Synthesis and biological evaluation of novel 2,3-dihydro-1H-1,5- benzodiazepin-2-ones; Potential imaging agents of the metabotropic glutamate 2 receptor

Article abstract of DOI:10.1039/c3md00110e

A focused library of novel 2,3-dihydro-1H-1,5-benzodiazepin-2-ones containing sites for ¹¹C-, ¹⁸F- and ¹²³I- labelling have been prepared and evaluated against membrane expressing human recombinant metabotropic glutamate 2 receptor (mGluR2). The compounds were found to be non-competitive antagonists with nanomolar affinity. HPLC evaluation of the physiochemical properties of these compounds identified two candidates for PET and SPECT imaging of mGluR2.

Full text of DOI:10.1039/c3md00110e

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Synthesis and biological evaluation of novel 2,3-
dihydro-1H-1,5-benzodiazepin-2-ones; potential
imaging agents of the metabotropic glutamate 2
receptor†
Cite this: Med. Chem. Commun., 2013,
4, 1118
Lynne Gilfillan,a Adele Blair,a Brian J. Morris,b Judith A. Pratt,c Lutz Schweiger,d
e
a
*
Sally Pimlott and Andrew Sutherland
A focused library of novel 2,3-dihydro-1H-1,5-benzodiazepin-2-ones containing sites for 11C-, 18F- and 123I-
labelling have been prepared and evaluated against membrane expressing human recombinant
metabotropic glutamate 2 receptor (mGluR2). The compounds were found to be non-competitive
antagonists with nanomolar affinity. HPLC evaluation of the physiochemical properties of these
compounds identified two candidates for PET and SPECT imaging of mGluR2.
Received 16th April 2013
Accepted 23rd May 2013
DOI: 10.1039/c3md00110e
www.rsc.org/medchemcomm
while mGluR2/3 antagonists may be useful as anti-depressants
and cognitive enhancers.4b,5,6 Recently, Woltering and co-workers
Introduction
Metabotropic glutamate receptors (mGluR) are a superfamily of
G-protein coupled receptors found embedded within cell
membranes. In the central nervous system (CNS), they modu-
late L-glutamate neurotransmission and are also considered to
affect dopaminergic and adrenergic neurotransmission.1 Eight
members of the family of mGluRs (1–8) have been cloned and
are separated into three groups based on their signal induction
pathway and sequence homology.2 Group 1 receptors (mGluR1
and 5) are positively coupled to the activity of phospholipase C,
whereas group II (mGluR2 and 3) and group III (mGluR4 and
6–8) receptors which have a different pharmacology, are both
negatively coupled to the activity of adenyl cyclase.3
initiated a programme of research to nd new mGluR2/3 ligands
with increased receptor selectivity and improved physiochemical
properties.7 Through a random screening programme, a library
of compounds based on a 2,3-dihydro-1H-1,5-benzodiazepin-2-
one core 1 (Fig. 1) were identied that showed excellent affinity as
non-competitive antagonists when tested against rat mGluR2
receptors. The most potent series of compounds contained 5- and
The development of pharmacological agents targeting the
mGluRs has been recognised as a possible approach for the
treatment of various CNS disorders such as depression, anxiety
and schizophrenia.4 More specically, mGluR2/3 agonists have
been shown to exhibit anxiolytic and antipsychotic properties
aWestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow, G12 8QQ, UK. E-mail: Andrew.Sutherland@glasgow.ac.uk; Fax: +44 (0)
141 330 4888; Tel: +44 (0)141 330 5936
bInstitute of Neuroscience and Psychology, University of Glasgow, Glasgow, G12 8QQ,
UK
cCentre for Neuroscience, Strathclyde Institute of Pharmacy and Biomedical Sciences,
University of Strathclyde, Glasgow, G4 0RE, UK
dJohn Mallard Scottish PET Centre, School of Medicine and Dentistry, University of
Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK
eWest of Scotland Radionuclide Dispensary, University of Glasgow and North Glasgow
University Hospital NHS Trust, Glasgow, G11 6NT, UK
† Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic data for all compounds synthesised, details of biological evaluation
and HPLC methods, as well as NMR spectra for all new compounds. See DOI:
10.1039/c3md00110e
Fig. 1 2,3-Dihydro-1H-1,5-benzodiazepin-2-one derivatives.
