Seyferth-gilbert homologation as a route to 18F-labeled building blocks: Preparation of radiofluorinated phenylacetylenes and their application in PET chemistry

Article abstract of DOI:10.1002/ejoc.201501377

A convenient method for the preparation of hitherto unknown ([¹⁸F]fluorophenyl)acetylenes ([¹⁸F]FPAs) using the Seyferth-Gilbert homologation is reported. The novel building blocks were efficiently prepared from easily accessible [¹⁸F]fluorobenzaldehydes by using the Bestmann-Ohira reagent. High radiochemical yields and excellent radiochemical purities were achieved within only 20 min of reaction time; 2- and 4-[¹⁸F]FPAs were applied to prepare radiofluorinated heterocycles by using different cycloaddition and cross-coupling reactions. Additionally, these building blocks were used to prepare three novel PET tracers. Thus, an artificial radiofluorinated protected amino acid [¹⁸F]10, a COX-2-specific ligand [¹⁸F]14, and a PSMA-selective inhibitor [¹⁸F]16 were obtained in high radiochemical yields. A convenient method for the preparation of hitherto unknown ([¹⁸F]fluorophenyl)acetylenes ([¹⁸F]FPAs) utilizing the Seyferth-Gilbert homologation is reported. The novel building blocks were applied to prepare radiofluorinated heterocycles and PET tracers utilizing different cycloaddition and cross-coupling reactions.

Full text of DOI:10.1002/ejoc.201501377

DOI: 10.1002/ejoc.201501377
Communication
Radiolabeled Synthons
18
Seyferth–Gilbert Homologation as a Route to F-Labeled
Building Blocks: Preparation of Radiofluorinated
Phenylacetylenes and Their Application in PET Chemistry
Philipp Krapf,[a,b][‡] Raphael Richarz,[a,b][‡] Elizaveta A. Urusova,[a,b,c] Bernd Neumaier,*[a,b,d]
and Boris D. Zlatopolskiy[a,b]
Abstract: A convenient method for the preparation of hitherto 2- and 4-[18F]FPAs were applied to prepare radiofluorinated
unknown ([18F]fluorophenyl)acetylenes ([18F]FPAs) using the heterocycles by using different cycloaddition and cross-cou-
Seyferth–Gilbert homologation is reported. The novel build- pling reactions. Additionally, these building blocks were used
ing blocks were efficiently prepared from easily accessible to prepare three novel PET tracers. Thus, an artificial radiofluori-
[18F]fluorobenzaldehydes by using the Bestmann–Ohira rea- nated protected amino acid [18F]10, a COX-2-specific ligand
gent. High radiochemical yields and excellent radiochemical [18F]14, and a PSMA-selective inhibitor [18F]16 were obtained
purities were achieved within only 20 min of reaction time; in high radiochemical yields.
Introduction
A broad spectrum of direct and indirect methods for 18F-
labeling has been developed.[1] Among them, the (3+2) azide-
alkyne Huisgen cycloaddition (azide-alkyne click reaction),[2]
originally transferred to radiochemistry by Marik et al.[2d] be-
came a widely used method for the preparation of PET tracers.
In particular, sensitive biomolecules including biopolymers
could be efficiently radiofluorinated by using this method. The
main advantages of this approach are: chemical and enzymatic
stability of the resulting 1,2,3-triazoles, regioselectivity of radio-
labeling, excellent compatibility with different functional
groups, and fast reaction kinetics under mild reaction condi-
tions. (3+2) Cycloadditions of radiofluorinated nitrile oxides and
nitrones with unsaturated compounds have also been explored
for radiolabeling.[2f] Furthermore, the Kinugasa reaction has
been shown to provide easy access to radiofluorinated β-
lactams starting from 18F-labeled nitrones and alkynes.[2h]
Positron emission tomography (PET) is an important non-inva-
sive imaging modality widely used in clinical diagnostics. PET
allows the real-time visualization of physiological and patholog-
ical processes on the molecular level by using in vivo tracing of
biologically active molecules labeled with β+-emitting nuclides.
Among them, fluorine-18 represents the most popular PET ra-
dionuclide since no carrier added (n.c.a.) 18F in the form of
[18F]fluoride is readily accessible in multi-Curie amounts by the
high-yielding 18O(p,n)18F nuclear reaction at low-energy cyclo-
trons. Furthermore, it exhibits favorable decay properties. Thus,
the energy of the emitted β+-particles is low [E(β+) = 630 keV]
resulting in PET scans with high intrinsic resolution due to the
short range of the emitted particles in tissue. Furthermore, the
half-life of 18F (109.8 min) is well-suited for the majority of PET
applications. Moreover, this relatively long half-life enables so-
phisticated multistep radiochemical syntheses and monitoring
of biological processes in the range of hours. Additionally, the
half-life of 18F facilitates “satellite” distribution of 18F-labeled
radiopharmaceuticals to distant clinical centers.
