Synthesis, biological evaluation and radiolabelling by 18F- fluoroarylation of a dopamine D3-selective ligand as prospective imaging probe for PET

Article abstract of DOI:10.1016/j.bmcl.2010.09.142

Radical ¹⁸F-fluoroarylation with fluorine-18-labelled arenediazonium chlorides has been successfully applied to the radiochemical synthesis of the dopamine D₃-selective ligand SH 317 ([ ¹⁸F]8). SH 317 has been evaluated as

Full text of DOI:10.1016/j.bmcl.2010.09.142

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6933–6937
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, biological evaluation and radiolabelling by 18F-fluoroarylation
of a dopamine D3-selective ligand as prospective imaging probe for PET
S. B. Höfling a, S. Maschauer b, H. Hübner a, P. Gmeiner a, H.-J. Wester c, O. Prante b, M. R. Heinrich a,
⇑
a Department für Chemie und Pharmazie, Pharmazeutische Chemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany
b Nuklearmedizinische Klinik, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstraße 12, 91054 Erlangen, Germany
c Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität, München, Ismaninger Str. 22, 81675 München, Germany
a r t i c l e i n f o
a b s t r a c t
Radical 18F-fluoroarylation with fluorine-18-labelled arenediazonium chlorides has been successfully
applied to the radiochemical synthesis of the dopamine D3-selective ligand SH 317 ([18F]8). SH 317
has been evaluated as a new PET ligand candidate by in vivo experiments.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 11 August 2010
Revised 27 September 2010
Accepted 28 September 2010
Available online 26 October 2010
Keywords:
18-Fluorine
Dopamine
Positron emission tomography
Ligands
Radiochemical labelling
Over the past decades, positron emission tomography (PET) has
gained more and more clinical importance as a powerful and highly
sensitive non-invasive method for imaging and quantification of
physiological and pathophysiological processes in vivo. Due to its
properties, that is, its broad availability, its low positron energy
(Emax = 635 keV) and manageable half-life (t1/2 = 109.7 min), no-
carrier-added (n.c.a.) fluorine-18 has become the most commonly
used PET isotope.1 Nevertheless, chemical synthesis including the
incorporation of fluorine-18 into target molecules in acceptable
overall reaction times of <2 h, often represents a major difficulty
in the development of new radiopharmaceuticals.2
depression, Parkinson’s disease and also drug addiction have been
related to disturbances of its expression and/or activity.6 With re-
spect to an in vivo investigation of the dopamine D3 receptor by
PET, only a few carbon-11 and fluorine-18-labelled compounds
have been evaluated so far (Fig. 1).
Recently, the D3/D2 radioligand [11C](+)-PHNO (4a) has been
successfully used for studying D3 receptor occupancy in vivo by
PET when the selective D3 antagonist SB-277011 was applied to
dissect the signal attributable to D3 receptors.10 Since insufficient
selectivity for D3 over D2 receptors or undesirable biokinetic prop-
erties have hindered the PET application of these promising ligands
so far, the development of a dopamine D3-selective ligand suitable
for PET imaging applications remains challenging.
For this existing synthetic challenge, the application of radical
18F-chemistry represents an alternative approach which has so
far only marginally been exploited. As we have shown recently,
short reaction times can be achieved when 18F-fluoroarylation
reactions are employed for radiochemical labelling.3 Starting from
Continuing our efforts on the development of subtype selective
dopamine receptor radioligands for PET imaging studies,13,15 we
herein report on the application of the radical 18F-fluoroarylation
methodology for the radiosynthesis of a dopamine D3-selective
ligand. For our studies, we selected cinnamoyl carboxamide 8, a
fluorinated derivative of ST 168 (7), as lead compound (Fig. 2),
due to its sub-nanomolar D3 affinity and adequate subtype
selectivity that has been described previously.16,17 Structurally
comparable carboxamides have recently shown high D3 receptor
affinities combined with remarkable selectivity over the dopamine
D2 receptor subtype (Ki(D3)/Ki(D2)) (Table 1).17
[
18F]fluoro-substituted arenediazonium salts,4,5 radioligands for a
variety of receptors in the central nervous system containing a
deactivated 4-[18F]fluorophenyl group could be accessible by
applying the radical 18F-fluoroarylation strategy.
