HPLC-free: In situ 18F-fluoromethylation of bioactive molecules by azidation and MTBD scavenging

Article abstract of DOI:10.1039/c9cc04901k

Sequential usage of azide and MTBD, which generates pure [¹⁸F]fluoromethyl tosylate and scavenges unreacted desmethyl precursors, provided an efficient HPLC-free strategy for the radiosynthesis of ¹⁸F-fluoromethylated compounds with

Full text of DOI:10.1039/c9cc04901k

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HPLC-free in situ 18F-fluoromethylation of bioactive molecules by
azidation and MTBD scavenging
Yingqing Lu,a,b‡ Ji Young Choi,a,c‡ Sang Eun Kim,a,b,c* Byung Chul Leea,b*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Sequential usage of azide and MTBD, which generates pure radiochemists to overcome the limitations arising due to the
[18F]fluoromethyl tosylate and scavenges unreacted desmethyl short half-life of carbon-11 (t1/2 = 20.3 min) and hence,
precursors, provided an efficient HPLC-free strategy for the expediting the development of new radiopharmaceuticals.
radiosynthesis of 18F-fluoromethylated compounds with high Today, 18F-fluoromethyl bifunctional molecules have been
radiochemical yields and purity. This in situ 18F-fluoromethylation employed on numerous probes.7-12 To reduce the
can serve as a facile and efficient tool for the development of defluorination caused by C–H bond cleavage and hence,
radiopharmaceuticals.
enhance the in vivo stability of probes, some deuterated 18F-
fluoromethyl labelling agents were also developed and
utilised.13-15
Positron emission tomography (PET) is an important nuclear
imaging modality that provides useful preclinical and clinical
information on the in vivo biodistribution of radioligand,
diagnosis of disease, and monitoring of treatment response.1
18F is the most preferred positron emitting radionuclide for PET
imaging because of its ideal physical properties (half-life (t1/2) =
109.7 min).2 There are two major approaches to prepare 18F-
labelled ligands, namely, direct3-5 and indirect approaches.6 In
contrast to the limitations of direct fluorination, which include
complex syntheses of precursors and metal catalysts,3a, 5 the
indirect method offers numerous advantages, such as easily
accessible prosthetic molecules, well-established radio-
labelling procedures, reliable radiochemical yields (RCYs), and
high adaptability to various 18F-labelled probes. In particular,
some radioligands such as [18F]fluorocholine,7 S-
[18F]fluoroalkylated diarylguanidines,8 and most of the 18F-
labelled proteins and peptides can only be obtained via the
indirect approach. Among the various prosthetic groups for
radiofluorination, 18F-fluoromethylation induces the least
structural modification in parent bioactive molecules, thereby
minimising the influence on the chemical and biological
properties of the radioligands. In addition, 18F-fluoromethyl
group is a credible alternative to 11C-methyl group, allowing
[18F]Fluoromethyl bromide is the representative prosthetic
group for 18F-fluoromethylation, but its high volatility (boiling
point = 9 °C) makes it difficult to be used for further alkylation
of bioactive molecules on an automated platform. The relatively
non-volatile [18F]fluoromethyl tosylate ([18F]1a) was introduced
as an alternative, and it exhibited comparable labelling
efficiency.16 However, the excess precursor of 1a,
bis(tosyloxy)methane (2a), inevitably remained in the reaction
mixture. If not separated by HPLC, it led to serious interferences
(low RCYs, by-products, etc.) in the next step involving the 18F-
fluoromethylation of O-desmethyl arenes. Therefore, to obtain
a good yield of the PET tracer, it was necessary to carry out two
HPLC purifications, one for the prosthetic group and one for the
final product, in order to obtain a PET tracer in good yield.
Scheme 1. O-18F-fluoromethylation on bioactive molecules using
a previously reported method (Route A)16 and the method used in
the present work (Route B).
Route A
Volatile intermediate (CH2R18F, R = Br or I)
One or Two HPLC purification
Multi-step reactions
HO
Low yield of methylation due to excess precursors
F-18 labelling
HPLC purification
CH2R18
F
methylation
HPLC purification
CH2R2
R = Br, I, or OTs
a. Department of Nuclear Medicine, Seoul National University College of Medicine,
Seoul National University Bundang Hospital, Seongnam, 13620, Republic of
Korea.