Several radiofluorinated alkynes have been synthesized and
applied as radiolabeled synthons for click chemistry.[3] However,
compared to the plethora of alkynes applied for nonradioactive
applications only a few radiofluorinated alkynes have been de-
veloped for PET chemistry. Furthermore, their preparation often
requires multiple reaction steps and time-consuming purifica-
tion procedures, resulting in low radiochemical yields (RCY).
[a] University Hospital of Cologne, Institute of Radiochemistry and
Experimental Molecular Imaging,
Kerpener Str. 62, 50931 Cologne, Germany
E-mail: bernd.neumaier@uk-koeln.de
http://radiochemie.uk-koeln.de/
Radiofluorinated arylacetylenes represent potentially very
useful building blocks, which could provide access to numerous
novel radiolabeled compounds of high interest. Their radiosyn-
thesis has not been reported yet, albeit a rapid development of
radiofluorination methods has taken place in recent years.[4,5]
Herein we describe the efficient preparation of hitherto un-
known ([18F]fluorophenyl)acetylenes ([18F]FPAs). These synthons
were synthesized from the corresponding [18F]fluorobenzalde-
hydes ([18F]FBAs) by using the Seyferth–Gilbert homologation
with the Bestmann–Ohira reagent.[6] The application of 2- and
[b] Max Planck Institute for Metabolism Research,
Gleueler Str. 50, 50931 Cologne, Germany
[c] German Centre for Neurodegenerative Diseases,
Ludwig-Erhard-Allee 2, 53175 Bonn, Germany
[d] Forschungszentrum Jülich, Institute of Neuroscience and Medicine,
Nuclear Chemistry (INM-5),
Wilhelm-Johnen-Str., 52425 Jülich, Germany
[‡] These authors contributed equally.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501377.
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4-[18F]FPAs as building blocks to produce various radiolabeled
Once a reliable and simple method for the efficient prepara-
compounds was studied. The latter were prepared by (3+2) tion of [18F]FPAs had been established, their versatility as syn-
cycloaddition reactions, the radio-Kinugasa reaction, the thons for radiolabeling was evaluated.
Initially, the utility of 2-[18F]FPA for click labeling was studied.
Accordingly, 2-[18F]FPA was allowed to react with a model azide
1 (Entry 1, Table 1) in the presence of CuSO4, sodium ascorbate,
and histidine in aqueous MeOH at ambient temperature. The
corresponding radiolabeled triazole [18F]2 was formed in an
RCC of 53 % already after 10 min of reaction time. In following
experiments the cycloaddition reactivity of 2-[18F]FPA with 1,3-
dipoles other than azides was examined (Entries 2–4, Table 1).
Thus, 2-[18F]FPA was allowed to react with nitrile oxide gener-
ated in situ from the corresponding N-hydroxyimidoyl chloride
3 by base-promoted elimination of HCl to afford the 18F-labeled
3,5-substituted isoxazole [18F]4 in 52 % RCC.
copper-free Sonogashira coupling and the Rh-catalyzed
(2+2+2) cycloaddition. Furthermore, these building blocks were
used to produce PET tracers. Thereby, 18F-labeled variants of
an amino acid [18F]10, a COX-2- ([18F]14) and a PSMA-specific
([18F]16) ligand were prepared.
Results and Discussion
[18F]Fluorobenzaldehydes were produced according to the re-
cently reported “minimalist” radiofluorination protocol.[7]
Shortly, [18F]fluoride was eluted from an anion exchange resin
with the appropriate onium salt precursor in MeOH. MeOH was
evaporated, the residual [18F]fluoride salt was redissolved in
DMSO and heated for 10 min to give n-[18F]FBAs in 20–75 %
radiochemical yields (RCYs; not corrected for decay) after purifi-
cation by solid-phase extraction (SPE) within 20–25 min
(Scheme 1). [Radiochemical yield (RCY) refers to the isolated
yield of the radiochemically and chemically pure radiolabeled
compound.]
Table 1. (3+2) Cycloadditions between 2-[18F]FPA and different 1,3-dipoles.
Scheme 1. Synthesis of n-[18F]FPAs. (i) Preparation of n-[18F]FBAs: 2-[18F]FBA:
X = Me3N+ClO4–, DMSO, 150 °C, 10 min (50–65 %); 3-[18F]FBA: X = (4-
MeOC6H4)I+I–, DMSO, 130 °C, 10 min (20–25 %); 4-[18F]FBA: X = Me3N+ClO4
,
–
DMSO, 150 °C, 10 min (65–75 %); (ii) Synthesis of n-[18F]FPAs: dimethyl (1-
diazo-2-oxopropyl)phosphonate (Bestmann–Ohira reagent) solution (10 % in
MeCN), K2CO3, 120 °C for 15 min. Therafter, distillation at 80 °C under a gentle
stream of helium was carried out {in the case of 4-[18F]FPA, NaBH4 (1–2 mg)
was added before distillation}.
