Structure-activity relationships of novel iodinated quinoline-2- carboxamides for targeting the translocator protein

Article abstract of DOI:10.1039/c3md00249g

In an effort to develop a new SPECT imaging agent for the translocator protein (TSPO), a series of novel iodinated quinoline-2-carboxamides have been synthesised and evaluated for binding affinity using rat brain homogenates. The outcome of the biological testing in combination with HPLC determination of the physicochemical properties of these compounds directed the design of new analogues resulting in 4-(2-iodophenyl)quinoline-2-N-diethylcarboxamide, a new TSPO ligand with higher affinity than the widely used clinical imaging agent PK11195.

Full text of DOI:10.1039/c3md00249g

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CONCISE ARTICLE
Structure–activity relationships of novel iodinated
quinoline-2-carboxamides for targeting the translocator
protein†
Cite this: Med. Chem. Commun., 2013,
4, 1461
Adele Blair,a Louise Stevenson,a Deborah Dewar,b Sally L. Pimlottc
a
*
and Andrew Sutherland
In an effort to develop a new SPECT imaging agent for the translocator protein (TSPO), a series of novel
iodinated quinoline-2-carboxamides have been synthesised and evaluated for binding affinity using rat
brain homogenates. The outcome of the biological testing in combination with HPLC determination of
the physicochemical properties of these compounds directed the design of new analogues resulting in
4-(2-iodophenyl)quinoline-2-N-diethylcarboxamide, a new TSPO ligand with higher affinity than the
widely used clinical imaging agent PK11195.
Received 3rd September 2013
Accepted 16th September 2013
DOI: 10.1039/c3md00249g
www.rsc.org/medchemcomm
The translocator protein (TSPO; 18 kDa), formerly known as the
The role of the TSPO as a marker for neuroinammation has
peripheral benzodiazepine receptor (PBR), is a highly hydro- resulted in the development of various radiolabelled high affinity
phobic, tryptophan-rich protein with ve trans-membrane agents that can be used for in vivo imaging of disease progression
spanning domains principally consisting of large a-helicies.1 in combination with functional modalities such as positron
The TSPO is an outer mitochondrial membrane protein found emission tomography (PET) and single photon emission
in many of the major organs such as the lung, heart, liver and computed tomography (SPECT).9,10 The most widely used ligand
kidney, and its role while tissue specic, revolves primarily is the isoquinoline carboxamide PK11195 1 (Fig. 1). [11C]- and
around steroid biosynthesis.2 The TSPO is also found in low
[
123I]-versions of PK11195 have been prepared for PET and
concentrations throughout the brain.3 Following chronic neu- SPECT studies,11,12 respectively and have provided evidence of
rodegeneration or acute brain injury, TSPO expression is continuing brain inammation in patients with various disorders
dramatically increased.4 In vivo studies in patients suffering such as dementia,13 encephalitis,14 multiple sclerosis,15 Parkin-
from Alzheimer's disease and multiple sclerosis showed TSPO son's disease16 and stroke.17 However, PK11195 has a number of
binding to be mainly localised in activated microglia.5 Microglia limitations including a high level of non-specic binding and a
are extremely sensitive to alterations in their microenviron- poor signal to noise ratio which complicates its quantication.10a
ment, and thus become activated due to injury or infection, The limitations of PK11195 have resulted in the development of
releasing pro-inammatory cytokines.6 As a consequence, TSPO several new classes of TSPO ligand, such as PBR28 2 (Fig. 1) that
expression and associated microglial activation are associated have improved physicochemical properties.10
with the early stages of neuroinammation in many human
Unfortunately, recent studies by Owens and co-workers have
degenerative diseases such as Alzheimer's disease7 and in shown that with the exception of PK11195, all TSPO PET ligands
stroke-induced brain injury.8 This makes the TSPO an attractive in current clinical application show substantial variability
diagnostic and therapeutic target for the treatment and study of between human subjects, recognising high-affinity, low-affinity
diseases associated with neuroinammation.1
or mixed-affinity binders in brain tissue in vitro.18 For these
aWestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow, G12 8QQ, UK. E-mail: Andrew.Sutherland@glasgow.ac.uk; Tel: +44 (0)141
330 5936
bInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life
Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
cWest 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/c3md00249g
Fig. 1 PK11195 1 and PBR28 2, examples of high affinity ligands of TSPO.