methylation &
MTBD scavenging
O
18F
CH2OTs18
18F]1a
F
F-18 labelling & azidation
CH2OTs2
2a
b. Center for Nanomolecular Imaging and Innovative Drug Development, Advanced
Institutes of Convergence Technology, Suwon, 16229, Republic of Korea
c. Department of Transdisciplinary Studies, Graduate School of Convergence Science
and Technology, Seoul National University, Seoul, 08826, Republic of Korea
E-mail: leebc@snu.ac.kr; kse@snu.ac.kr
[
Route B
Non-volatile intermediate (CH2OTs18F)
No HPLC purification
HO
Bioactive molecules
One-pot reaction
High yield of methylation
†
Electronic Supplementary Information (ESI) available. See DOI: 10.1039/
x0xx00000x
‡ These authors contributed equally to this work
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DOI: 10.1039/C9CC04901K
Figure 1. (A) 1H NMR spectra of (top to bottom) DMF-d7 solvent only, reaction mixture of 1a and 2a during azidation at 0 min, 5
min, 10 min, and 15 min. Signals 1–3 are from 1a, and signals 4–6 are from 2a. The reaction was performed with equimolar amounts
of 1a and 2a in the presence of NaN3 at 65 °C. (B) HPLC profiles of the mixture of 1a and 2a during the azidation at 0, 5, 10, and 15
min. Identification of system peak (a, TR = 4.0 min), peak for 1a (b, TR = 6.1 min), and peak for 2a (c, TR = 8.1 min).
However, the two consecutive HPLC purifications complicate
the routine automation (Route A, Scheme 1).
Banert’s experiment using alkyl halides17-18 and can be
attributed to the much faster second displacement on the
monomer intermediate than the first tosylate displacement.
To our surprise, 1a maintained excellent stability under the
reaction conditions of 1H NMR up to 15 min. Quantitative HPLC
measurement was employed to obtain the calibration curve
from known amounts of 1a and 2a (Figure 1B). The amounts of
1a and 2a remaining at a particular time point were calculated.
At 5 min, the reaction mixture contained at least 94.2% 1a,
showing its excellent stability and outstanding tolerance
towards attack by the azide. Even after 40 min and 90 min, the
reaction mixture contained more than 90.5% and 81% 1a,
respectively. In contrast, over 96.1% 2a was converted into 3a
within 10 min, while more than 99.9% 2a was converted in 40
min (SF 1B).
In this work, we demonstrate the in situ azidation using an
azide reagent to remove excess 2a; the azide reagent, however,
does not attack the 18F-labelled prosthetic group, [18F]1a.
Although the azidation of alkyl tosylates is well known,
sensitivity and selectivity of azides towards mono- and di-
tosylates are still not investigated. The selective azidation of
the ditosylate precursor allows quantitative methylation with
[18F]1a. The [18F]fluoromethylated bioactive compound is
generated by the complete scavenging of the excess
desmethyl
precursors
with
7-methyl-1,5,7-
triazabicyclo(4.4.0)dec-5-ene (MTBD) (Route B in Scheme 1).
Notably, the 18F-labelled bioactive molecule is obtained
without any HPLC purification.
Figure 1A shows the azidation in equimolar amounts (4.9
mol) of 1a and 2a in N,N-dimethylformamide-d7 (DMF-d7, 0.3
mL) with NaN3. Equimolar mixture of mono- and di-tosylates
(1a and 2a) was heated at 65 °C in the presence of NaN3 (12.3
mol). The progress of the reaction at 0, 5, 10, and 15 min was
monitored by 1H NMR and HPLC. In the 1H NMR spectra, signals
from benzene (signals 1–2 for 1a, signals 4–5 for 2a) and
Table 1 Azidation at 65 °C for 10 min using various azide reagentsa
O
S
O
S
O
S
OCH2F
OCH2OTs
OCH2F
azide, solvent
time, temp.
