Rapid18F-labelingviaPd-catalyzedS-arylation in aqueous medium

Article abstract of DOI:10.1039/d1cc00745a

We report radiolabeling of thiol-containing substratesviaPd-catalyzedS-arylation with 2-[¹⁸F]fluoro-5-iodopyridine, which is readily accessible using the “minimalist” radiofluorination method. The practicality of the procedure was confirmed by

Full text of DOI:10.1039/d1cc00745a

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Bernd Neumaier at the Forschungszentrum Jülich,
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Rapid 18F-labeling via Pd-catalyzed S-arylation in
aqueous medium
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This work describes radiolabeling of thiol-containing
substrates via Pd-catalyzed S-arylation with readily
accessible 2-[18F]fluoro-5-iodopyridine. The novel
procedure was applied for the convenient preparation
of a novel PSMA-specific PET-tracer as well as for the
fast labeling of peptides and proteins.
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18
Rapid F-labeling via Pd-catalyzed S-arylation
in aqueous medium†
Cite this: Chem. Commun., 2021,
57, 3547
Swen Humpert, ‡a Mohamed A. Omrane,‡ab Elizaveta A. Urusova,ab
cd
cd
abe
Received 8th February 2021,
Accepted 15th March 2021
Lothar Gremer,
Raisa N. Krasikova,
Dieter Willbold,
Heike Endepols,
*
fg
ab
ab
Bernd Neumaier
and Boris D. Zlatopolskiy
DOI: 10.1039/d1cc00745a
rsc.li/chemcomm
We report radiolabeling of thiol-containing substrates via Pd-catalyzed peptides.7 The [18F]AlF protocol was also used for direct radiola-
S-arylation with 2-[18F]fluoro-5-iodopyridine, which is readily accessible beling of proteins.8 In contrast, the conditions required for other
using the ‘‘minimalist’’ radiofluorination method. The practicality of the radiofluorination methods are incompatible with sensitive com-
procedure was confirmed by preparation of a novel PSMA-specific pounds and biomolecules like peptides, proteins and nucleic
PET-tracer as well as labeling of glutathione, Ab oligomer-binding acids. Furthermore, synthesis of radiolabeling precursors can be
RD2 peptide, bovine serum albumin and PSMA I&S.
challenging, so that direct 18F-labeling is not always well suited for
high throughput production of libraries of radiolabeled com-
Since its introduction in the 1970s, positron emission tomography pounds. In this case, a modular (indirect) approach that starts
(PET) and hybrid methods like PET/CT and PET/MRI have become with the preparation of a radiolabeled building block bearing a
indispensable tools for high precision medicine and drug reactive group is more preferable.9 In a second step, this pros-
development.1,2 This imaging technique utilizes probes labeled thetic group is coupled to an appropriate functionality of
with positron-emitting radionuclides (PET-tracers), which interact the molecule to be labeled. Whereas amino and thiol reactive
specifically with a molecular target or biochemical process of building blocks are conventionally used for 18F-fluorination of
interest. Fluorine-18 remains the most popular PET radionuclide peptides and proteins, tryptophan or tyrosine residues have
owing to its favorable decay properties and good accessibility in recently been targeted as well.10 While most biopolymers contain
the form of [18F]fluoride. However, further PET developments numerous amino groups (e.g. o-NH2 of Lys residues), the number
necessitate easy access to emerging and established PET-tracers. of SH-groups (e.g. Cys moieties) seldom exceeds 1–2 per mole-
A plethora of 18F-labeling techniques have been established.3,4 cule, enabling conjugation with higher site selectivity. As thiol-
In particular, recently developed late-stage radiofluorination selective prosthetic groups, 18F-labeled maleimides, vinyl
methods such as transition metal-mediated 18F-fluorination sulfones, phenyloxadiazolyl methylsulfones, and the Umemoto
have significantly simplified the accessibility of numerous PET reagent have been used.11–16 Among them, S-conjugation of
probes.5,6 Emerging approaches based on Al–F, B–F and Si–F maleimides affords radiolabeled thioethers as mixtures of two
chemistry enabled in many cases direct access to 18F-fluorinated stereoisomers, which are not always sufficiently stable under
physiological conditions.17 Vinyl sulfones18 lack complete selec-
tivity towards S- vs. N-nucleophiles and are less reactive than
a Institute of Neuroscience and Medicine, Nuclear Chemistry (INM-5),
maleimides. Furthermore, the preparation of these prosthetic
¨
¨
Forschungszentrum Julich GmbH, Julich 52428, Germany.