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6-membered heterocyclic motifs such as 1-imidazoles, 1,2,3-tri-
azoles and 4-pyridines at the 30-position (R3).
We have a longstanding interest in developing molecular
tracers for positron emission tomography (PET) and single
photon emission computed tomography (SPECT) imaging of
neurological receptor targets.8 Based on the 30-imidazole derived
2,3-dihydro-1H-1,5-benzodiazepin-2-ones identied by the Wol-
tering group, we proposed to discover novel candidates that could
be used for PET and SPECT imaging of mGluR2 in schizophrenia.
Such compounds would have the potential to be used for the
diagnosis of schizophrenia as well as in the evaluation of new
drugs and in the measurement of treatment response.
Herein, we report our studies on the design and synthesis of
novel 30-imidazole derived 2,3-dihydro-1H-1,5-benzodiazepin-2-
ones bearing an iodophenyl moiety (2, 3) for SPECT imaging or
methyl and uoro groups (4, 5) for PET imaging as well as a
compound with multiple labelling sites (6) which could be used
for either modality (Fig. 1). We also report the biological
assessment of these compounds against membrane expressing
human recombinant mGluR2 as well as their suitability as
neurological imaging agents by the evaluation of their physi-
ochemical properties.
Scheme 2 Reagents and conditions: (a) NH3, 1,4-dioxane, 100 ꢀC, 76%; (b)
MeOH, KOH, DMSO, 60 ꢀC, 97%; (c) 3-fluoropropan-1-ol, K2CO3, DMSO, 120 ꢀC,
71%; (d) Boc2O (2.2 eq.), Et3N, DMAP (0.2 eq.), CH2Cl2, 95% (R ¼ Me), 82% (R ¼ 3-
F-propyl); (e) TFA, CH2Cl2, 16 (100%), 17 (98%).
using potassium carbonate as the base gave the corresponding
bi-phenyl derivatives 10 and 11 in good overall yields.
The aromatic core for the generation of the potential PET
tracers was prepared as shown in Scheme 2. 1,5-Dichloro-2-
nitro-4-(triuoromethyl)benzene (12) was selectively aminated
with ammonia to give 13 in good yield.11 Introduction of the
potential PET labels by nucleophilic aromatic substitution of 13
with either methanol or 3-uoropropan-1-ol gave alkoxy deriv-
atives 14 and 15. Application of the two-step approach for Boc-
protection of the anilines then gave compounds 16 and 17.
The nal compound prepared in this series required both an
iodophenyl group and methoxy moiety for application in either
SPECT or PET imaging, respectively. The 1,2-diaminobenzene
core was initially prepared from 2-nitro-5-chloroaniline (18)
which was subjected to a regioselective iodination with iodine
monochloride (Scheme 3). Nucleophilic aromatic substitution
at the 5-position with methanol allowed introduction of the
methoxy group in excellent yield. The two-step Boc-protection
sequence was then employed to give 21 and this was followed by
a Suzuki–Miyaura reaction with 4-bromophenylboronic acid to
give functionalised biphenyl 22 in good yield over the ve steps.