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Fig. 2 Iodinated quinoline-2-carboxamides.
reasons, our search for a highly selective, high-affinity ligand
with suitable physicochemical properties for SPECT imaging of
TSPO has focused on structural analogues of PK11195. Based on
a quinoline-2-carboxamide motif originally identied by Cappelli
and co-workers,19 we prepared previously a series of compounds
composed of two structural variants, 3-iodomethylquinoline-2-
carboxamides and quinoline-2-carboxamides with iodinated
benzyl amides.20 As well as identifying N,N-diethyl-3-iodomethyl-
4-phenylquinoline-2-carboxamide (3) (Fig. 2) as a highly potent
ligand (Ki 12.0 nM) of TSPO, this work also generated some
insight regarding the size of amide side chain accommodated by
the TSPO binding pocket and further conrmed the requirement
of semi-rigid compounds for high affinity.
In this current study, our principle aim was to explore for the
rst time, the incorporation of an iodine atom into various
aromatic positions of the 4-phenylquinoline motif. This led to
the design of 6-iodo- and 8-iodoquinoline-2-carboxamides 4 as
well as 4-(2-iodophenyl)quinoline-2-carboxamides 5. We now
report the synthesis, biological evaluation and physicochemical
properties of this new generation of iodinated quinoline-2-
carboxamides.
Scheme 1 Reagents and conditions: (a) TMSCl, DMF, 100 ꢀC, 85%; (b) 6M HCl,
EtOH, D, 91%; (c) (i) LiAlH4, THF; (ii) 10% Pd/C, MeOH, 77%; (d) MnO2, CHCl3,
92%; (e) dimethylamine or morpholine, Me3Al, CH2Cl2, D (60% and 86%,
respectively); (f) (i) SOCl2, CH2Cl2; (ii) NaI, MeCN, D (12: 52%, 13: 59%).
To study the effect of incorporation of an iodine atom within
the benzene ring of the quinoline moiety, a 6-iodoquinoline-2-
carboxamide was targeted (Scheme 2). A 6-iodoquinoline-2-
carboxamide core was rapidly assembled using a one-pot
multicomponent reaction of 4-iodoaniline with ethyl glyoxalate
Results and discussion
While 3-iodomethylquinoline 3 showed high affinity for the (15) and phenylacetylene (14) in the presence of catalytic iodine
TSPO, its poor physicochemical data meant it was unlikely to be and air.23 This condensation/imino-Diels–Alder reaction/iso-
further developed as a SPECT imaging agent. Therefore, our merisation/aromatisation sequence of transformations gave
initial aim was the preparation of less lipophilic analogues of 3. ethyl 6-iodo-4-phenylquinoline-2-carboxamide (16) in 50%
As shown in Scheme 1, N,N-dimethyl-3-iodomethyl-4-phenyl- yield. Hydrolysis of the ester under standard conditions was
quinoline-2-carboxamide (12) and 3-iodomethyl-4-phenyl- followed by formation of the acid chloride and reaction with
quinoline-2-N-morpholinecarboxamide (13) were chosen as morpholine to give quinoline-2-carboxamide 22 in good overall
¨
targets. A one-pot Friedlander condensation using 2-amino- yield. To compare the steric inuence of a substituent at the
benzophenone (6) and ethyl 4-chloroacetoacetate (7) in the 6-position, the corresponding uoride analogue 23 was also
presence of chlorotrimethylsilane gave the corresponding prepared using 4-uoroaniline as the starting material and the
quinoline-3-carboxyl ester 8 in 85% yield.21 Lactonisation under same sequence of reactions. A similar approach was utilised for
acidic conditions then gave 9 in 91% yield.22 Switching the the preparation of an 8-iodoquinoline-2-carboxamide. Initially,
lactone position from C-3 to C-2 was achieved by reduction to formation of the 8-iodoquinoline was attempted using 2-
diol 10, followed by a regioselective oxidation with manganese iodoaniline and the iodine-catalysed multicomponent reaction.