groups usually involves multiple steps and subsequent HPLC
isolation, increasing synthesis time, diminishing radiochemical
yields (RCYs) and preventing automation. Recently, Al Shuaeeb
et al. disclosed a fast Pd-catalysed S-arylation of Cys-containing
molecules with various (hetero)aryl halides in aqueous medium
at ambient temperature.19 The aim of the present study was to
transfer this approach into PET-chemistry.
E-mail: b.neumaier@fz-juelich.de
b Institute of Radiochemistry and Experimental Molecular Imaging,
University Hospital Cologne, Cologne 50931, Germany
c Institute of Biological Information Processing, Structural Biochemistry (IBI-7),
¨
¨
Forschungszentrum Julich, Julich 52425, Germany
d
¨
¨
¨
Institut fur Physikalische Biologie, Heinrich-Heine-Universitat Dusseldorf,
¨
Dusseldorf 40225, Germany
e Department of Nuclear Medicine, University Hospital Cologne, Cologne 50937,
4-[18F]Fluoroiodobenzene ([18F]FIB) was developed for indirect
radiolabeling via Pd-catalyzed cross coupling reactions.20 However,
[18F]FIB prepared from respective aryl-l3-iodane21 or sulfonium
precursors22 must be purified by HPLC to remove aryl iodide side
products. Furthermore, in our hands, RCYs of [18F]FIB did not
Germany
f N. P. Bechtereva Institute of the Human Brain, St.-Petersburg 197376, Russia
g St.-Petersburg State University, St.-Petersburg 199034, Russia
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc00745a
‡ Contributed equally.
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antibody fragments and constructs thereof, as separation of
labeled products from remaining precursors can be difficult or
even impossible. High precursor content in PET-tracers can
affect PET image quality and cause adverse effects in patients.
Consequently, optimization of the different parameters of the
conjugation step with the aim to achieve reasonable RCYs at
lower thiol loading was carried out, first, using aliquots of
[18F]1 (Table S1, ESI†). Whereas with 2 mmol GSH almost
quantitative labeling was achieved, further reduction of pre-
cursor amount led to a high variability of RCYs and at GSH
amounts below 500 nmol to a sharp decline of RCYs. We
hypothesized that under the basic reaction conditions, the
thiol precursor could be rapidly consumed by oxidation to the
corresponding disulphide (oxidized glutathione).26 In order to
prevent oxidation, the conjugation reaction was carried out
under nearly neutral conditions using 0.1 M Na phosphate
buffer (PB; pH = 6.7–7.8) instead of Et3N. Furthermore, different
organic solvents like MeOH, MeCN and DMF were evaluated
(Table S1, ESI†). Under optimized reaction conditions 470%
RCYs§ were obtained with only 33 nmol 6. With 167 nmol 6
almost quantitative formation of [18F]7 in 50% MeCN was
observed already after 1 min reaction time.
Scheme 1 Synthesis of 5-iodo-2-[18F]fluoropyridine ([18F]1) and its con-
jugation with thiols 4, 6, 9, 12, 14 and 16. Conditions: (a) Tf2O, Py, 0 1C to
r.t., 16 h; (b) DABCO, THF, 0 1C, 5 days, 70–81% over two steps; (c) (i)
elution of [18F]FÀ (0.03–5 GBq) with 2 in MeOH, (ii) evaporation of MeOH,
80 1C, 10 min, (iii) DMSO, 100 1C, 15 min followed by RP SPE, 77 Æ 7%;
(d) XantPhos Pd G3, r.t. – 37 1C, 1–6 min. RD-2-Cys: all-D-tridecapeptide:
H-p-t-l-h-t-h-n-r5-c-NH2. BSAreduced: bovine serum albumin partially
reduced by TCEP. PSMA I&S: MA-s3-y-nal-k[Sub-K-CO-E]-OH. TCEP:
tris(2-carboxyethyl)phosphine; MA: mercaptoacetyl; nal: (R)-(2-naphthyl)alanyl;
Sub: suberoyl (1,8-octanedioyl); K-CO-E: Lys-ureido-Glu.
