Direct18F-Labeling of Biomolecules via Spontaneous Site-Specific Nucleophilic Substitution by F-on Phosphonate Prostheses

Article abstract of DOI:10.1021/acs.orglett.1c01211

We describe a high radiochemical yield late-stage direct 18F-labeling of bare biomolecules containing common active groups. Spontaneity and site-selectivity are attributed to the remarkably higher rates of nucleophilic substitution reactions on phosphonates than on other electrophiles by F- at various hydrogen bond forms. Rapid access to many medicinally significant 18F-labeled biomolecules is achieved at 21-68% radiochemical yields and 35.9-55.1 GBq μmol-1 molar activities both manually or automatically.

Full text of DOI:10.1021/acs.orglett.1c01211

pubs.acs.org/OrgLett
Letter
18
Direct F‑Labeling of Biomolecules via Spontaneous Site-Specific
Nucleophilic Substitution by F− on Phosphonate Prostheses
Chao Wang, Lei Zhang, Zhaobiao Mou, Wanru Feng, Zhongjing Li, Hongzhang Yang, Xueyuan Chen,
Shengji Lv, and Zijing Li*
Cite This: Org. Lett. 2021, 23, 4261−4266
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ABSTRACT: We describe a high radiochemical yield late-stage direct 18F-labeling of bare biomolecules containing common active
groups. Spontaneity and site-selectivity are attributed to the remarkably higher rates of nucleophilic substitution reactions on
phosphonates than on other electrophiles by F− at various hydrogen bond forms. Rapid access to many medicinally significant 18F-
labeled biomolecules is achieved at 21−68% radiochemical yields and 35.9−55.1 GBq μmol−1 molar activities both manually or
automatically.
wing to favorable chemical properties, nuclide proper-
Scheme 1. (a) Previously Reported Methods Allowing 18F-
Labeling of Biomolecules in One Step. (b) Direct 18F-
Labeling of Biomolecules through a Spontaneous F−
Nucleophilic Substitution Reaction on Phosphonate
Prostheses
O
ties, and worldwide production, 18F (t1/2 = 109.7 min,
97% β+, 0.64 MeV) is the most common positron-emitting
nuclide permitting in vivo visualization and quantification of
labeled molecules through positron emission tomography
(PET).1 Biomolecules such as certain small molecules, amino
acids, vitamins, and peptides are unique markers in growth,
development, immune regulation, and metabolism and thus are
ideal lead compounds for PET probes.2 However, bare
biomolecules usually contain active groups, such as the
amino, hydroxyl, and carboxyl groups, which are unsuitable
for nucleophilic attack by the common 18F source, [18F]F−.3
Thus, the direct 18F-labeling of biomolecules with high
radiochemical yields (RCYs) and molar activities (Am’s) is
challenging.4
Considering the gradually reduced RCYs and Am’s with the
increase in total synthesis time of the two-step or multistep
methods, many direct 18F-labeling methods have been
developed.5 Current direct methods include Al−18F bond
formation based on complex chelation,6 B/Si/P−18F bond
formation based on 18F/19F isotopic exchange7 and C−18F
bond formation (only a few examples) based on nucleophilic
substitution (Scheme 1a).8 However, separation of the desired
18F-labeled products from the precursors is not implemented in
these methods, and the high Am values rely on the high initial
activities of the 18F sources.7a Besides, bulky/hydrophobic
prostheses or specific solvent/pH requirements are sometimes
essential for these reactions, thereby limiting their applica-
tion.7b,c More importantly, there are only a limited number of
Received: April 9, 2021
Published: May 4, 2021
https://doi.org/10.1021/acs.orglett.1c01211
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4261−4266
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Figure 1. Rapid spontaneous site-specific nucleophilic substitution by F− on phosphonate prostheses. (a) Proposed fluorination hydrolysis reaction
pathway. (b) Scope of leaving groups. (c) Kinetic curves reflecting ln [1/(1 − RCY)] during the reaction in CH3CN at different temperatures over
time for determination of reaction rate constants. (d) Arrhenius plots of ln k against 1/T for the determination of activation energy. (e) Rapid
fluorination detected by 31P NMR.
theoretical and experimental studies on the effect of site-
specific labeling/tolerance of the active groups.9 Therefore,
methods for the direct, site-specific, and mild 18F-labeling of
unprotected biomolecules with high RCY and Am are highly
sought after.5
vitamins, and peptides has been examined to explore the
substrate scope of this feasible method.