O
O
N3CH2N3
3a
O
H3C
H3C
H3C
1a
2a
1a
Azide
source
Entry
Solvent
Conversion of 2a (%)b
Stability of 1a (%)c
1
2
3
4
NaN3
LiN3
KN3
KN3
KN3
DMF
DMF
DMF
DMA
DMA
96.1 ± 2.4
91.0 ± 3.8
>99.5
>99.5 (>99.5)d
>99.5
91.9 ± 1.7
94.7 ± 1.2
methyl groups (signals 3, 6, and
7 for 1a, 2a, and
91.0 ± 4.5
diazidomethane (3a), respectively) allow the identification of
different compounds. It is evident from the 13C NMR spectra
(Supplementary Figure (SF) 2) that the chemical shift of CH2 in
2a was 87.8 ppm while the same in 1a was observed at a higher
field (98.0 ppm). This suggests that the electron density on the
methyl group was relatively higher in 1a compared with that
in 2a. Therefore, in the competitive azidation between 1a and
2a, an azide anion is expected to attack the more electron-
deficient carbon in 2a. From the early stages of the reaction,
2a was rapidly consumed by the azide, and an equivalent
amount of 3a (signal 7) was produced in 5 min, as evident from
the 1H NMR spectra (Figure 1A). The chemical shift of CH2 (6.04
ppm, signal 6) in 2a changed to 4.94 ppm in 15 min. Besides,
the monomer substituted intermediate, azidomethyl tosylate,
could not be observed by NMR spectroscopy. This
phenomenon is similar to that observed in Hassner’s and
94.2 ± 3.9 (94.6 ± 2.8)d
5e
6
62.0 ± 3.9
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
nBu4NN3
DMF
DMA
DMA
DMSO
CH3CN
CH3CN
THF
Benzene
1,4-dioxane
t-BuOH
98.6 ± 1.3
98.9 ± 0.9
>99.5
93.6 ± 0.9
93.4 ± 2.0
94.0 ± 4.2
89.9 ± 3.3
7
8f
9
91.0 ± 2.1
10
11g
12
13
14
15
16
84.2 ± 4.5 (86.0 ± 3.6)d 98.6 ± 1.3 (98.8 ± 1.6)d
>99.5
>99.5
>99.5
93.1 ± 3.2
43.2 ± 5.6
53.9 ± 2.0
96.3 ± 3.1
86.2 ± 1.7
87.6 ± 2.0
98.1 ± 1.6
97.1 ± 2.3
90.1 ± 1.2
MeOH
aThe reaction (n > 3) was carried out with 2.5 equiv. of azides (12.3
mol) relative to the reactants (4.9 mol, 1a and 2a) in 0.3 mL of
solvents (DMF, DMA (N,N-dimethylacetamide), DMSO (dimethyl
b
sulfoxide), THF (tetrahydrofuran), or CH3CN (acetonitrile).
%
Conversion is calculated as the difference between the initial amount of
2 | Chemcomm., 2012, 00, 1-3
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2a added to the reaction and the amount of 2a remaining in the reaction
mixture after 10 min, as determined by HPLC. cAmount of 1a remaining
after azidation was calculated from HPLC using the calibration curve of
1a. dResults of deuterated compounds (1b and 2b). eReaction was
conducted at 100 °C for 5 min. fAzide (24.5 mol). gAzide (73.5 mol) at
80 °C for 5 min.
conditions, as confirmed by TLC (SF 4B) and HPLC (SF 9-11).
Also, to confirm the levels of azide impurities, the reaction
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DOI: 10.1039/C9CC04901K
mixture and the eluent from the cartridge were examined by
1H NMR spectroscopy and an ion chromatography (SF 12 and
S Table 1). These analyses showed only trace amounts of
nBu4NN3 in the final product solution (16 g and 1.1 g,
respectively) which are below the reported rodent median
lethal dose (LD50 = 27 mg/kg for rats).
Next, the influences of different azide reagents, solvents,
and reaction temperatures were explored to maximise the
elimination of 2a and minimise the loss of 1a (Table 1). We
performed the azidation at 65 °C for 10 min using different
azide reagents (12.3 mol) in an equimolar mixture (4.9 mol)
of 1a and 2a in DMF (0.3 mL). KN3 resulted in the highest yield
of 3a in DMF (Entries 1–3 and 6), though it also slightly affected
the stability of 1a. The loss of 1a was recovered by changing
the solvent to DMA or using the deuterated analogue 1b (Entry
4). Reaction with two-fold equivalents of azides also did not
result in any significant loss of 1a (Entry 8). However, 1a
underwent decomposition at high temperature (Entry 5).
Although nBu4NN3 is significantly more soluble in organic
solvents compared with other azides, the complete conversion
of 2a into 3a could not be achieved (Entry 9–10).
To our delight, this limitation could be overcome by a six-
fold increase in the concentration of nBu4NN3 (Entry 11). In
non-polar solvents such as benzene and 1,4-dioxane, nBu3NN3
had a remarkable reactivity (Entries 13 and 14) with 2a.
However, the stability of 1a in benzene was reduced by more
than 10%, as compared with that in polar aprotic solvents.
Interestingly, in polar protic solvents such as t-butanol and
methanol, thetendency for azidation was weak (Entries 15 and
16). Although 1a was very stable in these solvents, merely half
of 2a participated in the azide substitution.