Having optimized the novel protocol in small-scale experi-
ments, we turned to the study of its applicability for PET tracer
exceed 30%. In search of a more practical alternative to [18F]FIB, production on a practical scale. Accordingly, S-arylation of 6
we turned our attention to the hitherto unknown building block with [18F]1 was reevaluated using whole batches of the SPE
5-iodo-2-[18F]fluoropyridine ([18F]1).
purified radiolabeled building block (Fig. 1 and Table S2, ESI†).
[18F]1 was produced from easily accessible DABCO- In this case, a reciprocal influence of precursor 2 amounts on
substituted precursor 2, which was in turn prepared in two RCYs of [18F]1 and [18F]7 was observed. While higher precursor
steps from the commercially available 5-iodo-2-hydroxypyridine loading afforded [18F]1 in higher RCYs, it also increased
(3) according to the procedure of Richard et al.23 (Scheme 1 and the amount of nonradioactive impurities, presumably mainly
ESI†), using the ‘‘minimalist’’ protocol.21,24 To this end, 2-[4-(5-iodopyridin-2-yl)piperazin-1-yl]ethanol, which could not
[18F]fluoride was eluted from an anion exchange resin with a be removed by SPE and interfered with the consecutive con-
solution of 2 in MeOH. After evaporation of MeOH, the residue jugation step in the case of low GSH amounts (see Fig. 1B).
was taken up in DMSO and the reaction mixture was heated at Nevertheless under optimized conjugation conditions [Pd cat.
100 1C for 15 min.25 [18F]1 could be isolated by solid phase (0.5 mg), 50% MeCN in PB (pH = 7.3; 0.6 mL), r.t., 6 min] and
extraction (SPE) in RCYs of 77 Æ 7% (n 410) with excellent
radiochemical purity (499%) and reasonable molar activity
(29 GBq mmolÀ1 for 1.37 GBq of [18F]1) within 25–30 min.
The applicability of [18F]1 for radiolabeling via S-arylation
using the protocol of Al-Shuaeeb et al.19 was initially assessed
using Boc-Cys-OMe (4) as a model thiol (Scheme 1). Short
incubation (6 min) of [18F]1 with the substrate (2–6 mmol) in
THF (0.24 mL) using XantPhos Pd G3 catalyst (2–24 mol%)
and Et3N (3 equiv.) as base at ambient temperature afforded the
18F-labeled protected amino acid [18F]5 in RCYs§ of 490%
(Table S1, ESI†).
Next, application of the procedure for peptide labeling was
Fig. 1 (A) Dependency of RCYs of [18F]1 (blue) and [18F]7 (over two steps,
evaluated. Accordingly, reduced L-glutathione (H2N-g-Glu-Cys-
Gly-CO2H; GSH; 6) was conjugated with [18F]1 in 50% THF at
black) as well as RCY§ of the Pd-catalyzed S-arylation of GSH (6) with [18F]1
(red) on the amount of 2 used for preparation of [18F]1. (B) Dependency of
ambient temperature using XantPhos Pd G3 (2–8 mol%) and RCY of [18F]7 (over two steps, black) and RCY§ of the Pd-catalyzed
S-arylation of GSH (6) with [18F]1 (RCY only for the conjugation step, red)
Et3N (3 equiv.), furnishing [18F]7 in 490% RCY§ (Table S1,
on the amount of 6 used for the S-arylation step. RCY of [18F]1 (blue) is also
ESI†). In these experiments, 3 mmol of thiol 6 was applied,
shown. Conditions: experiments were carried out according to GP2
which is a substrate amount suitable for labeling of small
molecules including short peptides. However, it is unacceptably
(see Chapter 3.2.2. in ESI†) using 1 mmol 6 for the conjugation step (A) or
1 mg 2 for the preparation of [18F]1 (B). All experiments were carried out at
high in the case of larger peptides and proteins including least in triplicate.
