One-Step Synthesis of [18F]Fluoro-4-(vinylsulfonyl)benzene: A Thiol Reactive Synthon for Selective Radiofluorination of Peptides

Article abstract of DOI:10.1021/acs.orglett.0c04054

Radiolabeled peptide-based molecular imaging probes exploit the advantages of large biologics and small molecules, providing both exquisite selectivity and favorable pharmacokinetic properties. Here, we report an operationally simple and broadly applicable approach for the 18F-fluorination of unprotected peptides via a new radiosynthon, [18F]fluoro-4-(vinylsulfonyl)benzene. This reagent demonstrates excellent chemoselectivity at the cysteine residue and rapid 18F-labeling of a diverse scope of peptides to generate stable thioether constructs.

Full text of DOI:10.1021/acs.orglett.0c04054

pubs.acs.org/OrgLett
Letter
One-Step Synthesis of [18F]Fluoro-4-(vinylsulfonyl)benzene: A Thiol
Reactive Synthon for Selective Radiofluorination of Peptides
Gaoyuan Ma,§ James W. McDaniel,§ and Jennifer M. Murphy*
Cite This: Org. Lett. 2021, 23, 530−534
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ABSTRACT: Radiolabeled peptide-based molecular imaging
probes exploit the advantages of large biologics and small
molecules, providing both exquisite selectivity and favorable
pharmacokinetic properties. Here, we report an operationally
simple and broadly applicable approach for the 18F-fluorination of
unprotected peptides via a new radiosynthon, [18F]fluoro-4-
(vinylsulfonyl)benzene. This reagent demonstrates excellent chemoselectivity at the cysteine residue and rapid 18F-labeling of a
diverse scope of peptides to generate stable thioether constructs.
adiolabeled peptides are important positron emission
tomography (PET) imaging tools due to their selectivity
R
toward overexpressed cell surface receptors of many cancers,
which can be exploited for targeting purposes.1−5 Critical to
the continued development of valuable PET probes is the
availability of chemical methods to access diverse radiolabeled
peptides. Remarkable breakthroughs in 18F-chemistry to afford
18F-labeled peptides with minimal perturbation have unveiled
direct synthetic paths toward previously inaccessible radio-
labeled peptides.6−10 Despite recent advances in site-specific
radiofluorination, 18F-labeling of peptides is most frequently
conducted via conjugation with prosthetic groups.11−16
Selective bioconjugation reactions for 18F-labeling of
peptides have largely focused around modification of lysine
and cysteine side chains.17,18 Site-selective conjugation via
thiol-based chemistry is more desirable when compared to
unselective modification of lysine residues, which can produce
poorly defined, heterogeneous mixtures of labeled prod-
ucts.19,20 A powerful tool for site-specific bioconjugation to
cysteine and perhaps the most utilized prosthetic group for
selective 18F-labeling of peptides is the maleimide-based
synthon.15,21−25 Maleimide-based prosthetic groups (Figure
1A) have garnered persistent popularity due to their fast
kinetics and remarkable cysteine chemoselectivity; however,
significant limitations exist, the most notable being suscepti-
bility of the succinimidyl thioether linkage to hydrolysis via a
retro-Michael reaction.18,26−28 Furthermore, bioconjugation
with maleimide-based prosthetic groups creates stereoisomeric
mixtures of exo- and endo-isomers.29 In addition, many of these
synthons involve three-step syntheses, are obtained in <20%
radiochemical yield (RCY), and expend 95−115 min to obtain
the HPLC-purified prosthetic group.22−24
Figure 1. Thiol-reactive radiosynthons for 18F-labeling of cysteine-
containing peptides.
purification, resulting in a lengthy production process.30−32
Reported in 2014, [18F]-(2-(2-(2-fluoroethoxy)ethoxy)-
ethylsulfonyl)-ethane ([18F]F-DEG-VS) was utilized to label
a neurotensin analogue in moderate yield and maintained in
vivo stability with no [18F]fluoride release.33 More recently,
prosthetic groups based on heteroaromatic derivatives provide
an alternative class of thiol-reactive synthons with improved
stability over maleimides (Figures 1D,E).34−37 In addition, a
new reagent for 18F-trifluoromethylation has demonstrated
Received: December 7, 2020
Published: December 29, 2020
Several other radiosynthons have been reported for site-
selective cysteine conjugation via thiol alkylation (Figure 1).
