Synthesis and preliminary evaluation of a new fluorine-18 labelled triazine derivative for PET imaging of cannabinoid CB2 receptor

Article abstract of DOI:10.1016/j.bmcl.2013.11.023

Cannabinoid CB2 PET tracers are considered as a promising alternative to PBR/TSPO tracers for the in-vivo imaging of neuroinflammation. We describe here the synthesis and characterization of compound 3, a new potent and brain penetrating CB2 ligand based on an original triazine template. The PET tracer [¹⁸F]-dideutero-3 was prepared in a three steps radiosynthesis, and demonstrated significant uptake in rhesus macaque and baboon brain with a maximum SUV of about 0.7-0.9 g/mL, followed by a moderate washout over time.

Full text of DOI:10.1016/j.bmcl.2013.11.023

Bioorganic & Medicinal Chemistry Letters 24 (2014) 283–287
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and preliminary evaluation of a new fluorine-18 labelled
triazine derivative for PET imaging of cannabinoid CB2 receptor
Laurent Hortala a, Joëlle Arnaud a, Pascale Roux a, Didier Oustric a, Laurent Boulu a, Florence Oury-Donat a,
Patrick Avenet b, Thomas Rooney c, David Alagille d, Olivier Barret d, Gilles Tamagnan d, Francis Barth a,
⇑
a Exploratory Unit, Sanofi R&D, 371 rue du Professeur Blayac, 34184 Montpellier Cedex 04, France
b Exploratory Unit, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France
c Aging TSU, Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France
d Molecular NeuroImaging, 60 Temple St, New Haven, CT 06510, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Cannabinoid CB2 PET tracers are considered as a promising alternative to PBR/TSPO tracers for the in-vivo
imaging of neuroinflammation. We describe here the synthesis and characterization of compound 3, a
new potent and brain penetrating CB2 ligand based on an original triazine template. The PET tracer
Received 20 September 2013
Revised 8 November 2013
Accepted 10 November 2013
Available online 20 November 2013
[
18F]-dideutero-3 was prepared in a three steps radiosynthesis, and demonstrated significant uptake in
rhesus macaque and baboon brain with a maximum SUV of about 0.7–0.9 g/mL, followed by a moderate
washout over time.
Keywords:
Cannabinoid
CB2
Ó 2013 Elsevier Ltd. All rights reserved.
PET
Imaging
Triazine
The type 2 cannabinoid receptor (CB2R) was characterized in
1993 by Munro et al.1 three years after the cloning of the type 1
(CB1 receptor) by Matsuda et al.2 Both receptors are seven-trans-
membrane G protein-coupled receptors which are activated by
endogenous ligands (anandamide, 2-arachidonoylglycerol) as well
neuroinflammation in the progression of neurodegenerative dis-
eases,13 to help select the patient population for clinical trials
and as a pharmacodynamic marker in preclinical studies and clin-
ical trials. Positron Emission Tomography provides dynamic
images of the biodistribution of a radioactive tracer in the brain,
and can specifically and quantitatively assess receptor levels in
the brain in a noninvasive manner.
as hemp (Cannabis sativa) active components (D9-THC). While CB1
receptors are highly expressed in the central nervous system, the
CB2 receptor is predominantly located in the periphery and is asso-
ciated with the immune response. High levels of expression are de-
scribed in spleen, tonsils, blood and bone marrow.3 The CB2
receptor was initially considered to be absent from brain, but more
recently it was reported that CB2 appears in limited amounts in
DRG neurons, brain stem, cerebellum and other brain regions.4
Most importantly CB2 is highly overexpressed in microglial cells
and other immune cells in several neuroinflammatory conditions,
including stroke,5 multiple sclerosis,6 HIV-associated neuropatho-
logic comorbidities,7 glioma8 as well as neurodegenerative disease
such as Alzheimer disease,9 Parkinson disease,10 Huntington dis-
ease11 and amyotrophic lateral sclerosis.12
F
O
HN
N
11CH3
N
N
N
Cl
HO
N
O
R
Cl
In-vivo imaging of neuroinflammation using Positron Emission
Tomography (PET) provides a valuable tool that can be used as
an imaging biomarker to better characterise the role of
1: [11C]-PK11195
2: R= CH3
3: R=CH2F
18F]-d2-3: R= CD218F
[
⇑
Corresponding author. Tel.: +33 499776244.
E-mail address: francis.barth@sanofi.com (F. Barth).
Figure 1. Structure of [11C]-PK11195, and compounds 2, 3 and [18F]-d2-3.
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.11.023