The radiolabeled benzaldehydes were allowed to react with
the Bestmann–Ohira reagent [dimethyl (1-diazo-2-oxopropyl)-
phosphonate] in the presence of K2CO3 in MeOH/MeCN at
120 °C for 15 min to afford the desired radiofluorinated alkynes
in > 90 % radiochemical conversions (RCCs). [Radiochemical
conversion yield (RCC) refers to the amount of [18F]fluoride or
another immediate radiolabeled precursor, which was trans-
formed into the desired 18F-labeled compound; it was deter-
mined by radio-HPLC.] The radiolabeled synthons were isolated
by distillation in 40–60 % RCY (not corrected for decay; n > 20)
and with more than 98 % radiochemical purity (RP) within
20 min. In the case of 4-[18F]FPA, NaBH4 was added to the reac-
tion mixture before distillation to avoid contamination of the
[a] All syntheses were carried out manually. Before being analyzed, the reac-
tion mixtures were cooled to ambient temperature and diluted with water
(2 mL). Unless otherwise stated, each experiment was carried out at least in
triplicate (n ≥ 3). [b] 2-[18F]FPA (50–500 MBq) in MeOH (50 μL), CuSO4
(2.5 mg), histidine (3.8 mg), sodium ascorbate (9.8 mg) and 1 (5 mg) in H2O
(200 μL), 25 °C, 10 min. [c] 2-[18F]FPA (50–500 MBq) in EtOH (200 μL), 3
(10 mg), Et3N (10 μL), 120 °C, 30 min. [d] 2-[18F]FPA (50–500 MBq) in dioxane
(400 μL), 5 (10.5 mg), K2CO3 (8 mg), 150 °C, 30 min. [e] 7 (5 mg), CuI (9.8 mg),
Et3N (28 μL), MeCN (200 μL), 2 min, ambient temp. Then 2-[18F]FPA (50–
500 MBq) in MeOH (150 μL), 1,10-phenanthroline (18 mg) in MeCN (100 μL),
90 °C, 10 min.
Next the feasibility of the building block for the preparation
product with traces (< 5 %) of 4-[18F]fluorobenzaldehyde. of radiolabeled pyrazoles was studied. To this end, 2-[18F]FPA
Notably, this preparation method was insensitive to electronic was allowed to react with (4-bromophenyl)diazomethane gen-
and steric effects of substituents and worked equally well for erated in situ from the respective N-tosylhydrazone 5 (Entry 3,
all three [18F]FBAs.
Table 1) at 150 °C for 30 min to give the radiolabeled 3,5-substi-
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tuted pyrazole [18F]6 in 20 % RCC. Radiolabeled isoxazoles and tions the protected radiofluorinated artificial amino acid [18F]10
pyrazoles could be of potential use as imaging agents targeting, was obtained in an RCC of 83 % after 10 min at 120 °C.
i.e., HDAC 3 and 8,[8] αvβ3 integrins,[9] 20-HETE synthase[10] and
Alkyne trimerization represents a powerful tool for the de
novo construction of polysubstituted heteroaromatic and aro-
COX1/COX2.[11]
Radiofluorinated β-lactams are potentially applicable in PET matic systems. This reaction is widely used in the total synthesis
for the detection of bacterial and viral infections as well as of complex natural products.[16] Transfer of this method into
thrombosis, emphysema, and tumors.[12] Consequently, the suit- radiochemistry could provide a fast access to otherwise hardly
ability of ([18F]fluorophenyl)acetylenes for the preparation of available 18F-labeled polycyclic compounds.[17]
18F-labeled bicyclic β-lactams by the radio-Kinugasa reaction[2h]
using cyclic nitrone 7 and 2-[18F]FPA was investigated (Entry 4,
Table 1). In the presence of CuI as CuI source and 1,10-phen-
anthroline as CuI-stabilizing ligand this reaction provided the
corresponding radiofluorinated fused β-lactam [18F]8 in an RCC
of 52 % within 10 min.
Next, the ability of the radiofluorinated fluoroacetylenes to
participate in late transition metal mediated transformations
was studied.
As a proof of principle, model 4-[18F]fluorophenyl-substi-
tuted 1,2-dihydrobenzofuran [18F]12 was prepared by the reac-
tion of propargyl ether (11) with 4-[18F]FPA in the presence of
Wilkinson's catalyst [Rh(PPh3)3Cl] in unoptimized 18 % RCC.