Despite moderate success, bromoacetamides require three step
syntheses, azeotropic drying of [18F]fluoride and HPLC
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© 2020 American Chemical Society
Org. Lett. 2021, 23, 530−534
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chemoselective 18F-labeling of cysteine-containing peptides,
including a [18F]CF3-amyloid-β fragment (Figure 1F).10
Despite remarkable advancements, preparation of current
thiol-reactive radiosynthons require azeotropic drying of
[18F]fluoride and nearly all protocols involve HPLC
purification prior to cysteine conjugation. In addition,
multistep syntheses or the use of unstable precursors and
reagents pose further challenges, resulting in low yields. A
robust thiol-reactive synthon that produces a selective and
stable linkage while overcoming these limitations offers an
attractive alternative approach for peptide 18F-labeling
applications.
Here, we report the synthesis and development of
[18F]fluoro-4-(vinylsulfonyl)benzene ([18F]FVSB), a new
prosthetic group for site-specific conjugation to cysteine
residues to afford stable 18F-labeled peptides for applications
in PET molecular imaging (Figure 1G). This radiosynthon is
prepared in one step, enabled by the deoxyfluorination of a
highly stable uronium precursor via a tetrahedral intermediate,
and is utilized without azeotropic drying or HPLC purification.
Our objective was to provide a readily accessible thiol-reactive
synthon for the facile construction of stable, site-specific 18F-
labeled peptide conjugates. Critical advantages of a vinyl
sulfone motif for cysteine conjugation include the high
reactivity with free thiols and the formation of aqueous-stable
thioether linkages.18,38−42 Although reports of vinyl sulfone-
functionalized tags toward bioconjugation of peptides and
proteins exist, the versatility of this synthon has not been fully
explored in the context of 18F-labeling.41 We designed a vinyl
sulfonyl phenol substrate and opted to employ the 18F-
deoxyfluorination method reported by Neumann et al.6 This
methodology was chosen due to its robust scope, high
radiochemical conversion, use of a stable and accessible
precursor, as well as the ability to eliminate azeotropic drying.
We anticipated this approach would provide a direct path to a
vinyl sulfonyl 18F-arene in a rapid manner.
The 18F-deoxyfluorination to produce [18F]FVSB 7 began
with direct elution of aqueous [18F]fluoride from the anion-
exchange cartridge, forgoing the azeotropic drying step of
conventional radiofluorination approaches. In this method,
aqueous [18F]fluoride was trapped on the cartridge and
residual water was removed by flushing with 2-butanone/
ethanol (10:1, v/v) and N2 gas through the cartridge. Uronium
complex 6 in a solution of 2-butanone:ethanol was directly
passed through the cartridge, without base or additives, to
elute the [18F]fluoride. The reaction mixture was directly
heated to 130 °C for 30 min and afforded crude [18F]FVSB 7.
Initial optimization focused on the type of anion exchange
cartridge and the uronium 6 precursor amounts. [18F]Fluoride
elution using a Sep-Pak Accell Plus QMA plus light cartridge
was poor, presumably due to excess resin. Improvement in the
elution was observed with a custom-made cartridge using 1/
16′′ PTFE tubing containing 4 mg Biorad MP-1 resin in
between two polyethylene frits. Despite moderate elution,
inconsistency in the custom cartridges led us to identify a more
practical approach that would use a commercial cartridge.
Chromafix 30-PS-HCO3 cartridges were employed which gave
sufficiently high elution efficiency using 5 mg of uronium 6
with 94 2% RCY, determined by radio-TLC (Table 1, entry
a
Table 1. Reaction Optimization to Afford [18F]FVSB
b
c
entry
precursor (mg)
elution efficiency (%)
RCY
d
e
1
2
3
4
3
5
7
9
60
84
84
83
3
3
2
1
88
94
97
96
2
2
1
2
e
Preparation of the precursor, uronium 6, consists of a five-
step synthesis and began with commercial thiophenol 1, which
underwent alkylation with bromoethanol followed by oxidation
with Oxone to afford sulfone 3 (Scheme 1). Treatment with
thionyl chloride and pyridine supplied the chloro intermediate
which subsequently underwent elimination under basic
conditions to furnish vinyl sulfone 4 in 81% yield. Uronium
precursor 6 was obtained upon treatment of phenol 4 with
chloroimidazolium chloride and Ag2CO3 in chloroform and
used after simple filtration with no additional purification.6
d
a
Conditions: precursor, [18F]fluoride (∼500 μCi), 10:1 butanone/
b
EtOH (1 mL), 130 °C, 30 min. Determined by dividing the activity
eluted from the cartridge by the initial activity loaded on the cartridge.
c
RCY was determined by radio-TLC. Product identity was confirmed
d
e
by radio-HPLC. n = 2. n = 5. Ar = 2,6-diisopropylphenyl.