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Scheme 2 Preparation of precursor 9. Conditions: (a) CCl3(CQNH)OtBu,
BF3ÁEt2O, CH2Cl2/cyclohexane (1 : 3), 3 h, 63%; (b) Et2NH, CH2Cl2, 3 h, 89%;
(c) 11, PhO(CO)-Glu(OtBu)2 [prepared from HClÁH-Glu(OtBu)2: PhO(CO)Cl,
Py, THF, 0 1C–r.t., 2 h], DMSO, 60 1C, 16 h, 66%; (d) TFA/H2O/TIS (90 : 5 : 5),
2 h, 70%.
Fig. 2 Biodistribution of [18F]8 in a healthy rat determined by mPET.
(A): Horizontal view of a summed image taken 60–120 min p.i. (B): Same
as A, only with the PSMA blocking agent 2-PMPA (23 mg kgÀ1). Note that
preferential enrichment of [18F]8 is observed in the PSMA-positive ganglia
with a signal-to-noise ratio of 25 in the SCG (1.5 with 2-PMPA). Liver
uptake had a SUVbw of 143 (155 with 2-PMPA). Abbreviations: DRG: dorsal
root ganglia; SCG: superior cervical ganglion; SG: salivary gland; SJ:
shoulder joint.
[18F]1 prepared from 1.0 mg DABCO salt 2, well reproducible
conjugation RCYs§ of 80–90% and 20–30% were obtained using
1 mmol or 250 nmol 6, respectively (Fig. 1B and Table S2, ESI†).
Further reduction of the GSH amount was possible if [18F]1
isolated by HPLC [RCY = 69 Æ 4% (n 410)] was used.
Being interested in the development of novel PET probes for
prostate carcinoma (PCa) imaging,27,28 we applied the proce-
dure for the preparation of a prostate specific membrane
antigen (PSMA) specific tracer [18F]8. The corresponding thiol
precursor 9 was synthesized from Fmoc-Cys(MMt)-OH (10) as
follows (Scheme 2 and ESI†): Fmoc-Cys(MMt)-OH was esterified
using tert-butyl 2,2,2-trichloroacetamidate followed by N-Fmoc-
deprotection with Et2NH in CH2Cl2 to afford H-Cys(MMt)-OtBu
(11), which was subsequently allowed to react with crude
PhO(CO)-Glu(OtBu)2 prepared from phenyl chloroformate and
HClÁH-Glu(OtBu)2 to give the corresponding protected urea.
Finally, deprotection furnished 9 in 26% over four steps. The
mPET imaging in healthy rats, using PSMA-expressing peripheral
ganglia as surrogates for small PSMA-positive tumor lesions
(Fig. 2).27,30
[18F]8 enabled the delineation of the superior cervical and
dorsal root ganglia with excellent signal-to-noise ratio. The
PSMA specificity of [18F]8 accumulation in ganglia was con-
firmed by inhibition experiments (Fig. 2). Low bone radio-
activity uptake indicated high stability of the tracer to in vivo
defluorination.
conjugation reaction between SPE-purified
[ 9
18F]1 and
Next, we applied the novel protocol for the preparation of a
radiolabeled analog of the brain-penetrating all-D arginine-rich
dodecapeptide RD2 (H-ptlhthnr5-NH2).31 RD2 binds specifically
to amyloid beta (Ab) and was developed for the treatment of
Alzheimer’s disease through elimination of toxic Ab42 oligo-
mers. Consequently, radiofluorinated RD2 analogs could
potentially be applied for Ab-PET-imaging. An additional
D-Cys residue was introduced at the C-terminus of RD2 and
the resulting peptide 12 (300 nmol) was conjugated with HPLC
purified [18F]1 affording after HPLC isolation and formulation
the radiolabeled RD2 conjugate [18F]13 in 40 Æ 7% (n = 7) RCY
over two steps (Table 1, entry 2). [18F]13 was also prepared in
41 Æ 5% RCY (n = 3) using the SPE purified [18F]1 and higher
amounts of 12 (3 mmol) (Table 1, entry 3) with a molar activity
amounting to 16–100 GBq mmolÀ1 (for 0.21–1.29 GBq; n = 4).