Fluorination on phosphonate prostheses is achieved in two
steps, including the nucleophilic addition of F− on the
phosphorus atom and elimination of the phenoxide anion
(Figure 1a). The activation energies and rate constants were
predicted by density functional theory (DFT) calculations at
the M06/6-311++G(2d,2p)//B3LYP/6-31+G(d)** level of
theory using the Gaussian 09 program.11 The calculated
activation energy for model compound 1 is 8.4 kcal mol−1 and
the derived rate constant is 3.6 × 106 L mol−1 s−1 (Figure S29),
indicating a very fast process at room temperature (rt).
Intermediate INT-2 undergoes hydrolysis in two steps to
generate PFA. Although the energy barrier of the hydrolysis is
18.6 kcal mol−1, the reaction should be accessible at rt. The
reaction free-energy change (ΔG) is −12 kcal mol−1, implying
that both fluorination and the subsequent hydrolysis are
spontaneous. Formation of difluoride-substituted intermediate
INT-5 is found to be more favorable when F− is in excess
(Figure S30), consistent with the previously proposed reaction
mechanism.12 Considering the trace amount of [18F]F− used in
the present labeling experiments, which was not expected to
generate the difluoride-substituted intermediate, the mecha-
In this study, direct 18F-labeling on phosphonate prostheses
via spontaneous F− nucleophilic substitution (Scheme 1b) has
been comprehensively investigated. The rate constants (k) and
the corresponding activation energies (Ea) of these nucleo-
philic addition−elimination reactions are determined both
theoretically and experimentally. Fluorination efficiency has
been evaluated by comparing the reaction rates between the
phosphonate prostheses and classical fluoride acceptor. F− at
various hydrogen bond forms with typical active groups are
intentionally used as nucleophiles. Site-selectivity for 18F-
labeling has been tested by gradually adding interfering
additives bearing active groups and different proportions of
water. The obvious change in polarity upon the conversion of
phosphonate to phosphonofluoridic acid (PFA) may allow
easy separation of the 18F-labeled products from their
precursors, therefore giving high Am’s.10 The 18F-labeling of
many typical biomolecules such as amino acid mimics,
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Letter
nistic pathway shown in Figure S29 should be both kinetically
and thermodynamically possible.
extremely fast at a higher temperature. The RCYs were
measured by radio-TLC and recorded at 5, 15, 30, 60, 120, and
300 s.18 The pseudo-first-order model is generally applied for
18F-labeling due to the low concentration of [18F]F− compared
to that of the precursor.19 Line graphs of ln [1/(1 − RCY)]
versus reaction time were used to determine the labeling
efficiency, with the slopes representing the specific initial rate
constant at a specific temperature (Figure 1c). The actual
second-order rate constant can be obtained from the quotient
of the slope and the concentration of 1a (3.2 × 10−3 M).
These rate constants were used to create an Arrhenius plot (ln
k versus 1/T) to calculate the activation energy, which was 7.6
kcal mol−1 (Figure 1d). This value is close to that obtained
through DFT calculations (8.5 kcal mol−1) and is substantially
lower than those of the Si−18F-based isotope exchange
reaction (15.7 kcal mol−1) and nucleophilic 18F-fluorination
on ethylene glycol-di-p-tosylate, a conventional example of
C−18F bond formation (17.0 kcal mol−1).20 31P NMR spectra
confirmed that an equivalent amount of phosphonate reacted
completely with tetrabutylammonium fluoride within 5 min
(Figure 1e).