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L. Hortala et al. / Bioorg. Med. Chem. Lett. 24 (2014) 283–287
Radiolabelled ligands of the peripheral benzodiazepine receptor
A c log D value between 1 and 3 is usually considered as optimal
for PET tracers, in order to maximize brain penetration while trying
to minimize nonspecific binding. However it is also known that
high lipophilicity is inherent to all cannabinoids because of their
hydrophobic interaction with the receptor binding site. In fact,
most attempts to decrease log D of cannabinoid ligands lead to a
drastic drop in affinity.21,22 Compound 2 was therefore considered
as an acceptable compromise between affinity and lipophilicity.
The structure of compound 2 was modified in order to allow
easy introduction of a radioelement suitable for PET imaging. We
chose to replace the methoxy group of compound 2 by a OCH2F
group to generate compound 3. This modification was expected
to lead to very minor modifications of the physicochemical and
biological properties of the parent compound, and to allow easy
introduction of 18F, the most widely used PET radionuclide (t1/
2 = 110 min), via alkylation of the corresponding phenol with a flu-
oromethyl alkylating agent as previously described.23
Compound 2 was prepared as shown in Scheme 1 by reacting
2,4-dichloro-6-methoxytriazine 4 with 2-(4-fluoro-phenyl)-ethyl-
amine followed by Suzuki coupling of the chlorotriazine 5 with
the boronate derivative 6.24 Compound 3 (2-{2-chloro-5-[4-(2-(4-
fluorophenyl)ethylamino)-6-(fluoromethoxy)-1,3,5-triazin-2-
yl]phenyl}propan-2-ol) was then prepared from 2 by demethyla-
tion of the methoxy group to afford the phenol 7, followed by
Boc protection of the free NH group and alkylation of the phenol
8 by fluoromethyltosylate25 to give the intermediate 9, and finally
removal of the Boc protecting group.
(PBR), also known as translocator protein 18 kDa (TSPO), have been
used since the mid 1980’s for PET imaging of neuroinflammation.
Similar to the CB2R, TSPO expression is very low in healthy brain
tissue, but it increases in diseases associated with neuroinflamma-
tion. The prototype TSPO PET tracer, [11C]-PK11195 1 (Fig. 1) has
been used to image neuroinflammation in patients with various
CNS disease such as stroke,14 multiple sclerosis15 and Alzheimer
disease16 but it also has several limitations such as high level of
nonspecific binding and poor signal-to-noise ratio.17 In addition,
the second generation TSPO ligands show heterogeneous low and
high affinity binding across human subjects due to the presence
of a TSPO polymorphism (rs6971). There is therefore still a need
to develop PET ligands for new molecular targets that could pro-
vide more sensitive and selective imaging biomarkers of neuroin-
flammation. Due to its specific properties, the CB2 receptor is an
interesting candidate and several CB2 ligands have been proposed
recently as PET tracers for imaging neuroinflammation.18 Preclini-
cal and preliminary clinical evaluation of [11C]-NE40, a 2-oxoquin-
oline CB2 ligand has been described recently.19,20
We present here the synthesis, radiolabelling and preliminary
in vitro and in vivo characterization of a new high affinity CB2 can-
nabinoid receptor ligand, compound 3 based on an original triazine
template.
The triazine 2 (Fig. 1) was selected from a proprietary library of
cannabinoid CB2 ligands as a starting point for the development of
a CB2 PET tracer due its favorable biochemical and physicochemi-
cal profile:
Similarly to 2, compound 3 was a potent ligand for human re-
combinant CB2 receptors expressed in CHO cells26 (IC50 = 1.4 nM)
and was selective versus human CB1 receptors (IC50 = 180 nM).
This selectivity ratio is above the value generally considered for
PET ligands which is in the range 30–100.27 In a functional assay
- high affinity for hCB2 receptor (IC50 = 0.58 nM)
- good selectivity versus hCB1 receptor (IC50 = 300 nM)
- moderate lipophilicity (c log D7.4 = 3.96; ACD Labs 7.0)
F
F
Cl
HN
HN
N
N
N
N
N
N
a
b
Cl
N
O
N
O
Cl
N
O
HO
Cl
4
5
2
F
c
F
O
N
O
N
HN
d
N
N
N
N
OH
HO
Cl
N
OH
HO
Cl
8
7
F
F
e
O
O
N
HN
N
N
N
N
f
HO
N
O
HO
N
O
9
3
F
Cl
F
Cl
Scheme 1. Synthesis of compounds 2 and 3. Reagents and conditions: (a) 1 equiv 2-(4-fluoro-phenyl)-ethylamine, 1 equiv DiPEA, ACN, 0 °C; (b) 1.2 equiv 2-[2-chloro-5-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propan-2-ol 6, 3 equiv CsCO3, 0.1 equiv Pd(dppf)Cl2, DME/H2O 4:1, reflux; (c) 60 equiv MeONa, MeOH, reflux; (d)
1.5 equiv Boc2O, 1 equiv CsCO3, THF, reflux; (e) 1 equiv fluoromethyltosylate, 2 equiv CsCO3, DMF in sealed tube 80 °C; and (f) 5 equiv TFA, DCM, rt.