The nal stage of the synthesis of the selectively protected 1,2-
diaminobenzenes required the reduction of the 2-nitro group. As
several of these compounds (10, 11 and 22) contained labile
Results and discussion
We began our studies with the synthesis of 3- and 4-iodophenyl
derivatives for application in SPECT imaging. Our general
strategy involved the preparation of selectively protected 1,2-
diaminobenzenes which could be coupled and cyclised with a
b-keto ester to generate the 2,3-dihydro-1H-1,5-benzodiazepin-
2-one core. Iodination would then be incorporated at the last
stage allowing this step to be modied for eventual radio-
iodination. As such, 2-nitroaniline (7) was iodinated regiose-
lectively using iodine monochloride9 and this was converted to
Boc-protected derivative 9 using a two-step strategy involving di-
protection,10 followed by selective removal of one of the Boc-
protecting groups (Scheme 1). This approach was found to be
more efficient for all 1,2-diaminobenzenes prepared during this
study rather than direct mono-Boc protection of the aniline. A
palladium(0)-mediated Suzuki–Miyaura reaction under stan-
dard conditions with 3- or 4-bromophenylboronic acid and
Scheme 3 Reagents and conditions: (a) ICl, NaOAc, AcOH, 80 ꢀC, 92%; (b)
MeOH, KOH, DMSO, 60 ꢀC, 94%; (c) Boc2O (2.2 eq.), Et3N, DMAP (0.2 eq.), CH2Cl2,
96%; (d) TFA, CH2Cl2, 100%; (e) 4-I-PhB(OH)2, (Ph3P)4Pd (2 mol%), K2CO3, DMF–
H2O, 66%.
Scheme 1 Reagents and conditions: (a) ICl, NaOAc, AcOH, 90 ꢀC, 88%; (b) Boc2O
(2.2 eq.), Et3N, DMAP (0.2 eq.), CH2Cl2, 70%; (c) TFA, CH2Cl2, 98%; (d) 3- or 4-I-
PhB(OH)2, (Ph3P)4Pd (2 mol%), K2CO3, DMF–H2O, 10 (72%), 11 (78%).
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stannylation of the bromides with hexamethylditin was fol-
lowed by an oxidative iododestannylation and this gave the
target iodides, 2, 3 and 6 cleanly, in good yields over the two
steps (Scheme 5).
With the series of 2,3-dihydro-1H-1,5-benzodiazepin-2-ones
in hand, a functional [35S]GTPgS assay using membrane
expressing human mGluR2 was optimised.16 The [35S]GTPgS
assay is commonly used to determine binding to G-protein
coupled receptors in vitro. On stimulation of the receptor, in
this case mGluR2, with an agonist such as L-glutamate, [35S]-
guanosine 50-(g-thio)triphosphate ([35S]GTPgS) binds irrevers-
ibly to the Ga subunit of the G-protein. This accumulation of
[35S]GTPgS can be quantied by liquid scintillation analysis.
Addition of a non-competitive antagonist disrupts binding of
the agonist and thus, lowers accumulation of the [35S]GTPgS.
Before biological testing of the 2,3-dihydro-1H-1,5-benzo-
diazepin-2-ones, control experiments were performed to
Scheme 4 Reagents and conditions: (a) SnCl2$2H2O, EtOAc/pyridine, 23 (91%),
24 (72%), 25 (63%), 26 (85%), 27 (83%), 28 (75%); (b) 40% glyoxyl, MeOH then
NH4Cl, CH2O, H3PO4, 58%; (c) t-BuOAc, LiHMDS, THF, 80%; (d) D, toluene; (e) TFA,
CH2Cl2, yields over two steps: 31 (39%), 32 (55%), 33 (66%), 4 (48%), 5 (72%), 34
(69%).
Scheme 5 Reagents and conditions: (a) (Me3Sn)2, (Ph3P)4Pd (10 mol%), 1,4-
dioxane, 90 ꢀC; (b) NaI, chloramine-T, EtOH, 2 (69%), 3 (42%), 6 (47%).