Among the dopamine receptors, which can be differentiated
into five subtypes, D1–D5, the D2 subtype has been the most inter-
esting target for a long time. Recent research has also focussed on
the D3 subtype, since a variety of diseases such as schizophrenia,
We aimed at the radiosynthesis of 18F-labelled SH 317 ([18F]8)
since its cinnamoyl amide substructure could probably be assem-
bled in the final synthetic step by radical fluoroarylation. In this
manuscript, we report on the synthesis and 18F-radiosynthesis,
⇑
Corresponding author. Tel.: +49 9131 85 24115; fax: +49 9131 85 22585.
E-mail address: Markus.Heinrich@medchem.uni-erlangen.de (M.R. Heinrich).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.09.142

6934
S. B. Höfling et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6933–6937
O
O
N
S
HN
RO
N
N
O11CH3
S
N
N
N
[
11C]RGH 1756 (3)
11
C]FAUC 346 ( ): R = 11CH3
2 : R = (CH2)218F
1
[
O
11CN
H
N
O
N
CF3
N
N
18F
X
Y
N
HO
N
N
Cl
N
6
O
5
11
4a
[
C]-(+)-PHNO ( ): X = 11CH2, Y = CH3
[
18F]PHNO (4b): X = CH2, Y = 18FCH2
Figure 1. Carbon-11 and fluorine-18-labelled dopamine D3 receptor ligands [11C]FAUC 346 (1),7 fluorine-18-labelled derivative of FAUC 346 2,8
(+)-PHNO (4a),10 naphthoxazine derivative 4b,11 CBJ 090 biaryl amide derivative 512,13 and imidazolidinone 6.14
[
11C]RGH 1756 (3),9
[
11C]
H3CO
N2
Cl
O
N
18F
18
N
O
11
[
F]
O
N
H
TiCl3
R
R
N
H
X
N
H
R
(CH3CN-H2O)
X
ST 168 (7): R = Cl
ST 186: R = H
SH 317 (8): R = F
18F
10
X = Cl, Br
9
O
R
via
N
H
Figure 2. ST 168 (7) and radioligand SH 317 (8).
18F
12
the biological evaluation and in vivo properties of 18F-labelled SH
317 ([18F]8).
Scheme 1. Radiochemical synthesis of cinnamoyl amides
9
by radical
[ 9 could be
18F]fluorinated cinnamoyl amides
fluoroarylation.
In general,
obtained in a radical fluoroarylation reaction starting from b-halo-
genated acrylic amides 10 that were treated with fluorine-18-la-
belled arenediazonium chlorides [18F]11 in the presence of the
reductant titanium(III)-chloride as described previously (Scheme
1).18–20 This reaction proceeds in a radical addition–elimination
sequence via intermediate 12. Since radical arylations are in gen-
eral insensitive to non-protected functional groups such as amines,
carboxylic acids or alcohols, they are well-suited for 18F-labelling
applications when mild and aqueous reaction conditions are
needed. Moreover, radical arylation reactions proceed rapidly and
the application of 18F-labelled arenediazonium chloride (11) could
therefore allow easy access to radioligands containing the meta-
bolically stable [18F]fluorophenyl moiety.
