Fast and efficient 18F-labeling by [18F]fluorophenylazocarboxylic esters

Article abstract of DOI:10.1002/chem.201303409

Introduction of [18F]fluoride ion into the aromatic core of phenylazocarboxylic esters was achieved in only 30 seconds, with radiochemical yields of up to 95% (85(±10) %). For labeling purposes, the resulting 18F-substituted azoester can be further converted in radical-arylation reactions to give biaryls, or in substitutions at its carbonyl unit to produce azocarboxamides.

Full text of DOI:10.1002/chem.201303409

DOI: 10.1002/chem.201303409
Communication
&
Isotopes
18
Fast and Efficient F-Labeling by [18F]Fluorophenylazocarboxylic
Esters
Stefanie K. Fehler,[a] Simone Maschauer,[b] Sarah B. Hçfling,[a] Amelie L. Bartuschat,[a]
Nuska Tschammer,[a] Harald Hꢀbner,[a] Peter Gmeiner,[a] Olaf Prante,*[b] and
Markus R. Heinrich*[a]
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ious approaches based on electrophilic 18F-fluorination[16] and
multicomponent reactions.[17,18] However, no widely used radio-
tracers have yet emerged from these new labeling techniques.
Many pharmaceuticals and biologically active lead structures
contain a substituted phenyl substructure (p1) in conjugation
with a second p system (p2), at which p1 can often be replaced
by a fluorophenyl unit without substantial loss of biological ac-
tivity (Scheme 1).[19] Herein, we present a simple method for
Abstract: Introduction of [18F]fluoride ion into the aromat-
ic core of phenylazocarboxylic esters was achieved in only
30 seconds, with radiochemical yields of up to 95%
(85(Æ10)%). For labeling purposes, the resulting 18F-substi-
tuted azoester can be further converted in radical-aryla-
tion reactions to give biaryls, or in substitutions at its car-
bonyl unit to produce azocarboxamides.
Positron emission tomography (PET) has been established as
a highly selective methodology for molecular imaging in pre-
clinical and clinical in vivo studies.[1] Besides its importance in
tumor diagnostics, PET has considerable importance for inves-
tigations of diverse plasma membranes and receptor and
transporter proteins.[2] To this end, convenient routes to suit-
able radiopharmaceuticals represent an important prerequisite
for accessibility, and the radionuclide 18F is commonly used
due to its broad availability and favorable physicochemical
properties.[3] Efficient, fast, and reliable labeling strategies with
[18F]fluoride ion, which are generated in a cyclotron through
a (p,n)-type nuclear reaction of 18O, have undergone remark-
able advances in recent years. When phosphazene bases[4] or
DMF in microfluidic systems[5] are used, or if the anion ex-
change is carried out with the complex [K+ꢀ2.2.2.]OHÀ,[6] the
otherwise time-consuming azeotropic drying of [18F]fluoride
ion is no longer required. A related preparation of [18F]fluoride
Scheme 1. General lead structure and derived PET ligands.
18F-fluorine labeling, which is characterized by a) a few efficient
reaction steps; b) very short reaction times for [18F]fluoride ion
incorporation; c) good-to-quantitative radiochemical yields;
and d) a targeted application towards the development of two
new radioligands for PET. The conjugated p system p2 is
hereby replaced by an identical substructure (type I) or by
a bioisosteric azocarboxamide (type II).