carbon–bromine bonds, a mild procedure was required. Initial
attempts using transfer hydrogenation with ammonium formate
led to reduction of both the bromide and nitro groups. However,
a successful transformation was identied using tin(II) chloride
dihydrate which led to the reduction of 9–11, 16, 17 and 22 under
basic conditions in generally high yields (Scheme 4).12 The b-keto
ester fragment 30 required for coupling with the 1,2-dia-
minobenzenes to generate the 2,3-dihydro-1H-1,5-benzodiaze-
pin-2-ones was prepared using a two stage approach. Methyl
3-(10H-imidazol-10-yl)benzoate was initially synthesised from
methyl 3-aminobenzoate (29) using an imidazole ring synthesis
described by Zhang and co-workers.13 Claisen condensation with
tert-butyl acetate gave 30 in 80% yield.14 Coupling of 30 with the
1,2-diaminobenzenes was performed under reux to give the
corresponding b-ketoamides.7 Subsequent treatment with TFA to
remove the Boc-protecting group and facilitate cyclisation led to
the isolation of the 2,3-dihydro-1H-1,5-benzodiazepin-2-ones in
good yields over the two steps.
The nal stage of the synthesis of the SPECT compounds
involved the iodination of the bromophenyl groups. Initial
attempts using a direct copper catalysed halogen exchange
reaction resulted in only isomerisation of the cyclic imine to the
Fig.
2
Graphs of control experiments with membrane expressing human
mGluR2, at: (a) 100 mM L-glutamate and (b) 10 mM L-glutamate (DPM ¼ disinte-
corresponding enamine.15 Instead, a palladium(0)-mediated grations per minute).
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optimise the assay. Initially, addition of [35S]GTPgS and
guanosine diphosphate to the membrane showed the expected
basal binding (Fig. 2a). Stimulation with 100 mM L-glutamate
resulted in a 117% increase over basal binding. Next, addition
of the known competitive antagonist LY341495 (10 mM) showed
the expected reduction of binding back to basal level.17 To gauge
the level of non-specic binding of [35S]GTPgS, the assay was
repeated with the addition of 10 mM [32S]GTPgS. This conrmed
the high specicity of [35S]GTPgS for the G-protein. Finally, a
further series of experiments using only 10 mM L-glutamate
showed a similar level of stimulation (95%) and therefore, this
Table 2 Physiochemical values
log Pa
Pm
Km
218.40
%PPBc
b
b
Compound
31
2
3
4
5
4.60
5.73
5.77
4.67
5.06
5.72
0.51
>2.27
>2.27
0.44
0.77
>2.13
94.92
98.46
98.67
92.41
95.12
98.32
>1144.81
>1144.81
176.15
343.73
>1138.17
6
a
b
Determined using C18 column. Determined using immobilised
c
articial membrane (IAM) column. Determined using human serum
albumin (HSA) coated column.
Table 1 Inhibition of membrane expressing human recombinant mGluR2 by
2,3-dihydro-1H-1,5-benzodiazepin-2-ones
concentration was used during the biological evaluation of the
2,3-dihydro-1H-1,5-benzodiazepin-2-ones (Fig. 2b).
Compound
IC50a (nM)
As a standard, commercially available Ro 64-5229 35, a
known selective non-competitive mGluR2 antagonist was
initially tested using the assay described above. This produced
an IC50 value (533 nM) of similar magnitude to that previously
reported for 35 when tested against rat mGluR2 transfected cell
membranes (Table 1).18 The series of 2,3-dihydro-1H-1,5-ben-
zodiazepin-2-ones were then evaluated. As can be observed for
Table 1, all of the compounds showed excellent affinity for
mGluR2 with IC50 values ranging from 89 to 133 nM. In
particular, the sterically less-encumbered compounds 31 and 4
showed six times more potency than the standard, non-
competitive antagonist, Ro 64-5229 35.19
Selecting potential candidates as neurological imaging agents
for further development requires determination of a range of
physiochemical properties. For the compound to transverse brain
capillary endothelial cells and penetrate the blood brain barrier,
permeability across the plasma membrane is important.