2). While 3 mg of uronium 6 gave poor [18F]fluoride elution,
no improvement in elution efficiency and comparable RCY was
obtained when >5 mg of 6 was used (Table 1, entries 1, 3, and
4).
a
Scheme 1. Preparation of Uronium 6 Precursor
We hypothesized that HPLC purification could be avoided
and that [18F]FVSB may be promptly utilized for peptide
conjugation. We next focused on cartridge purification of
[18F]FVSB and screened various commercial cartridges (Table
S4). Purification by Oasis HLB plus short LP cartridges
resulted in removal of unreacted [18F]fluoride and enabled
isolation of [18F]FVSB within 43 min in 46
4% decay-
corrected RCY with 85% radiochemical purity (RCP) (Tables
S1 and S2, Figures S11 and S12). The molar activity was
calculated for HPLC-purified [18F]FVSB and determined to be
>2.87 Ci·μmol−1 (106.2 GBq·μmol−1). Notably, precursor 6
could be stored at −4 °C for up to 12 months or at room
temperature for up to 6 months and used with no discernible
loss in quality or RCY.
a
Reagents and conditions: (a) 2-bromoethanol, 1.0 N aq NaOH,
MeOH, 23 °C, 21 h; (b) Oxone, MeOH, 23 °C, 2 h; (c) SOCl2,
pyridine, CH2Cl2, 23 °C, 20 h; (d) Et3N, THF, 23 °C, 24 h; (e)
Ag2CO3, 5, CHCl3, 60 °C, 4.5 h.
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Peptides containing the Arg-Gly-Asp (RGD) sequence
display high affinity for integrin αvβ3 and are useful for PET
molecular imaging of angiogenesis.43 As such, we initially
investigated the bioconjugation of cysteine-containing peptides
with [18F]FVSB 7 using the linear tetramer 8, Arg-Gly-Asp-Cys
(RGDC) (Table 2). Conjugate addition of 5 mg of peptide 8
afford octamer 10 as the single radioactive product in 83
10% RCY.44 Of note, competitive reactivity with tryptophan
was not observed by radio-HPLC, verifying the indole ring of
tryptophan is compatible with the labeling protocol (Figure
S20).
Cyclic RGD peptides have also garnered sufficient interest as
PET tracers prompting us to synthesize cyclic RGDfC
analogue 11 which was achieved in 87 2% RCY.45,46 Due
to the recent success in targeting prostate specific membrane
antigen (PSMA) for PET imaging of prostate cancer, we
applied the approach toward radiolabeling of a PSMA analogue
which gave construct 12 in 80 3% RCY.47 Synthesis of an
18F-labeled neuromedin B analogue 13 was accomplished in 93
1% RCY. Additionally, larger peptides, such as the bombesin
analogue 14 containing 14 amino acids was successfully
radiolabeled in 55 11% RCY.48 The presence of unreacted
[18F]FVSB in the HPLC trace for analogue 14 suggests that
cosolvent systems to increase solubility for larger peptides
could remedy the incomplete conversion for specific cases.
To reinforce the compatibility of [18F]FVSB in the presence
of other nucleophilic residues, such as histidine or lysine,
competition studies were conducted (Figures S25−S29).