Molar activities (AM) of [18F]1 and [18F]2 by starting with 18
F
(222 MBq) after azidation were 96.5 and 85.4 GBq/mol,
respectively, while those without azidation were 96.8 and 85.8
GBq/mol, respectively. Similar values under the two
conditions indicated that the reaction with azide did not affect
their molar activities.
Table 2 Radiofluorination and azidation of 2a-ba
1) K2.2.2/K18F, CH3CN/H2O
120 oC, 10 min
O
S
O
S
OCX218F
OCH2OTs
O
O
H3C
H3C
2) nBu4NN3
80 oC, 5 min
2a-b
[
18F]1a-b (X = H or D)
Results
RCY (%)b
77.0 ± 6.4 (78.9 ± 4.2)c
1.3 ± 0.3 mol (1.4 ± 0.3 mol)c
99.4 ± 0.5 (99.6 ± 0.3)b
Not detectede
Unreacted 2a-b
Stability of [18F]1a-b (%)d
Unreacted 2a-b after azidation (%)
aThe synthetic details describe in ref. 19. bThe [18F]1a (or [18F]1b)
fraction was measured by gamma counter, and the radiochemical yield
(RCY, decay corrected) was calculated. HPLC condition describes in
Supporting Information (Experimental Section). cFor deuterated
[18F]fluoromethyl tosylate ([18F]1b). dStability of [18F]1a-b was
measured by comparing of radio-TLC yields between before and after
azidation (SF 3, n = 5). eSee SF 9.
Scheme 2 Synthesis of 18F-fluoromethyl compounds using the
With the optimal conditions in hand (Entry 11), we
proceeded for the radiolabelling reaction. [18F]Fluoromethyl
tosylate analogues ([18F]1a-b) were prepared from
bis(tosyloxy)methane analogues (2a-b) via nucleophilic
aliphatic substitution (Table 2). The isolated RCYs were 77.0 ±
6.4% for [18F]1a and 78.9 ± 4.2% for [18F]1b (decay corrected)
based on the HPLC analysis. Besides, a by-product, tosyl
[18F]fluoride, was formed with 1a during fluorination,16a and
the ratio of [18F]1a to tosyl [18F]fluoride was 72:28 (SF 9).
Before azidation, the amount of the remaining 2a and 2b were
calculated to be 1.3 ± 0.3 and 1.4 ± 0.3 µmol, respectively.
During azidation, nBu4NN3 (84.4 µmol) was added to convert
2a-b to 3a-b in 5 min, and no precursors (2a-b) were detected
in the chromatogram. The radio-TLC analysis indicated that
[18F]1a-b was highly stable with 99% [18F]1a-b remaining in the
mixture after azidation. This was in agreement with the results
in Table 1 (Entry 11) and indicated that the optimal condition
for non-radioactive reactions could be adapted for
radiolabelling reactions. Remarkably, tosyl [18F]fluoride was
reduced after azidation. This could be because of the
substitution of fluoride with azide via a SN2 reaction. The
measurement of radio-TLC (SF 3) showed that the amount of
free 18F increased while that of tosyl [18F]fluoride decreased
after azidation, thus verifying our assumption. Moreover, in
the further O- or N-alkylation reaction, the remaining tosyl
[18F]fluoride continued to decompose completely under basic
current method.
CX2OTs2
Route B
18
2a
2b
1a
1b
X = H:
= D:
or [ F]
2a 2b
or
(
)
18
or [ F]
Y = O or N
18F-labeling & azidation
Y
Methylation & MTBD scavenger
CX2OTs18
F
18F
([18F] or [ F]
18
i) Desmethyl precursor, Cs2CO3,
18-crown-6, CH3CN, 120 oC, 10 min
ii) MTBD, CH3CN, 25 oC, 5 min
1a
1b
)
O
N
O
N
O
18F
O
18F
[
18F]4, 72.0% (AM = 10.6 GBq/umol)
[
18F]Fluoromethyl-PBR28, 56.2%
(AM = 14.4 GBq/umol)
18F
O
NHBoc
OtBu
X
18F
N
OH
O
[
[
18F]6a, 60.6% (X = CH2, AM = 38.6 GBq/umol)
18F]6b, 61.8% (X = CD2)
[
18F]Fluorocholine, 63.2%
With the optimised 18F-labelling and methylation protocols
in hand, the in situ O-18F-fluoromethylation of 4-phenylphenol
was achieved at a RCY of 72.0% (Scheme 2). Due to the
absence of 2a, as confirmed by HPLC, a much purer [18F]1 (in
Route B) allowed the quantitative O-alkylation of [18F]1 to give
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[18F]4. However, using the conventional method (Route A), the
RCY of [18F]4 dramatically dropped to 27.8% (decay corrected)
in the presence of a relatively large amount of 2a (SF 4A).