L. Hortala et al. / Bioorg. Med. Chem. Lett. 24 (2014) 283–287
285
in CHO hCB2 CRE-luc cells,28 compound 3 behaved as a full agonist,
with an EC50 of 0.78 nM.
alkylated with distilled [18F]FCD2I, and NBoc group was removed
by heating the reaction mixture in 1 M HCl either at 120 °C for
2 min or at 90 °C for 5 min. Radiochemical experiments were
performed using a GE TRACER lab FXF–N synthesizer module, and
the final compound was purified using a semi preparative HPLC
system and a Eclipse XDB-C18 column. The overall yield was low
(0.3–1.6%), due to the inherent complexity of the fluoromethyla-
tion synthesis. [18F]-d2-3 was obtained with a radiochemical purity
To assess brain penetration, we measured drug levels in plasma
and brain following a single intravenous administration of 3 mg/kg
of compound 3 to male CD1 mice. Mean maximal brain concentra-
tion (2300 ng/g) was reached 5 min post-dosing (i.e., the first sam-
pling time) and declined in parallel with the plasma with a
moderate apparent terminal half-life (t1/2 = 0.96 h). Compound 3
was quantified in brain with a ‘brain/plasma’ exposure AUC (0-
inf) ratio assessed at 1.9, indicating a good penetration in mouse
brain.
superior to 90% and a specific activity of 117 mCi/
lmol.
[
18F]-d2-3 was evaluated in vivo in rhesus macaque (Macaca
mulatta) at baseline and following pretreatment with a selective
CB2 agonist (10)30 at 3.0 mg/kg, and in a neuroinflammation model
in baboon (Papio anubis) at baseline and following pretreatment
with the endotoxin lipopolysaccharides (LPS) at 0.1 and 0.05 mg/
kg. Compound 10 was administered intravenously (iv) 20 min
prior to the radiopharmaceutical injection, and LPS was adminis-
tered iv 4 h prior to the radiopharmaceutical. Following adminis-
tration of 110 34 MBq of [18F]-d2-3, PET images were acquired
over 180 min on a Siemens Focus 220 microPET camera for the rhe-
sus macaque and on a Siemens Biograph mCT camera for the ba-
boon (Siemens Healthcare Molecular Imaging, Knoxville, TN,
USA), with arterial blood samples drawn throughout. Radioactivity
To develop a suitable PET tracer from compound 3, we decided
to replace the CH2F group by deuterated CD218F. It has been re-
ported that [18F]fluoromethoxy radiotracers may be unstable in-
vivo because of defluorination, which leads to potentially high
bone uptake. Isotopic replacement with deuterium has been
shown to effectively reduce the defluorination rate in-vivo.29
[
18F]-d2-3 was obtained in three steps as described in Scheme 2.
Labelled fluoroiododideuteromethane [18F]-FCD2I was obtained
by reaction of CD2I2 with [18F] potassium fluoride in the presence
of potassium carbonate and Kryptofix 2.2.2 and subsequently dis-
tilled in a stream of helium. The phenol derivative 8 was then
D
I
D
I
F
F
O
N
a
O
N
N
HN
N
c
b
D
18F
D
I
N
D
N
N
D
HO
O
O
HO
18F
18F
Cl
Cl
D
D
18F]-d2-3
[
18F]-d2-9
[
Scheme 2. Synthesis of [18F]-d2-3. Reagents and conditions: (a) K18F, K2CO3, Kryptofix [2.2.2], ACN/H2O; (b) 8, CsCO3, DMF, 90 °C, 5 min; and (c) HCl 1 M, 90 °C, 5 min.
Parent Fraction
Whole Blood
100
10
1
1.0
0.8
0.6
0.4
0.2
0.0
Baseline
LPS 0.05mg/kg
LPS 0.1mg/kg
Baseline
LPS 0.05mg/kg
LPS 0.1mg/kg
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Time (min)
Time (min)
Plasma
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Frontal cortex
Occipital cortex
Temporal cortex
Parietal cortex
Cerebellum
100
10
1
Baseline
LPS 0.05mg/kg
LPS 0.1mg/kg
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Time (min)
Time (min)
Figure 2. (Top left) parent compound fraction in plasma, (top right) whole blood and (bottom left) total plasma (parent plus radiometabolites) time activity curves at baseline
and post administration of LPS at 0.1 and 0.05 mg/kg. (Bottom right) time activity curves in different regions at baseline in a baboon (Papio anubis) following intravenous
administration of [18F]-d2-3.