Due to the formation of hydrogen bonds between F− and
the active groups, the degree of freedom, and the
nucleophilicity of F− decrease significantly, which hinders the
labeling reaction from proceeding independently.13 Conse-
quently, the C−18F bonds formed by nucleophilic substitution
reactions rarely tolerate active groups such as amino and
hydroxyl groups.3,14 The activation energies and rates of
reaction between five F− nucleophiles, including simple F− and
F− bonded by hydrogen bonds with four typical active groups,
and a typical fluoride acceptor SiFA were simulated (Table
1).15 It was found that irrespective of the fluorine sources, the
Table 1. Effect of Different F− Nucleophiles on Activation
Energy and Rate Constant of the Reaction between 1 and
SiFA
In order to verify the site-selectivity of this phosphonate-
specific nucleophilic substitution, up to 3 μmol (10 equiv) of
interfering compounds bearing amino or hydroxyl groups, such
as p-aminophenol and o-aminobiphenyl, were added into the
reaction system. Moderate RCYs (Table 2 entry 2−5) suggest
a
activation energy
a
(kcal mol−1
)
rate constant (L mol−1 s−1
)
F−nucleophiles
1
SiFA
1
SiFA
3.60 × 106
563.6
401.8
63.4
6.70 × 103
0.200
0.463
0.142
Table 2. Tolerance of Active Groups
i
ii
iii
iv
v
8.50
13.7
13.9
15.0
15.1
12.2
18.4
17.9
18.6
18.3
a
stoichiometric ratio (additive/
precursor)
RCY
(%)
entry
additive
1
2
3
4
5
6
7
8
none
o-aminobiphenyl
o-aminobiphenyl
p-aminophenol
p-aminophenol
H2O
NA
1:1
10:1
1:1
10:1
2:1
4:1
76
70
62
73
40
14
4
3
9
6
9
4
53.1
0.234
a
Simulated conditions: CH3CN, 0 °C.
activation energy of 1 (8.5 kcal mol−1) is lower than that of
SiFA (12.2 kcal mol−1), and the rate constant was 100-fold
higher than that of SiFA. This suggested that fluorination on
phosphonate prostheses was kinetically more favorable than
the 18F-labeling on SiFA.
H2O
H2O
8
5
10:1
0
a
Reaction conditions: 1a (0.3 μmol), CH3CN (100 μL), [18F]KF/
K222 (1−3 mCi), 25 °C, 5 min. n = 3.
Phosphonates were synthesized in 42−78% yields via the
DBU-promoted alkylation reaction (for 1a−10a, 15a−17a,
and 20b) or Sandmeyer-type reaction (for 11a−14a).16
C o m p o u n d 2 0 b , 2, 5 - d i o x o p y r r o l i d in - 1 - y l 4-
((diphenoxyphosphoryl)methyl)benzoate), a bifunctional link-
er, can conjugate with biomolecules bearing amino groups.
The corresponding PFAs (1−17) were obtained through
fluorination and hydrolysis in 27−54% yields.17 All the
compounds were characterized by 1H, 13C, 31P, and 19F
NMR spectroscopies and high-resolution mass spectrometry.
Different reaction times, precursor amounts, solvents, and
temperatures were examined, and the RCYs of [18F]1 and
[18F]2 were determined by radio-TLC (radio-thin layer
chromatography) or radio-HPLC (n = 3) (Tables S3−S6).
Five minute labeling in anhydrous CH3CN at rt with 0.3 μmol
precursor was found to be the optimal labeling condition for
attaining >80% RCY. Compounds 2a−2e with different leaving
groups were designed to explore the effect of the leaving
abilities on RCYs. The RCYs for the cases of all diphenyl esters
and diphenyl thioester substituted precursors 2a−2e were in
the range 85−94% (Figure 1b).
good site-selectivity in the reaction system containing
interfering compounds. A certain proportion of water (9−
18%) was also tolerant in the reaction system (entry 6−7) with
the RCY decline from 14 to 8% correspondingly when water
was gradually added from 9 to 18%.
High RCYs were achieved when various substrates bearing
functional groups such as nitro, cyano, bromo, methoxy, and
naphthyl ([18F]6−[18F]10) were used. Additionally, substrates
with several heterocyclic scaffolds, including pyridines,
benzofurans, and benzothiazoles ([18F]11−[18F]14) were
found to be easily accessible. Hydroxyl, carboxyl, and amino
([18F]15−[18F]17) groups were also tolerated. These groups,
however, are barely tolerated in the existing nucleophilic 18F-
fluorination methods. Medicinally important biomolecules,
such as 18F-labled amino acid mimics ([18F]18 and [18F]19),
[18F]PFA-pyridoxamine, [18F]PFA-folic acid, and [18F]PFA-
E[c(RGDyK)]2 were, respectively, radio-synthesized in RCYs
of 69%, 35%, 23%, 46%, and 21% (Figure 2).