The synthesis of precursor 19 started from commercially avail-
able N-(2-methoxyphenyl)-piperazine (13) (Scheme 2). Alkylation
of 13 with 4-bromobutyronitrile (14) gave 15 which was reduced
to amine 16 under hydrogen (25 bar) in the presence of Raney
nickel as catalyst.17 Coupling of amine 16 with (E)-b-bromoacrylic
acid (17) using chlorovinylamine 18 as activating reagent
furnished the labelling precursor 19.21 The fluorinated, non-radio-
active D3 ligand SH 317 (8) was accessible via radical fluoroaryla-
tion with diazonium salt 11 or by coupling of amine 16 with
(E)-3-(4-fluorophenyl)acrylic acid (20) in the presence of the acti-
vating agent 18. The alternative synthetic route to 8 via 20 was
Table 1
Receptor binding data for compound 8 at the human dopamine receptors D2long, D2short, D3 and D4 and the porcine receptors D1, 5-HT1A, 5-HT2 and
a
1 in comparison to previously
reported ligands
Compound
Ki values SDa (nM)
Ratiog D2/D3
b
c
c
c
c
d
e
f
D1
D2long
D2short
D3
D4.4
5-HT1A
5-HT2
a1
SH 317 (8)
1100 170
27 8.5
20.7 0.816
22.6 1.0
13.54 1.2
120
21 0.71
0.34 0.049
0.69 0.1116
0.44 0.09
0.33 0.1
0.51
43 3.5
28 1.4
330 160
5.2 1.4
79 (62)
3016
51
41
235 (82)
ST 168 (7)16
ST 18616
613
—
—
270
—
—
42
—
—
170
—
—
160
—
—
230
—
—
8.0
a
b
c
d
e
f
Ki-Values (nM) are mean values of two independent experiments each done in triplicate.
[3H]SCH 23990.
[3H]spiperone.
[3H]WAY600135.
[3H]ketanserin.
[3H]prazosin.
g
Ratio of Ki(D2long)/Ki(D3) and Ki(D2short)/Ki(D3) in parentheses.

S. B. Höfling et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6933–6937
6935
COOH
N
Br
17
NC
Br
H2 (25 bar)
Raney - Ni
(NH3 aq.)
14
H3CO
N
H3CO
N
H3CO
N
K2CO3, KI, 65 ºC
(acetone)
Cl
18
quant.
84%
72%
HN
NC
N
N
H2N
13
15
16
COOH
9%
F
20
H3CO
N2
Cl
18
H3CO
F
11
N
N
N
O
O
TiCl3
N
(CH3CN-H2O)
Br
N
H
N
H
19
SH 317 (8)
F
Scheme 2. Synthesis of the labelling precursor 19 and SH 317 (8).
chosen since the radical pathway via 11 usually requires the ole-
finic substrate 19 in large excess to be efficient.3a,22 Since a large
amount of unreacted 20 was recovered from reaction mixture con-
taining 16 and 17, the activating agent 18 appears to be by far not
as effective for cinnamic acid 20 as for acrylic acid 17.23 Notably, no
E/Z isomerization was observed when ligand SH 317 (8) was stirred
over 10 days in phosphate buffer (pH 7), confirming the conforma-
tional stability of 8.
incorporation into growing CHO cells stably expressing the dopa-
mine D3 and the D2long receptors,31 respectively, when for both
subtypes a neutral antagonism was determined compared to the
reference quinpirole. This result is not in agreement with the pub-
lished data for the chloro derivative 7 at the D3 receptor that has
been described as a partial agonist in a mitogenesis assay using
NG 108-15 cells,16 and may be explained by the structural modifi-
cations or, more likely, the use of different cell systems.32
To evaluate the binding properties of the fluorinated test com-
pound, competition binding experiments were done using the hu-
The promising in vitro binding characteristics of 8, especially its
sub-nanomolar D3 affinity, prompted us to perform ex vivo rat
brain autoradiography studies with the 18F-labelled radioligand.