dioxide. Optimisation of this ve-step route allowed the scalable However, this returned none of the desired 8-iodoquinoline-2-
synthesis of lactone 11 in 55% overall yield. Treatment of 11 carboxamide. Instead, 2-iodoaniline was condensed with ethyl
with trimethylaluminium and either dimethylamine or mor- glyoxalate (15) using anhydrous magnesium sulfate as a dehy-
pholine gave the corresponding 3-hydroxymethylquinoline-2- drating agent (Scheme 2). The resulting imine was then subjected
carboxamides. Chlorination of the hydroxymethyl group with to
a copper-catalysed tandem Grignard-type addition with
thionyl chloride followed by a substitution reaction with phenylacetylene followed by a Friedel–Cras alkenylation,24 which
sodium iodide gave compounds 12 and 13 in good overall yield. gave the challenging 8-iodoquinoline-2-carboxamide target 18 in
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Scheme 2 Reagents and conditions: (a) I2, MeNO2, (16: 50%, 17: 57%) or (a)
MgSO4, CH2Cl2, then Cu(OTf)2, (18: 22%); (b) NaOH, EtOH/H2O, D, (19: 70%, 20:
82%, 21: 84%); (c) (COCl)2, DMF, CH2Cl2, D; (d) morpholine, CH2Cl2, D, (22: 92%,
23: 61%, 24: 57%).
Scheme 3 Reagents and conditions: (a) (i) p-TsOH, cyclohexane, D; (ii) PPA, 120 ꢀC,
48%; (b) POBr3, K2CO3, MeCN, D, 99%; (c) 2-nitrophenylboronic acid, Pd(PPh3)4,
K3PO4, DMF, 120 ꢀC, 91%; (d) SnCl2$2H2O, EtOH, D, 99%; (e) p-TsOH$H2O, MeCN
then NaNO2, KI, H2O, 83%; (f) NaOH, EtOH, H2O, D, 100%; (g) (COCl)2, DMF, CH2Cl2,
D; (h) morpholine or diethylamine, CH2Cl2, D, (31: 60%, 32: 51%).
an optimised 22% yield. Hydrolysis of the ester, formation of the
acid chloride and reaction with morpholine gave 8-iodoquino-
line-2-carboxamide 24. A morpholine amide for targets 22–24
was selected so that the biological and physical properties of all
three compounds and that of 3-iodomethylquinoline-2-carbox-
amide 13, could be directly compared. Furthermore, it was conditions.29 Following the previously reported diethyl
proposed that a more rigid amide could facilitate binding of analogue 3 which had a Ki of 12.0 nM but poor physicochemical
these compounds to the TSPO.
properties,20 compounds 12 and 13 were designed with amide
To mimic the position of the halogen in PK11195 1, two nal side chains that would lower lipophilicity.30 The analogous
compounds incorporating an iodine atom at the ortho-position dimethyl compound 12 proved to be signicantly less potent
of the phenyl ring were prepared (Scheme 3). The quinoline core than 3 (Table 1), which may be a consequence of a lower barrier
was prepared by condensation of aniline (25) with diethyl oxal- to rotation of the smaller amide group. The more rigid and
acetate (26), followed by an acid-mediated ring closure of the larger morpholine carboxamide 13 retained signicant binding
resulting imine.25 Bromination with phosphorus oxybromide and affinity with a Ki value of 27.8 nM. Furthermore, with better
a Suzuki–Miyaura reaction with 2-nitrophenylboronic acid gave physicochemical properties than 3, this iodomethylquinoline-2-
28 in excellent yield. The 2-nitro group was then used to incor- carboxamide will serve as a lead for the future development of
porate the iodine atom. Initially, the nitro group was reduced to compounds from this class.
the corresponding amine using tin(II) chloride dihydrate.26
As a morpholine amide showed promise with the 3-iodo-
Diazotisation followed by a Sandmeyer reaction with potassium methylquinoline-2-carboxamide series, it was proposed to utilise
iodide gave 29 in 83% yield.27 Hydrolysis of the ethyl ester, this group for the development of new compounds incorporating
formation of the acid chloride and reaction with morpholine or an iodine atom at the 6- and 8-position of the benzene ring of the
diethylamine gave targets 31 and 32 in good overall yield.