[18F]PFA-E[c(RGDyK)]2, which can detect the expression
of the αvβ3 integrin receptor in vivo, was fully evaluated as a
proof-of-concept radiotracer.21 E[c(RGDyK)]2 was prefunc-
18F-Labeling of [18F]1 was conducted at temperature
gradients between −25 and −5 °C because the reaction was
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Letter
Figure 2. Substrate scope. Radiolabeling conditions: precursor (0.3 μmol), [18F]KF/K222 (1−3 mCi), 25 °C, 5 min. n = 3.
tionalized with 20b to afford benzyl phosphonate-E[c-
(RGDyK)]2 as the precursor. [18F]PFA-E[c(RGDyK)]2 was
successfully synthesized on a commercial automated synthesis
module with a RCY of up to 25% in 55 min (Figure S25).
Notably, [18F]PFA-E[c(RGDyK)]2 could be efficiently sepa-
rated from its precursor using HPLC, as their retention times
differed by 7.1 min. The Am of the product prepared using the
automated module was 35.9−55.1 GBq μmol−1, with an initial
activity of 1.2 Ci, which is 3-fold higher than most of the
current 18F-labeled E[c(RGDyK)]2 tracers. The log P value for
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01211.
■
sı
Materials and methods, chemical syntheses, detailed
experimental procedures, optimization details, radio-
HPLC/TLC traces, and NMR (1H, 13C, 31P and 19F)
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
the [18F]PFA-E[c(RGDyK)]2 was −0.53
0.03. [18F]PFA-
E[c(RGDyK)]2 was incubated in PBS solution and ethanol at
37 °C for 2 h, and no defluorination and disintegration of
[18F]PFA-E[c(RGDyK)]2 was observed. Comparison of the
radiosynthesis parameters/tracer parameters of the method
reported herein with those of the other methods and the
quality control data are detailed in the Supporting Information
(Table S7).
Zijing Li − Centre for Molecular Imaging and Translational
Medicine, State Key Laboratory of Molecular Vaccinology
and Molecular Diagnostics, School of Public Health, Xiamen
University, Xiamen, Fujian 361102, P.R. China;
orcid.org/0000-0003-2156-6479; Email: zijing.li@
xmu.edu.cn
Authors
In summary, we have introduced a spontaneous F− site-
specific nucleophilic substitution on phosphonates to rapidly
label biomolecules with positron-emitting 18F in a single step.
Experimental and theoretical studies reveal that this 18F-
labeling reaction has a remarkably low activation energy,
proceeds under mild reaction conditions, and displays high
site-selectivity/active group tolerance. This feasible method
was successfully automated on a commercial multifunction
radiosynthesis module to allow an efficient synthesis of 18F-
tracers with high Am’s. We believe that this methodology will
provide a valuable strategy for the direct nucleophilic 18F-
labeling of some of the most challenging biomolecules.
Chao Wang − Centre for Molecular Imaging and
Translational Medicine, State Key Laboratory of Molecular
Vaccinology and Molecular Diagnostics, School of Public
Health, Xiamen University, Xiamen, Fujian 361102, P.R.
China
Lei Zhang − Tianjin Engineering Technology Centre of
Chemical Wastewater Source Reduction and Recycling,
School of Science, Tianjin Chengjian University, Tianjin
300384, P.R. China
Zhaobiao Mou − Centre for Molecular Imaging and
Translational Medicine, State Key Laboratory of Molecular
Vaccinology and Molecular Diagnostics, School of Public
Health, Xiamen University, Xiamen, Fujian 361102, P.R.
China
4264
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Letter
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Wanru Feng − Centre for Molecular Imaging and
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China
Zhongjing Li − Centre for Molecular Imaging and
Translational Medicine, State Key Laboratory of Molecular
Vaccinology and Molecular Diagnostics, School of Public
Health, Xiamen University, Xiamen, Fujian 361102, P.R.
China
Hongzhang Yang − Centre for Molecular Imaging and
Translational Medicine, State Key Laboratory of Molecular
Vaccinology and Molecular Diagnostics, School of Public
Health, Xiamen University, Xiamen, Fujian 361102, P.R.
China
Xueyuan Chen − Centre for Molecular Imaging and
Translational Medicine, State Key Laboratory of Molecular
Vaccinology and Molecular Diagnostics, School of Public
Health, Xiamen University, Xiamen, Fujian 361102, P.R.
China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01211
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was financially supported by the National Natural
Science Foundation of China (81971674), Science Fund for
Distinguished Young Scholars of Fujian Province
(2019J06006), Fundamental Research Funds for the Central
Universities (20720180050), and Scientific Research Founda-
tion of State Key Laboratory of Molecular Vaccinology and
Molecular Diagnostics (2016ZY002).
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