investigated in a mixed organic solvent system. The mesylate precursor was radiolabeled and
[18F]-(E)-PSS232 was obtained in 22% RCY in 70% DMSO/MeCN. The reaction
temperature used here was higher than the reported method, but neither precursor degradation
nor thermal (E),(Z)-isomerization was observed. Surprisingly, increasing the amount of

precursor from 1 to 2 mg provided a higher RCY comparable to the RCY of [18F]-(E)-
PSS232 obtained in the conventional drying method.16 When the tosyl-precursor of
[18F]FMISO was radiolabeled with [18F]fluoride containing trace amounts of water,
[18F]FMISO RCYs of 12–22% were obtained in 70% DMA/MeCN solvent before the
deprotection step. The RCY was also significantly improved to 46% when the amount of
precursor was increased from 1 to 2.5 mg. In this experiment, deprotection of the -THP group
was intentionally omitted only to assess the labeling efficiency in a mixed solvent medium.
Careful examination of the UV trace for the reaction revealed no by-product formation
caused by the presence of water and the higher reaction temperature compared to the reported
method.14 [18F]Fallypride, used as a D2/D3 receptor imaging PET radiotracer,17 was selected
to demonstrate aliphatic radiofluorination in a mixed organic system. The one-step
radiofluorination of the tosyl-fallypride precursor provided a RCY of 45% in 70%
DMA/MeCN. Finally, we validated the adaptability of this method by its implementation in
commercial radiosynthesizers for the automated production of clinical PET radiotracers.
[18F]Fallypride was chosen as a viable clinical PET radiotracer and radiosynthesis was
performed using a GE TRACERlab™ FXFN Pro and a GE TRACERlab™ FXFN (GE
Healthcare, Madison, WI, USA), which are widely distributed commercial instruments at
clinical sites (see ESI for details). Cyclotron-produced [18F]fluoride ions were trapped on a
QMA cartridge and released into a reaction vessel with an eluent containing K 2.2.2./K2CO3
in MeCN/H2O (600 μL). The tosyl-fallypride precursor dissolved in DMA (1.4 mL) was
introduced to the reaction vessel resulting in an overall 2 mL reaction volume with 70%
DMA organic content. The reaction was subsequently performed at 140 °C for 10 minutes
without azeotropic drying. After radiofluorination, an aliquot of the reaction mixture was
taken and diluted with a 40% MeCN/H2O solution to analyze the product by radio-HPLC.
The automated production of [18F]fallypride matched the RCY value (46%, n = 2) of the

manual batch production in a reaction vessel (45%, n = 2). Preparative HPLC isolation of the
resulting [18F]fallypride in a mixed organic solvent validated the use of this method for the
large-scale production of PET radiotracers, albeit with somewhat lower RCY (decay-
corrected, 25%, n = 2). These radiosyntheses with established radiotracers demonstrate that
azeotropic drying-free fluorination can be readily extended to produce PET radiotracers in
mixed organic systems, thereby obviating laborious [18F]fluoride drying. These non-drying
approaches can be used to replace existing radiotracer production, as well as in the
development of PET radiotracers to expedite rapid radiochemistry screening and streamlining
production for preclinical studies.
In conclusion, the operationally simple and practical azeotropic drying-free
radiofluorination method proved viable for the production of PET tracers with aliphatic
fluorination sites. Aliphatic radiofluorination in a mixed organic solvent showed good water
tolerance, providing alternative routes to existing labeling methods. This study demonstrated
that moderate, though useful, RCYs can be achieved regardless of trace water in a mixed
organic solvent. In addition, the mixed organic method enables rapid radiochemistry
optimization for early stage PET radiotracer development, which may be useful for PET
tracer production in preclinical investigations. The scope and results obtained with this
aliphatic radiofluorination methodology can be applied to the streamlined production of
aliphatic PET radiotracers, thus simplifying the overall radiopharmaceutical development
with automation, which is especially important in clinical settings.
Acknowledgements
The financial support for this research was provided by the National Research Foundation of
Korea (NRF), the Ministry of Science, ICT & Future Planning (2015R1D1A1A02061420)

and in part by a faculty research grant of Yonsei University College of Medicine (6-2017-
0101).
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at.
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TOC Figure
Cyclotron-produced
18F- in H218O
- Azeotropic drying-free
- Facile and practical
- Readily automatable
- Broad substrate scope
18F-/K222/K2CO3
18F- in
mixed organic solvents
O
18F
O
O
N
PET radiotracers
H
N
O
O
O2N
N
N
18F
18F
N
N
OH

Highlights
- Azeotropic drying-free radiofluorination in mixed organic solvent.
- Applicability to broad substrate scope for aliphatic radiofluorination.
- Operationally simple and facile automation for preclinical/clinical tracer production.
- Rapid optimization of radiochemistry for newly developed compounds.