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L. Hortala et al. / Bioorg. Med. Chem. Lett. 24 (2014) 283–287
Figure 3. Average PET images at baseline in the axial (left), sagittal (middle) and coronal (right) planes in a baboon (Papio anubis) over the first 10 min following intravenous
administration of [18F]-d2-3.
in whole-blood and plasma was measured in all samples, radio-
metabolites were measured by reverse-phase HPLC in a subset of
samples and plasma protein binding free fraction was measured
by ultrafiltration (CentrifreeÒ, Millipore). PET images were aligned
onto the monkey structural T1-weighted MRI and a volume of
interest (VOI) template (including cortical regions and cerebellum)
was then applied to the PET series in MRI space to extract the re-
gional time activity curves (TAC). PET data was analyzed with Lo-
gan graphical analysis and the arterial input function of parent in
plasma to derive the distribution volume (encompassing both
nonspecific and specific binding).
These studies in nonhuman primates demonstrated brain pene-
tration of [18F]-d2-3 with a percent injected dose of 0.5% for the
whole brain and maximum SUV around 0.7–1.0 g/mL, and a suit-
able metabolism with slow decrease of the parent compound over
time and two radiometabolites both more polar than the parent.
Results obtained with the selective CB2 agonist 10 as well as in
the neuroinflammation model are encouraging. The decreased
parent curve as well as the increased distribution volume post
LPS administration are both suggestive of an increased CB2 expres-
sion in the tissue in response to the endotoxin, increasing the spe-
cific signal and the trapping of the radiopharmaceutical in the
tissue.
In normal rhesus macaque and baboon, HPLC analysis of arterial
plasma revealed two main radio-metabolites, both more polar than
the parent [18F]-d2-3 which was slowly metabolized with about
35% of intact parent remaining at 180 min post injection. The par-
ent fraction in plasma decreased faster post administration of LPS
with about 15% of parent remaining in arterial plasma at 180 min
post injection (see Fig. 2). On the other hand, whole-blood and
plasma activity curves decreased more slowly compared to the
baseline. Similar results were found with a translocator protein
(TSPO) radiopharmaceutical, another marker of inflammation, fol-
lowing injection of LPS at 0.1 mg/kg in female baboons.31 PET data
demonstrated brain penetration with an overall brain uptake of
about 0.5% of the injected dose for the whole brain. Similar uptake
was seen in the different brain regions with a maximum SUV of
about 0.7–1.0 g/mL (see Figs. 2 and 3) detected within the first
20 min of imaging. At baseline, the distribution volume (equivalent
to the brain/plasma AUC(0-inf) ratio) was estimated around
2.0 mL/cm3, consistent with the findings in mouse brain. Following
pretreatment with 10, the distribution volume was reduced to
about 1.0–1.2 throughout the brain, suggesting blocking of the
CB2 specific signal by the selective CB2 agonist 10. On the other
hand, pretreatment with the endotoxin LPS resulted in an increase
of about 30% of the distribution volume at both doses of 0.1 and
0.05 mg/kg (see Table 1), again similar to findings obtained
with a TSPO radiopharmaceutical post administration of LPS at
0.1 mg/kg.31
In summary, [18F]-d2-3, a high affinity CB2 radioligand for PET
imaging was synthesized via a three step radiosynthesis by alkyl-
ation of the phenol precursor 9 with [18F]-FCD2I followed by NBoc
group removal. [18F]-d2-3 demonstrated significant brain uptake
and moderate washout over time in rhesus macaque and baboon.
This tracer is a promising candidate for the in vivo evaluation of
neuroinflammation and progression of disease. Further experi-
ments are needed in order to evaluate global and regional brain up-
take in neuroinflammation models.
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Baseline
Endotoxin LPS 0.1 mpk
Endotoxin LPS 0.05 mpk
Brainstem
Midbrain
Frontal
Temporal
Parietal
2.2
2.3
2.1
1.9
2.1
1.8
1.9
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3.1
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2.6
Occipital
Cerebellum

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