2À
ion with [K+ꢀ2.2.2]2C2O4 subsequently proved to be advan-
tageous for protein labeling.[7] In addition, chemoselective la-
beling strategies based on the concept of click chemistry intro-
duced by Sharpless and co-workers[8] have been recently intro-
duced to accommodate the 109 min half-life of 18F.[9]
Our study is based on the observation that the aromatic
core of phenylazocarboxylic esters becomes highly activated
towards nucleophilic aromatic substitution through the azocar-
bonyl unit.[20,21] Depending on the choice of leaving group, di-
phenyl ethers, diphenyl amines, and phenylalkyl amines can
then be prepared under mild conditions. In addition, the azo-
carboxylic ester moiety allows a further modification of the ar-
omatic core through various aryl-radical reactions.[22,23] Against
this background, we started to investigate whether phenylazo-
carboxylic esters might be useful for the otherwise challenging
incorporation of [18F]fluoride ion into aromatic systems, as well
as for subsequent labeling reactions.[24]
However, the introduction of 18F into aromatic substructures
of a complex pharmacophore remains challenging.[10] In addi-
tion to reactions through 4-[18F]fluoroaryl radicals,[11] various
strategies have been developed to achieve 18F-fluoroarylation
with 1-bromo-4-[18F]fluorobenzene and 4-[18F]fluorophenyl-lith-
ium,[12] or through aryliodonium compounds and 4-[18F]fluoro-
1-iodobenzene[13] with consecutive Sonogashira-, Suzuki-, or
Stille-type arylation reactions.[14] Recently, diarylsulfoxides have
also been applied for the synthesis of [18F]fluoroarenes.[15] The
spectrum of compounds now available containing
a [18F]fluoroaryl substructure has been further extended by var-
Preliminary attempts with the nitro-substituted azocarboxyl-
ic ester 1[20] had already indicated that azocarbonyl units are
well suited to achieve incorporation of [18F]fluoride ion by nu-
cleophilic aromatic 18F-for-nitro substitution into a benzene nu-
cleus (Scheme 2). By this means, the 18F-labeled azoester [18F]2
was obtained in 74% yield after a reaction time of only five mi-
nutes. Because trialkylammonium substituents are known as
even better leaving groups in nucleophilic aromatic substitu-
tions, we also prepared the trimethylammonium salt 3 in two
steps from fluorophenylazoester 2 (Scheme 2).[25]
After an optimization of the reaction conditions, we ob-
served that the trimethylammonium salt 3 gave [18F]2 in
30 seconds and in high radiochemical yield of 85%. Moreover,
the labeling strategy based on 3 has the significant advantage
over the use of nitro compound 1 in that the radiolabeled
[a] S. K. Fehler,+ Dr. S. B. Hçfling, A. L. Bartuschat, Dr. N. Tschammer,
Dr. H. Hꢀbner, Prof. Dr. P. Gmeiner, Prof. Dr. M. R. Heinrich
Abteilung fꢀr Chemie und Pharmazie, Pharmazeutische Chemie
Friedrich-Alexander-Universitꢁt Erlangen-Nꢀrnberg
Schuhstrasse 19, 91052 Erlangen (Germany)
E-mail: Markus.Heinrich@fau.de
[b] Dr. S. Maschauer,+ Prof. Dr. O. Prante
Labor fꢀr Molekulare Bildgebung und Radiochemie
Nuklearmedizinische Klinik
Friedrich-Alexander-Universitꢁt Erlangen-Nꢀrnberg
Schwabachanlage 6, 91054 Erlangen (Germany)
E-mail: olaf.prante@uk-erlangen.de
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303409.
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matic substrate 5 does not contain a free amino
functionality, similar to the cases of benzene (5a), 4-
fluoroanisole (5b), furan (5d), or 2-methylfuran (5e),
the compound can be already present in the reac-
tion mixture at the first step with a further addition
in the second step (variant A). According to var-
iant B, which is recommended for reactions with 4-
anisidine (5c) and furfurylamine (5 f), the addition of
5 to the mixture was carried out in the second step,
because the formation of the carboxylate [18F]4
would otherwise be accompanied by side reactions.
Following variants A or B, all model substrates 5a–f
gave the desired biaryl compounds [18F]6a–f in radi-
ochemical yields of 41–51% (Table 1). Inspired by
the structure of recently reported norepinephrine
transporter (NET) ligands,[29] we proceeded to apply our new
protocol for the radical arylation of 2-((4-fluorophenoxy)me-
thyl)morpholine (5g). The desired product [18F]6g showed
quite high binding affinity and selectivity towards NET,[30] and
was obtained in 30% radiochemical yield. The lower yield
hereby is most probably due to the more complex structure of
the substrate 5g, which includes more sites potentially sensi-
tive to hydrogen abstraction by highly reactive aryl radicals.[23]
The most important by-product in all radical arylations, with
yields up to 40%, was found to be [18F]fluorobenzene arising
from hydrogen abstraction by the aryl radical.[23a] Because the
arylation reactions are conducted under air, the formation of
minor amounts of 4-[18F]fluorophenol (up to 10%) is not sur-
prising.[22]
Scheme 2. Nucleophilic substitution of the phenylazocarboxylic esters 1 and 3 with
[18F]fluoride ion.