The radiochemical synthesis of [18F]8 started from 1,4-dinitro-
benzene (21), following the previously described procedures3,5
with modifications (Scheme 3). Applying a modified cryptate sys-
tem by the use of K2CO3/KH2PO4 and reducing the concentration
of 21 to 50 mM for the nucleophilic 18F-fluorination of 21 in the
first reaction step, we obtained an improved radiochemical yield
(RCY) of 90–95% for [18F]22 (see Supplementary data). Former
studies reported an RCY of only 50–80% employing the commonly
24
25
26
man dopamine receptors D2long, D2short
,
D3 and D4.4 stably
expressed in CHO cells. Binding affinities to porcine D1, the seroto-
nin receptors 5-HT1A and 5-HT2 and the a1 adrenoreceptor were
also determined.27 Table 1 displays binding affinities of SH 317
(8) in comparison with previously reported data, ST 168 (7) and
ST 18616 as well as the previously studied pyridinylphenyl carbox-
amide 6.13 The experiments indicated an excellent sub-nanomolar
affinity of test compound 8 for the D3 receptor (Ki = 0.34 nM) to-
gether with a good D3/D2 selectivity (>60-fold) which is in good
agreement with the previously reported data.16 Compound 8 also
revealed an acceptable a1 binding affinity, being one magnitude
lower than its D3 affinity (Table 1). However, considering the rela-
tively low D3 receptor density in the rat striatum (68 fmol/mg),28
where it is co-localised with the predominating D2 subtype
(143 fmol/mg),28 the selective recognition of D3 receptors by 8
might be problematic. In comparison with the D3-preferring radio-
ligand [11C]-(+)-PHNO that has Ki values of 0.16 nM at D3 and
8.5 nM at D2 receptors,29 compound 8 showed a similar binding
profile (Table 1). As [11C]-(+)-PHNO reached an in vivo binding
potential (Bmax/Kd) of 3–4,30 and has been successfully used for
studying D3 receptor occupancy in vivo by PET recently,10a we
assumed that ligand [18F]8 could also be suitable for in vivo PET
imaging of D3 receptors, especially of those in extrastriatal
regions.
used cryptate–carbonate system.3,5 18F]22 was further reduced to
[
aniline [18F]23 which was isolated by solid phase extraction on a
silica gel cartridge. Diazotization furnished the [18F]fluorophenyl
diazonium chloride [18F]11 which was subsequently applied to
the radical 18F-arylation reaction with labelling precursor 19 in
the presence of titanium(III) chloride in an aqueous solution at
room temperature. The radiochemical yield of [18F]8 was 17–32%
after 10 min, as determined by radio-HPLC of a sample withdrawn
from the reaction mixture. We did not observe any influence on the
RCY by varying the reaction temperature (0–80 °C) or the amount
of 19 (up to 70 lmol). However, a significant amount of up to 30%
of the byproduct [18F]fluorobenzene was observed. The 18F-aryla-
tion of 19 in the final step of the synthesis proceeded quickly, lead-
ing to an overall decay-uncorrected RCY of 1–3% in a total
synthesis time of about 100 min starting from [18F]fluoride (see
Supplementary data). Including the final HPLC purification and for-
mulation, this procedure provided [18F]8 in sufficient amounts
(10–15 MBq) to perform further in vitro and in vivo studies.
To assess the lipophilicity of [18F]8 as a measure of blood–brain
barrier (BBB) permeability, we determined the log D7.4 value by
extraction of the radioligand in n-octanol–phosphate buffered sal-
ine (pH 7.4, 1:1). [18F]8 revealed a log D7.4 value of 2.07 0.24
(n = 7), suggesting sufficient brain uptake of [18F]8 when applied
in vivo.
However, the affinity ratio (D2/D3) and therefore the binding
potential of a radioligand for each receptor subtype may differ
significantly between the in vitro and in vivo situation, due to
differences in the level (and density) of active states of G-pro-
tein-coupled receptors in the system. Importantly, this is most
relevant for agonist ligands, which preferentially bind to the active
GPCR conformation (high-affinity state), whereas antagonists dis-
play equal affinity for the active and inactive state. Therefore, we
studied the intrinsic activity of 8 by measuring the [3H]thymidine

6936
S. B. Höfling et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6933–6937
NO2
NO2
NH2
K [Kryptofix-2.2.2] 18F
H3PO3, Pd/C
O2N
18F
18F
18F]22
[
18F]23
H3CO
21
[
19
N2
Cl
NaNO2, HCl
TiCl3
O
N
N
(H2O)
18F
N
H
18F]8
[
18F]11
[
18F
Scheme 3. Radiochemical synthesis of [18F]8.