Additionally, synthesis via Route A required HPLC purification
to obtain [18F]4, while Route B enabled the isolation of [18F]4
using a C-18 Sep-Pak cartridge. For some reported radioligands,
e.g., [18F]fluoromethy-PBR28, protected [18F]fluoromethyl-
tyrosine, and [18F]fluorocholine, we passed the mixture after
azidation through Accell CM cartridge, to remove the
unreacted azide ions. Scheme 2 shows the highly pure [18F]1a-
b obtained after azidation, which has an excellent reactivity
towards the bioactive precursors (desmethyl PBR28 and
desmethyl protected tyrosine (5)). It forms the desired
products in good RCYs (56.2–72.0%). After 18F-labelling, the
reaction mixture was treated with MTBD to capture the
unreacted desmethyl precursor via forming an ion salt (SF 5).19
HPLC was used to monitor the reaction progress, and less than
1.8% precursor (5) of protected [18F]fluoromethyl-tyrosine
([18F]6a) remained after 3 min of the reaction. Complete
capture of 5 was confirmed by HPLC after treating them with
MTBD for 5 min (SF 10). The obtained mixture could be simply
separated by passing it through silica and light C18 cartridges
to give pure [18F]fluoromethy-PBR28 or [18F]6a, without the
assistance of HPLC (SF 6, 7 and 10). This is because MTBD,
precursor-MTBD ion salt, and 3a were totally captured by silica
cartridges. In case of [18F]fluorocholine, the precursor was
isolated by employing the Accell CM plus short cartridge
instead of MTBD.
In conclusion, we demonstrated for the first time a highly
selective, one-pot azidation reaction that occurs on
bis(tosyloxy)methane analogues (2a-b) but not on
fluoromethyl tosylate analogues (1a-b). Taking advantage of
the selective azidation, pure [18F]1 could be obtained without
the aid of HPLC. The in situ 18F-fluoromethylation of bioactive
molecules with [18F]1 promises to provide better RCYs and
purities for 18F probes. Moreover, MTBD, a scavenger for
phenol moieties, can capture unreacted precursors, allowing
an HPLC-free purification to give the final product. This new
protocol suggests that [18F]1 can be extensively utilised for the
development of 18F-labelled radiopharmaceuticals as well as
for the automated synthesis of 18F probes.
591-607. (c) P. M. Matthews, E. A. Rabiner, J. Passchier and R.
View Article Online
N. Gunn, Br. J. Clin. Pharmacol., 2012, 73, 175.
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This work was supported by the National Research
Foundation of Korea grant (NRF-2017R1A2A2A05001433,
NRF-2018M2A2B3A02071842) and the Korean Health
Technology R&D Project through the Korean Health Industry
Development Instituted (KHIDI), funded by the Ministry of
Health & Welfare, Republic Korea (No. HI16C0947).
18 K. Banert, Y. H. Joo, T. Rüffer, B. Walfort and H. Lang,
Tetrahedron Lett., 2010, 51, 2880-2882.
19 To a reaction vial containing K2.2.2/K18F (45 MBq), 2a or 2b (2 mg,
5.6 µmol), H2O (20 µL), and CH3CN (0.75 mL) were added and
then heated at 120 °C for 10 min. The reaction mixture was
treated with nBu4NN3 (24 mg, 84.4 µmol) at 80 °C for 5 min and
then was penetrated into Accell CM plus short cartridge to
provide [18F]1a. In the presence of Cs2CO3 (3 equiv.) and 18-
crown-6 (4 equiv.), the reaction mixture including [18F]1a was
o
reacted with the desmetyl precursor (1 mg, 1 equiv.) at 120 C
Conflicts of interest
The authors declare no conflict of interest.
for 10 min. After cooling the reaction vial, MTBD (20 µL) was
treated and the mixture was stirred at 25 oC for 5 min. The
reaction mixture was consecutively passed through silica and
C18 Sep-Pak cartridges to provide the product.
Notes and references
1
(a) D. Papathanassiou, C. Bruna-Muraille, J.-C. Liehn, T. D.
Nguyen and H. Cure´, Crit. Rev. Oncology. Hematology., 2009,
72, 239-254. (b) J. K. Willmann, N. Van Bruggen, L. M.
Dinkelborg and S. S. Gambhir, Nat. Rev. Drug Discov., 2008, 7,
4 | Chemcomm., 2012, 00, 1-3
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