Next, the protocol was applied for 18F-fluorination of small
proteins using bovine serum albumin (BSA, 14) as a model
substrate. This structurally well characterized protein contains
one Cys residue and 17 disulfide bonds. Native BSA (6 nmol)
was partially reduced using TCEPÁHCl (10 equiv.) at 37 1C for
1 h and directly conjugated to [18F]1. After 20 min incubation at
(20 mmol), performed in 50% MeCN in PB (pH 7.3; 0.6 mL)
using XantPhos Pd G3 (0.5 mg) and Et3N to adjust the pH of the
reaction mixture to ca. 8.0, afforded after HPLC purification
and formulation [18F]8 as a ready to use solution in RCYs of
55 Æ 3% (n = 6) over two steps and within 90–100 min (Table 1,
entry 1). Molar activity of [18F]8 was determined to be
11–78 GBq mmolÀ1 (for 0.015–1.84 GBq; n = 4). Pd content in
the final tracer solution amounted to 6.4 ng/batch (ICP-MS) and
was well below any level of concern.29 [18F]8 was examined by
Table 1 Conjugation of [18F]1 with thiol-containing substrates
Entry
Substrate
Amount
Product RCY Æ SDe, f [%] (n)
1a,b,c,d Cys-CO-Glu (9) 20 mmol
[
[
[
[
[
18F]8
55 Æ 3 (6)
40 Æ 7 (7)
41 Æ 5 (3)
40 Æ 9 (3)
10 Æ 3 (3)
2a,b,c,d RD2c (10)
3a,b,c,d RD2c (12)
4a,b,c,d BSA (14)g
5a,b,c,d PSMA I&S (16)
300 nmol
3 mmol
6 nmol
18F]11
18F]13
18F]15
18F]17
0.5 mmol
a
Reaction solvent: entry 1 : 50% MeCN in PB (600 mL; pH adjusted by
Et3N to 8); entries 2 and 3 : 50% MeCN in PB (440 mL); entry 4 : 25% 37 1C, radiolabeled BSA [18F]15 was isolated by gel permeation
b
MeCN in BB (400 mL); 50% MeCN in PB (600 mL). XantPhos Pd G3:
chromatography (GPC) in RCYs of 40 Æ 9% (n = 3) (Table 1,
c
entries 1–3, 5 : 0.5 mg; entry 4 : 75 mg. T (t): entries 1 and 5: r.t. (6 min);
entry 4). No formation of [18F]15 was observed in the absence of
d
entries 2 and 3: r.t. (12 min); entry 4 : 37 1C (20 min). Entries 1, 3, 4, 5:
SPE purified [18F]1; entry 2: HPLC-purified [18F]1. Isolated yields after the Pd catalyst. If unreduced BSA was used, [18F]15 was isolated
e
f
g
HPLC (entries 1–3, 5) or GPC (entry 4). Number of runs. Reduced
with TCEP. PB: 0.1 M Na phosphate buffer (pH 7.3); BB: 0.1 M Na borate
buffer (pH 8.0). RCY: radiochemical yield over two steps. SD: standard
deviation. TCEP: tris(2-carboxyethyl)phosphine.
in 12 Æ 2% RCY (n = 3) (Table S3, ESI†).
Planar scintigraphy and single photon emission tomography
(SPECT) using 99mTc-labeled tracers is still an important
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´
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5-iodo-2-[18F]fluoropyridine is a convenient method for thiol-
selective radiolabeling. Rapid kinetics under mild aqueous
conditions makes it well-suited for Cys-specific 18F-labeling of
peptides and proteins. The method could also be applied for
the preparation of PET-tracers from conjugates originally
designed for 99mTc labeling. Noteworthy, PSMA-specific
[18F]8 prepared by this novel protocol turned out to be a
promising candidate for prostate carcinoma imaging.
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Conflicts of interest
There are no conflicts to declare.
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