Moreover, we performed preliminary CNS biodistribution stud-
ies with [18F]8 using brain autoradiography after intravenous
injection of the radiotracer in Sprague–Dawley rats.33 The regional
brain distribution of [18F]8 was compared with the results obtained
from animals that were injected with a combination of [18F]8 and
the D3-selective ligand BP 897 to test for specific receptor binding
of [18F]8 in vivo. The dose of BP 897 (1 mg/kg) was chosen since
it is known that D3 and D2 receptors are saturated at doses
>0.5 mg/kg.6a Rats were sacrificed by decapitation at 45 min post
injection (p.i.). The ex vivo autoradiography and histology of the
rat brain slices of control and co-injected animals are shown in
Figure 3.
radioactive metabolites from [18F]8. However, similar cinnamoyl
amides have been reported to be stable in vivo,35 and the uptake
of [18F]8 into the brain ventricles confirmed our studies on 18F-la-
belled pyridinylphenyl amides, that also significantly accumulated
in the brain ventricles.13 Interestingly, the expression of D3 recep-
tors on the ependymal cell layer that covers the brain ventricles
had been demonstrated by Tomé et al. using immunocytochemis-
try.36 The determination of the biokinetics of [18F]8 and its transport
and binding to the ventricular compartment need elucidation by
further in vivo experiments.
In summary, the three step synthesis of diazonium salt [18F]11
could be improved within this study and the radical 18F-fluoroary-
lation method has been successfully applied to the radiochemical
synthesis of the dopamine D3-selective ligand SH 317 ([18F]8). In
comparison with previously reported arylations of styrene deriva-
tives,3a low yields were obtained when applying the fluoroaryla-
tion strategy to acrylic amides. Acrylic amides are therefore
probably not ideal substrates for labelling techniques based on free
aryl radicals. Nevertheless, the 18F-arylation strategy provided suf-
ficient yield of a new PET ligand candidate and allowed its evalua-
tion by in vivo experiments.
The regional distribution of the D3 receptor in the rat brain has
been determined by quantitative in vitro autoradiography in previ-
ous studies, indicating the nucleus accumbens, the islands of
Calleja, the ventral pallidum, the caudate–putamen (striatum) and
cortex as D3 receptor-positive brain regions.28,34 In our experiments,
we detected specific uptake of [18F]8 mainly in the striatum and
cortex (Fig. 3), as determined by integration of regions of interest
(ROI) and comparison with BP 897-co-injected animals, which re-
vealed a reduced tracer uptake of about 90% in striatal and cortical
regions (see Supplementary data). However, specific binding of
Since radiochemical 18F-labelling by radical reactions enables
the introduction of the fluorophenyl moiety into a variety of
radiopharmaceuticals for PET when established methods are inca-
pable, we are currently working on alternative sources for 18F-fluo-
rinated aryl radicals to facilitate the overall radiochemical yield of
this strategy.
[
18F]8 in other D3 receptor reference regions, such as the nucleus
accumbens or the islands of Calleja, was not visualised. Instead,
we observed a high accumulation of [18F]8 in the brain ventricles
with ratios of VT/ST = 3.7 0.8 (n = 6) and VT/CX = 2.1 0.2 (n = 6)
( Fig. 3). In BP 897-co-injected animals the ventricular uptake of
[
18F]8 was reduced by 50%. It is tempting to speculate that the
uptake of [18F]8 in the brain ventricles could be ascribed to binding
Acknowledgements
to the ependymal cell layer or could be due to the occurrence of
The authors would like to thank the Friedrich-Alexander-
Universität Erlangen-Nürnberg (FAU) and the Deutsche
Forschungsgemeinschaft (DFG) [DFG (HE5413/3-1), DFG (WE
2386/5-1), DFG (PR 677/2-3)] for generous financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.09.142.
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