quinoline moiety. For both of these compounds 22 and 24, the
As each class of compound was prepared, it was tested for binding affinity with the TSPO was found to be particularly low
binding affinity against the TSPO. A competition binding assay (0.030 and 0.076 mM, respectively; Table 1). The proposed
with rat brain homogenates measuring the displacement of binding site of these ligands is composed of two lipophilic
[3H]-PK11195 was used.28 In this study, the binding affinity of pockets which accommodate the aryl groups as well as a pocket
PK11195 1 was also determined for direct comparison with the requiring a H-donor bond that binds the amide moiety.1a These
new compounds (Table 1). The rst set of compounds tested results clearly demonstrate that substituents on the benzene ring
were the 3-iodomethylquinoline-2-carboxamides 12 and 13. of the quinoline have a dramatic effect on the ability of these
Although the iodomethyl moiety is a well-known alkylating compounds to bind within these lipophilic pockets and that for
agent, the presence of bulky di-ortho-substituents mean that high affinity, this part of the quinoline must be free of substit-
these compounds are relatively stable under physiological uents. This theory was supported with the biological testing of
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Table 1 Binding affinity of quinoline-2-carboxamides 12, 13, 22, 23, 24, 31 and
32 with the TSPO
Table 2 Physicochemical values
Compound
Pm
Km
%PPBb
a
a
Compound
Ki (nM)a
clog Pb
1
0.64
0.55
0.54
0.55
0.25
0.41
0.26
0.67
225.78
238.61
246.85
244.35
84.09
182.15
115.34
287.03
92.28
95.02
95.30
95.38
87.75
98.19
91.24
94.09
12
13
22
23
24
31
32
10.0 ꢁ 0.3
4.62
a
Determined using immobilised articial membrane (IAM) column.
Determined using human serum albumin (HSA) coated column.
b
1339 ꢁ 168
27.8 ꢁ 2.9
3.57
3.74
4.09
3.11
4.09
3.57
As 6- and 8-iodo-substituents interfered with binding to the
TSPO, incorporation of iodine at other positions was consid-
ered. ortho-Substituents on the pendent phenyl ring produce
relatively rigid compounds that retard rotation of the carbox-
amide such as PK11195 1. Therefore, two 4-(2-iodophenyl)-
quinoline-2-carboxamides 31 and 32 were prepared and tested
against the TSPO (Table 1). Surprisingly, 31 bearing a mor-
pholine amide showed relatively low affinity for the TSPO with a
Ki value of 929 nM. This may be due to a combination of the
relatively large amide side chain and the large ortho-substituent
on the phenyl ring preventing the correct conformation for
effective binding to the TSPO. However, diethyl analogue 32 was
found to have particularly high affinity for the TSPO with a Ki
value of 5.01 nM, twice the potency of PK11195 1 in our assay. In
this case, a better balance has been achieved with the large
iodine atom and a relatively bulky tertiary amide providing both
rigidity that prevents complete rotation of the amide but also
some exibility allowing the best conformation for effective
binding to the TSPO.
To further assess these compounds as potential neurological
imaging agents, the permeability (Pm), the membrane partition
coefficient (Km) and the percentage of plasma protein binding
(%PPB) were determined for each compound using HPLC
methods (Table 2).28 A previously reported study established the
limits of these parameters for predicting in vivo performance of
a potentially useful imaging agent (Pm < 0.5, Km < 250, %PPB <
95%).31 Based on this criteria, the highly potent 3-iodome-
thylquinoline-2-carboxamide 13 has better permeability than
PK11195 1 (as well as a lower log P value, Table 1). The
membrane partition coefficient and percentage of plasma
protein binding are also within acceptable limits. The other
highly potent compound, 4-(2-iodophenyl)quinoline-2-carbox-
amide 32 was found to have a suitable value for percentage of
plasma protein binding, while both permeability and the
membrane partition coefficient were just above the acceptable
upper limits. Although the physicochemical values for 32 are
not ideal, they are encouraging enough to warrant further
development of 32 as a molecular imaging agent for the TSPO.
29890 ꢁ 12090
5738 ꢁ 1057
76100 ꢁ 6550
929 ꢁ 243
5.01 ꢁ 1.13
4.47
a
Ki values are the mean ꢁ SD of three independent experiments, except
b
for compounds 22 and 24, where n ¼ 2. Calculated using ChemDraw
Ultra 9.0.1.
the 6-uoroquinoline 23 which showed a greater than ve-fold
increase in affinity compared to 6-iodoquinoline 22. Thus,
Conclusions
incorporation of a much smaller atom has a less dramatic effect In summary, the structure–activity relationship of novel quin-
on the binding affinity.
oline-2-carboxamides has been investigated for the TSPO. The
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