Competition between N-Boc-cysteine and N-Boc-lysine with
[18F]FVSB yielded, exclusively, the desired cysteine-conjugate
addition product in 85 0% RCY, while the lysine-conjugate
addition product was not observed (Figure S27). Similarly,
competition between N-Boc-cysteine and N-Boc-histidine
afforded the cysteine-conjugate addition product in 88 2%
RCY and the histidine-conjugate addition product in only 1
2% RCY (Figure S29). Importantly, these studies reveal the
overwhelming predominance for bioconjugation to occur at
the cysteine residue, even when histidine or lysine residues are
present. Lastly, reactivity toward N-terminal amines was
evaluated with an RGD peptide lacking a cysteine residue. In
this case, with no available thiol, amine conjugation toward
[18F]FVSB proceeded in only 6% RCY; therefore, the presence
of N-terminal free amines is well tolerated and does not
impede generation of the desired thiol-conjugated product
(Figure S30).
a
Table 2. Bioconjugation Optimization
b
entry precursor (mg)
buffer
additive
RCY (%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
3
1
borate (pH 8.5)
HEPES (pH 7.3)
borate (pH 8.5)
borate (pH 8.5)
borate (pH 8.5)
HEPES (pH 7.3)
borate (pH 8.5)
borate (pH 8.5)
borate (pH 8.5)
65
59
70
47
86
27
90
89
4
4
7
5
7
1
0
c
d
25% MeOH
75% MeOH
50% MeOH
50% MeOH
50% MeOH
6
79 11
a
Conditions: ∼400−700 μCi 7 per reaction, solvent (500 μL).
b
Reactions performed in duplicate. nonisolated RCY is estimated by
c
radio-HPLC analysis of crude peptide 9. Reaction temperature = 23
d
°C. Reaction temperature = 45 °C. Ar = 4-[18F]fluorophenyl.
to [18F]FVSB 7 proceeded in sodium borate (pH 8.5) buffer in
30 min in 65 4% RCY, as determined by radio-HPLC (entry
1). Bioconjugation in HEPES (pH 7.3) buffer afforded peptide
conjugate 9 in 59 4% RCY (entry 2). Optimization of the
reaction temperature revealed that mild temperatures (23−35
°C) gave highest RCYs and heating to 45 °C decreased the
RCY to 47 5% (entries 1, 3, 4 and Table S6).
In many cases, unreacted [18F]FVSB 7 was present after 30
min yet increasing the reaction time is undesirable for PET
applications. We sought to push the thiol conjugation to
completion by exploring a solvent additive, such as DMF or
MeOH, which may enhance peptide solubility (Table S7).
With 25% MeOH, 18F-labeled conjugate 9 was obtained in 86
7% RCY in sodium borate buffer (entry 5). Too much
methanol was detrimental to the reaction (entry 6), yet 50%
MeOH in either buffer afforded 18F-labeled conjugate 9 in 90
0% RCY (entry 7). Comparable RCYs were obtained by
lowering the peptide precursor amount to 3 mg (entry 8 and
Table S5). Lastly, for labeling precious peptides with limited
supply, 1 mg of precursor was sufficient to afford the
radiolabeled peptide conjugate in high RCY (entry 9).
Although DMF could be used, we opted to employ MeOH
because the peptide solubility appeared better in MeOH over
DMF and, due to its lower boiling point, MeOH can be readily
removed by evaporation.
To evaluate the peptide conjugates for stability against
elimination of the vinyl sulfone and loss of the radiolabel,
peptide 9 was incubated for 1 h at 35 °C in various conditions
and the remaining conjugate was calculated by HPLC analysis
(Figures S31−34). In aqueous glutathione or in pH 2.6 acetic
acid buffer, 97% of conjugate 9 and 0% of [18F]FVSB were
observed. In pH 9.5 sodium borate buffer, 82% of conjugate 9
and 5% of [18F]FVSB were observed. These results suggest
that, after 1 h, 5% elimination of the vinyl sulfone occurs under
basic conditions and no observable elimination occurs under
neutral or acidic conditions.
In summary, we report a simple, metal-free approach for 18F-
labeling of cysteine containing peptides via a novel prosthetic
group, [18F]FVSB. To our knowledge this is the first aryl vinyl
sulfone radiosynthon to be reported which can be produced in
43 min in high molar activity and directly used for peptide
conjugation without HPLC purification. The robustness of our
method is highlighted by the diversity of peptide conjugates
that were successfully 18F-labeled in up to 93% RCY. We
contend that the [18F]FVSB radiosynthon we report here will
offer significant improvement over current strategies for
multiple reasons. First, its simplicityour method is a one-
step radiofluorination of a stable precursor that is facile to
synthesize and provides [18F]FVSB in high RCY. Second,
The optimized bioconjugation conditions were applied to a
series of thiol-containing peptides to examine the versatility of
[18F]FVSB toward complex substrates which mimic potential
PET tracers (Figure 2). The unprotected, linear RGDC
peptide 8 readily delivered 18F-construct 9 in 84 8% decay-
corrected RCY with exclusive reactivity at the cysteine residue.