product [18F]2 can be easily separated from the large excess of
3 by simple solid-phase extraction. With regard to a further
conversion of the central intermediate [18F]2 into representa-
tive p systems of type I (Scheme 1), we first investigated radi-
cal arylations; in essence, aryl radicals can be generated from
phenylazocarboxylic esters under acidic, basic, and thermal
conditions[22] with phenyl diazenes arising as short-lived inter-
mediates.[26] But because radiochemical labeling reactions are
conducted with only picomolar masses, established prepara-
tive procedures of millimolar scales are most often not directly
transferable to this task. Therefore, it was unsurprising that
a newly developed, two-step arylation protocol emerged as es-
pecially useful for radical arylations with the 18F-labeled phenyl-
azocarboxylic ester [18F]2. In the first step, tetrabutylammoni-
um hydroxide was used to convert [18F]2 into the azocarboxy-
late [18F]4,[27] from which aryl radicals were then generated
under acidic conditions (Table 1).[28] If the structure of the aro-
Besides radical arylations through 4-[18F]fluorophenyl radi-
cals,[10] the azocarboxylic ester [18F]2 may also be attached to
a target molecule by a substitution at its carbonyl group.[22,31]
Inspired by the structures of known
dopamine-D3 selective ligands with bi-
phenyl substructures,[32] the azocarbox-
Table 1. Radical arylations with 18F-labeled phenylazo-carboxylic ester [18F]2.[c]
amide was evaluated as a new bioisos-
tere for the second p2 system of the
ligand (Scheme 1, type II).[33] After a first
optimization of the reaction conditions
by using 4-methoxybenzylamine (7),
the synthesis of the desired azocarbox-
amide [18F]8 was achieved in 30 min
and in quantitative yield (Scheme 3).
The reaction of the 18F-labeled azocar-
boxylic ester [18F]2 with phenylpipera-
zine 9 under otherwise identical condi-
tions gave the dopamine-D3 receptor
ligand [18F]10, also in quantitative
yield. Change of the solvent to ethanol
led to a further improvement, in which
quantitative conversion of [18F]2 to
[18F]10 could be achieved with a lower
excess of amine 9 and in a shorter re-
action time of 10 min (see the Support-
[a] Variant A: 5a, b, d, and e as additives in the first and second step. [b] Variant B: 5c, f, and g
added in the second step. [c] Decay-corrected radiochemical yield determined by HPLC referenced
to [18F]2 (ca. 108 equiv of 5a–g were used).
ing Information).
In advance of PET imaging experi-
ments of dopamine receptors with
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ed radiochemical yield of 30–35%. Complete stabili-
ty of the radioligand [18F]10 in serum and plasma in
vitro was demonstrated by radio-HPLC (>99% after
60 min at 378C).[37] Investigation of its physicochemi-
cal properties indicated a logD of 2.1Æ0.1, which in-
dicates moderate lipophilicity, predicting permeabili-
ty for the blood-brain barrier in PET studies (see the
Supporting Information).[38]
Figure 1 shows the regional distribution of [18F]10
in coronal rat-brain slices at the striatal level and
confirms the specific binding of the radioligand to
D3 receptors at the nucleus accumbens (shell) and
the islands of Calleja, because these structures are
known to have high D3 receptor density.[39] The low
binding to the dorsal striatum further underlines the
D3 over D2 subtype selectivity of [18F]10, and the
complete displacement of binding by BP897 verifies
the specificity in these structures (Figure 1, right).
Compound [18F]10 also demonstrated specific bind-
ing to serotonin 5-HT1A receptors in the hippocam-
Scheme 3. 18F-labeling through substitution of [18F]2 at the carbonyl unit (decay-correct-
ed radiochemical yields, ca. 108 equiv of 7 or 9).
[18F]10, receptor-binding studies were conducted with stably
transfected CHO cell lines. The binding affinities determined
for the unlabeled ligand 10 at a battery of monoaminergic G-
protein coupled receptors displayed high affinity and signifi-
cant selectivity for the dopamine receptor subtype D3.[34] Ex-
pression of this receptor type in brain is of considerable inter-
est for PET studies of Parkinson’s disease, schizophrenic psy-
choses, and drug addiction. Further functional experiments
(GTP-g-S assay) showed no D3 receptor-mediated G-protein ac-
tivation over a range of ligand concentrations from 10À11 to
10À5 m. Therefore, compound 10 can be classified as a dopa-
mine D3 receptor antagonist.
pus and in the neocortex (see the Supporting
Information).
In summary, we have found that azocarboxylic esters enable
an extremely fast and high-yielding introduction of [18F]fluoride
ion into benzene cores. In addition to the simple separation of
the azo compound [18F]2 from its labeling precursor, [18F]2
represents a valuable central intermediate, which is broadly ap-
plicable in 18F-labeling reactions. We developed suitable condi-
tions for radical arylations, as well as for substitutions at the
carbonyl unit. Targeted applications of [18F]2 for brain PET
studies led to a NET and a D3/5-HT1A ligand with promising
properties, especially considering that [18F]10 is the first 18F-la-
beled radioligand that correctly visualizes D3 receptor distribu-
tion in rat ventral striatum without interfering binding to the
D2 subtype. Further in vivo experiments are currently under-
way to establish [18F]6g and [18F]10 as tools for PET imaging
applications.