Furthermore, for compounds which mainly transport across cell
membranes through passive diffusion, determining the
membrane partition coefficient is crucial for successful develop-
ment. Based on a recently reported study of HPLC methods for
determining these key physiochemical properties of imaging
agents,20 the partition coefficient (log P), permeability (Pm), the
membrane partition coefficient (Km) and the percentage of
plasma protein binding (%PPB) of all six 2,3-dihydro-1H-1,5-
benzodiazepin-2-ones were assessed (Table 2). The previously
reported study performed by Tavares et al., of ten successful
imaging agents established the limits of each of these parameters
(log P < 4, Pm < 0.5, Km < 250, %PPB < 95%). Based on these
criteria, compounds 31 and 4 were found to have the best physi-
ochemical properties for further development. While the log P
values were just above the acceptable limit, Tavares et al., do
emphasise that log P is the weakest predictor of brain penetration.
More importantly, 31 and 4 gave excellent results for permeability,
membrane partition coefficient and percentage of plasma protein
binding. Based on these results, 31 and 4 have been selected for
further development as molecular imaging agents for mGluR2.
Having established 2,3-dihydro-1H-1,5-benzodiazepin-2-ones
31 and 4 as potential imaging agents for mGluR2, it was impor-
tant to identify synthetic approaches for the radiolabelling of
these compounds. Radioiodination of compound 31 for SPECT
533 ꢁ 27
89 ꢁ 5
132 ꢁ 7
133 ꢁ 24
91 ꢁ 30
100 ꢁ 14
89 ꢁ 46
a
IC50 values are the mean ꢁ SD of three independent experiments
except for compounds 3 and 6, where n ¼ 2.19
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imaging could be envisaged using the standard two-step stan- allows rapid access to a precursor which on alkylation with [11C]-
nylation/oxidative iodo-destannylation already utilised for the methyl iodide would give the radiolabelled version of compound
synthesis of compounds 2, 3 and 6 (Scheme 5). Thus, application 4 for PET imaging. Alkylation with other groups would also result
of this approach with 31 as the precursor and using [123I]- or in the late-stage preparation of further non-labelled analogues in
[
125I]-sodium iodide would allow introduction of radioiodine at this series for biological testing.
the nal step. While there are toxicity issues in using organotin
compounds for the preparation of neurological SPECT imaging
agents, the radioiodinated products are generally puried to a
high level using HPLC.
Conclusions
In summary, six novel 2,3-dihydro-1H-1,5-benzodiazepin-2-ones
The synthesis described for the preparation of compound 4 bearing sites for radiolabelling have been successfully prepared
(Schemes 2 and 4) where the methyl group is introduced at an using a two-stage convergent approach involving the coupling
early stage would not be amenable to [11C]-labelling of this and cyclisation of a range of 1,2-diaminobenzenes with an
compound. Therefore, a synthetic route was developed to a imidazole derived b-keto ester. Biological evaluation of these
suitable precursor that would allow [11C]-methylation as the nal compounds against membrane expressing human mGluR2
step (Scheme 6). Previously synthesised chloroaniline 13 was using a functional [35S]GTPgS assay showed these compounds
subjected to a nucleophilic aromatic substitution reaction with to have excellent affinity as non-competitive antagonists for
benzyl alcohol which gave 36 in 60% yield. Boc-protection of 36 mGluR2. Evaluation of the key physiochemical properties
using the two-step approach followed by reduction of the nitro- required for a successful neurological imaging agent using
group with tin(II) chloride dihydrate gave selectively protected 1,2- established HPLC methods identied compounds 31 and 4 as
diaminobenzene 38 in excellent overall yield. Coupling of 38 with potential SPECT and PET tracers for mGluR2, respectively.
b-keto ester 30 and TFA mediated cyclisation gave 2,3-dihydro- Work is currently underway to establish a radiosynthesis of
1H-1,5-benzodiazepin-2-one 39 in 65% yield over the two steps. these compounds from precursors 31 and 40 and evaluate their
Finally, removal of the benzyl protecting group using boron tri- mGluR selectivity and biodistribution in vivo.
bromide gave phenol 40 in 81% yield. This seven-step approach
Acknowledgements
The authors gratefully acknowledge nancial support from
SINAPSE (studentship to LG), the Scottish Funding Council
(studentship to AB) and the University of Glasgow.
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1122 | Med. Chem. Commun., 2013, 4, 1118–1123
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