An analogue of the gastrin-releasing peptide receptor (GRPR)
tracer MG11 was successfully conjugated to [18F]FVSB 7 to
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Letter
Figure 2. Site-selective 18F-labeling of peptides via cysteine bioconjugation with [18F]fluoro-4-(vinylsulfonyl)benzene. Reaction conditions: peptide
(3 mg), 7 (0.5−1.5 mCi), sodium borate buffer pH 8.5 (250 μL), MeOH (250 μL), 35 °C, 30 min. Radiochemical purity (RCP) was determined
by radio-HPLC and was calculated by dividing the integrated area of the 18F-labeled product peak by the total integrated area of all 18F-labeled
peaks. Identity of each labeled product was confirmed by coinjection with the authentic 19F-reference standard. The decay-corrected radiochemical
yield (RCY) was calculated by dividing the final activity of the labeled product by starting [18F]FVSB activity, multiplied by the RCP. [a]5 mg
peptide, HEPES buffer pH 7.3 (250 μL), DMF (250 μL).
conjugation to [18F]FVSB yields a highly stable thioether
linkage using 2 μmol peptide. Third, and perhaps most crucial,
our method eliminates the time-consuming azeotropic drying
mization screens, compound characterization, HPLC
traces, and NMR spectra (PDF)
and HPLC purification stepsa noteworthy benefit for
fluorine-18 methodology. Additionally, exclusive reactivity at
the cysteine residue in the presence of other nucleophilic
residues was demonstrated, confirming the high chemo-
selectivity of our approach.
AUTHOR INFORMATION
■
Corresponding Author
Preliminary attempts at automation have been conducted
using the ELIXYS FLEX/CHEM radiochemical synthesis
module (Sofie Biosciences). Starting with 21 mCi of
[18F]fluoride, the automated protocol resulted in an elution
Jennifer M. Murphy − Department of Molecular and Medical
Pharmacology and Crump Institute for Molecular Imaging,
David Geffen School of Medicine, University of California Los
Angeles, Los Angeles, California 90095, United States;
orcid.org/0000-0002-8492-4918; Email: jmmurphy@
mednet.ucla.edu
efficiency of 82
0% and afforded [18F]FVSB in 63
1%
RCY, determined by radio-TLC (n = 2, unoptimized),
demonstrating the process can successfully be automated for
PET applications. High activity production of [18F]FVSB for
protein labeling and PET imaging studies are currently
underway in our laboratory.
Authors
Gaoyuan Ma − Department of Molecular and Medical
Pharmacology and Crump Institute for Molecular Imaging,
David Geffen School of Medicine, University of California Los
Angeles, Los Angeles, California 90095, United States
James W. McDaniel − Department of Chemistry and
Biochemistry, University of California Los Angeles, Los
Angeles, California 90095, United States
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04054.
Materials and methods, chemical syntheses, detailed
experimental procedures, radiochemical protocols, opti-
Complete contact information is available at:
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Letter
Vandlen, R.; Kaur, S.; Sliwkowski, M. X.; Scheller, R. H.; Polakis, P.;
Junutula, J. R. Nat. Biotechnol. 2012, 30, 184−189.
(28) Adumeau, P.; Davydova, M.; Zeglis, B. M. Bioconjugate Chem.
2018, 29, 1364−1372.
Author Contributions
§G.M. and J.W.M. contributed equally to this work.
Notes
(29) Alley, S. C.; Benjamin, D. R.; Jeffrey, S. C.; Okeley, N. M.;
Meyer, D. L.; Sanderson, R. J.; Senter, P. D. Bioconjugate Chem. 2008,
19, 759−765.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(30) Dolle, F.; Hinnen, F.; Vaufrey, F.; Tavitian, B.; Crouzel, C. J.
Labelled Compd. Radiopharm. 1997, 39, 319−330.
This work was supported by the American Cancer Society
(132467-RSG-18-149-01-CCE) and the Crump Institute for
Molecular Imaging. We are grateful for their financial support
for this research. We thank the UCLA Biomedical Cyclotron
for providing [18F]fluoride for these studies.
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