Widely used agents for PET imaging of dopamine receptors
do not distinguish between the D2 and D3 subtypes, showing
instead their composite.[35] Although [11C]PHNO had been de-
veloped as a D3 subtype ligand for PET imaging studies,[36] its
selectivity is incomplete. Attempts to develop an 18F-labeled
radioligand for brain PET studies of the dopamine D3 receptor
have hitherto been unsuccessful.[2d] Due to its convenient ac-
cessibility and promising D3/D2 subtype selectivity, we evaluat-
ed the radioligand [18F]10 in autoradiographic experiments in
rat-brain sections. The radiosynthesis of [18F]10 proceeded
through a simple solid-phase extraction of the intermediate
[18F]2, so that purification by HPLC was only required for the
final product (Scheme 3). After a total synthesis time of 35–
40 min from [18F]fluoride ion, we achieved a nondecay-correct-
Experimental Section
All animal experiments were performed according to protocols ap-
proved by the local Animal Protection Authorities (Regierung Mit-
telfranken, Ansbach, Germany, No. 54-2532.2-18/12).
Synthesis of tert-butyl 2-(4-[18F]fluorophenyl)azocarboxylate
([18F]2)
The QMA-cartridge with [18F]fluoride (600—800 MBq) was eluted
with a solution of Kryptofix 2.2.2 (15 mg) and K2CO3 (1.0m, 15 mL)
in acetonitrile (900 mL). Water was removed by evaporation to dry-
ness with acetonitrile (3ꢂ400 mL) by using a stream of nitrogen at
858C. The precursor 2-(4-(N,N,N-trimethylammonium)phenyl)azo-
carboxylic acid tert-butyl ester trifluoromethanesulfonate (3;
2.5 mg, 6.0 mmol) in anhydrous acetonitrile (400 mL) was added to
the dried K+/Kryptofix 2.2.2/18F complex, and the solution was
stirred for 30 s at 858C. Afterwards, the yellow solution was diluted
with HCl (0.2m, 15 mL) and passed through a cartridge (tC18,
Waters). The cartridge was washed with acetonitrile/0.2m HCl
Figure 1. In vitro autoradiography of coronal rat-brain slices after incubation
with [18F]10 (left) and [18F]10 in the presence of the D3 receptor ligand
BP897 (50 nm, right). ICj: Islands of Calleja, NAc: Nucleus accumbens.
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To a solution of 4-(4-(2-methoxyphenyl)piperazin-1-yl)but-1-ylamine
(9; 100 mL), K2CO3 (30 mg) and [18F]2 in ethanol (100 mL) or ethyl
acetate (100 mL) was added. After 10 min at 358C (ethanol) or
30 min at 458C (ethyl acetate), [18F]10 was identified by retention
time (tR) on the radio-HPLC system and by co-injection of the cor-
responding reference compound 10 (Chromolith RP-18e, 100ꢂ
4.6 mm, 10–90% acetonitrile (0.1% TFA) in water (0.1% TFA) in
a linear gradient over 5 min, 4 mLminÀ1, tR =2.15 min). The radio-
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radio-HPLC from a sample withdrawn from the reaction mixture.
After evaporation of the solvent, the residue was dissolved in ace-
tonitrile/water (0.1% TFA) 50:50 (500 mL), and [18F]10 was purified
by semipreparative HPLC (Kromasil C8, 125ꢂ8 mm, 4 mLminÀ1
,
25–60% acetonitrile (0.1% TFA) in water (0.1% TFA) in a linear gra-
dient over 30 min, tR =8.5 min) and subsequent SPE (solid-phase
extraction, SepPak C18 light, Waters). Compound [18F]10 (137–
180 MBq) was eluted from the cartridge with ethanol (1 mL), the
solvent was evaporated in vacuo, and the residue was dissolved in
aqueous sodium chloride solution for further in vitro and in vivo
studies. When using ethyl acetate as solvent, [18F]10 was synthe-
sized in an overall nondecay-corrected radiochemical yield of 20–
24% (referred to [18F]fluoride) in a total synthesis time of about
70–80 min and in specific activities of 4–10 GBqmmolÀ1. For etha-
nol as solvent, [18F]10 was obtained in an overall nondecay-correct-
ed radiochemical yield of 30–35% (referred to [18F]fluoride) in
a total synthesis time of about 35–40 min and with a specific activ-
ity of 12 GBqmmolÀ1
.
Acknowledgements
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The authors would like to thank the Deutsche Forschungsge-
meinschaft (DFG, PR 677/2-3, WE 2386/5-1, HE 5413/3-1) and
the FAU (Emerging-Field-Initiative Neurotrition). We are further
grateful to PET Net GmbH for the supply of [18F]fluoride, and
thank Dr. Paul Cumming for critical reading of the manuscript.
Keywords: azo compounds
·
dopamine
·
fluorine
·
nucleophilic substitution · positron emission tomography
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