Finally, [18F]14 and [18F]16 were prepared to illustrate the
potential of the novel labeling synthons for tracer production
and development. [18F]14 represents a probe potentially suit-
able for the visualization of cyclooxygenase 2 (COX-2), an en-
zyme associated with inflammatory processes and tumor pro-
The Sonogashira reaction represents a powerful tool for the gression.[18] On the other hand [18F]16 containing the Lys-
preparation of arylalkynes and conjugated enynes.[13] It has ureido-Glu fragment could be applied for imaging of the pros-
been extensively used for the synthesis of different materials, tate-specific membrane antigen (PSMA),[19] e.g., in prostate
pharmaceuticals and natural products.[7] However, Sonogashira carcinoma,[20] breast cancer[21] and tumor-associated neovascu-
cross-coupling with radiofluorinated alkynes has not been re- lature.[22] Both molecular probes were afforded in > 70 % RCCs
ported yet. Only 4-[18F]fluoroiodobenzene has been used as a by the azide-alkyne “click” cycloaddition between 2-[18F]FPA
building block for the radio-Sonogashira coupling.[14] We stud- and the corresponding azide precursors 13 and 15 under stand-
ied the Sonogashira reaction between 4-[18F]FPA and protected ard conditions (Table 3). [18F]14 and [18F]16 were isolated by
(4-iodophenyl)alanine 9 (Table 2). Usually, radio-Sonogashira semipreparative HPLC in RCYs of 25 % and 30 % (corrected for
cross-couplings were carried out by using Pd complexes with decay; starting from 18F-fluoride), respectively, within an overall
triarylphosphine ligands and CuI as a metal co-catalyst. We ap- synthesis time of 60 min. The specific activity of [18F]14 and
plied the protocol of Yang et al.,[15] which eliminates the need
of any co-catalyst and ligands. Accordingly, the radio-Sonoga-
shira reaction was performed under air in water by using only
Table 3. Preparation of [18F]14 and [18F]16.
PdCl2 as a catalyst and pyrrolidine as a base. Under these condi-
Table 2. Late transition metal mediated reactions of 4-[18F]FPA.
[a] All syntheses were carried out manually. Before being analyzed, the reac-
tion mixtures were cooled to ambient temperature and diluted with water
(2 mL). Unless otherwise stated, each experiment was carried out at least in
triplicate (n ≥ 3). [b] 9 (35 mg), PdCl2 (0.35 mg), pyrrolidine (100 μL) in H2O
(250 μL), 50 °C, 5 min. Then 4-[18F]FPA (50–500 MBq) in MeCN (150 μL),
120 °C, 10 min. [c] 4-[18F]FPA (50–500 MBq) in EtOH (150 μL), Rh(PPh3)3Cl
(1 mg), 40 °C, 5 min. Thereafter, 11 (20 μL), 120 °C, 15 min. [d] The synthesis
of [18F]12 was carried out one time (n = 1).
[a] All syntheses were carried out manually. Before being analyzed, the reac-
tion mixtures were cooled to ambient temperature and diluted with water
(2 mL). Unless otherwise stated, each experiment was carried out at least in
triplicate (n ≥ 3). [b] CuSO4 (2.5 mg), 2-[18F]FPA (50–500 MBq) in MeOH
(50 μL), histidine (3.8 mg, 50 μL), sodium ascorbate (9.8 mg) and 13 (15 mg)
in H2O (150 μL), 25 °C, 10 min. [c] 2-[18F]FPA (50–500 MBq) in MeOH (50 μL),
CuSO4 (2.5 mg), histidine (3.8 mg), sodium ascorbate (9.8 mg) and 15 (4 mg)
in H2O (150 μL), 50 °C, 20 min.
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[18F]16 was 140 GBq/μmol and 232 GBq/μmol, respectively. The
biological evaluation of [18F]14 and [18F]16 is in progress and
will be reported in due course.
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Acknowledgments
The authors thank J. Zischler for his help in the preparation of
this manuscript.
Keywords: Radiopharmaceuticals · Fluorine-18 · Click
chemistry · Seyferth-Gilbert homologation · Alkynes
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Received: October 30, 2015
Published Online: December 15, 2015
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Communication
Radiolabeled Synthons
A convenient method for the prepara-
tion of hitherto unknown ([18F]fluoro-
phenyl)acetylenes ([18F]FPAs) utilizing
the Seyferth–Gilbert homologation is
reported. The novel building blocks
were applied to prepare radiofluorin-
ated heterocycles and PET tracers util-
izing different cycloaddition and cross-
coupling reactions.
P. Krapf, R. Richarz, E. A. Urusova,
B. Neumaier,* B. D. Zlatopolski-
y .................................................... 430–434
Seyferth–Gilbert Homologation as a
Route to 18F-Labeled Building
Blocks: Preparation of Radiofluor-
inated Phenylacetylenes and Their
Application in PET Chemistry
DOI: 10.1002/ejoc.201501377
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