Design, synthesis and evaluation of18F-labeled bradykinin B1 receptor-targeting small molecules for PET imaging

Article abstract of DOI:10.1016/j.bmcl.2016.06.066

Two fluorine-18 (¹⁸F) labeled bradykinin B1 receptor (B1R)-targeting small molecules,¹⁸F-Z02035 and¹⁸F-Z02165, were synthesized and evaluated for imaging with positron emission tomography (PET). Z02035 and Z02165 were deri

Full text of DOI:10.1016/j.bmcl.2016.06.066

Bioorganic & Medicinal Chemistry Letters 26 (2016) 4095–4100
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and evaluation of 18F-labeled bradykinin
B1 receptor-targeting small molecules for PET imaging
Zhengxing Zhang a, Hsiou-Ting Kuo a, Joseph Lau a, Silvia Jenni a, Chengcheng Zhang a, Jutta Zeisler a,
François Bénard a,b, Kuo-Shyan Lin a,b,
⇑
a Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada
b Department of Radiology, University of British Columbia, 950 West 10th Avenue, Vancouver, BC V5Z 4E3, Canada
a r t i c l e i n f o
a b s t r a c t
Two fluorine-18 (18F) labeled bradykinin B1 receptor (B1R)-targeting small molecules, 18F-Z02035 and
18F-Z02165, were synthesized and evaluated for imaging with positron emission tomography (PET).
Z02035 and Z02165 were derived from potent antagonists, and showed high binding affinity
(0.93 0.44 and 2.80 0.50 nM, respectively) to B1R. 18F-Z02035 and 18F-Z02165 were prepared by cou-
pling 2-[18F]fluoroethyl tosylate with their respective precursors, and were obtained in 10 5 (n = 4) and
22 14% (n = 3), respectively, decay-corrected radiochemical yield with >99% radiochemical purity.
18F-Z02035 and 18F-Z02165 exhibited moderate lipophilicity (LogD7.4 = 1.10 and 0.59, respectively),
and were stable in mouse plasma. PET imaging and biodistribution studies in mice showed that both
tracers enabled visualization of the B1R-positive HEK293T::hB1R tumor xenografts with better contrast
than control B1R-negative HEK293T tumors. Our data indicate that small molecule antagonists can be
used as pharmacophores for the design of B1R-targeting PET tracers.
Article history:
Received 20 May 2016
Revised 23 June 2016
Accepted 24 June 2016
Available online 27 June 2016
Keywords:
Bradykinin B1 receptor
Antagonist
Fluorine-18
Molecular imaging
Positron emission tomography
Ó 2016 Elsevier Ltd. All rights reserved.
Positron emission tomography (PET) is a highly sensitive and
quantifiable molecular imaging modality that can detect distribu-
tion of a minimal amount (pM) of radiotracers in the body. The
most widely used clinical PET tracer is 18F-labeled 2-fluoro-
2-deoxyglucose (18F-FDG). As a close analog of glucose, 18F-FDG
is avidly taken up by cells with increased glucose needs, and is
used for the diagnosis and prognosis of cancer, and to monitor
response after treatment.1–3 However, 18F-FDG is not suitable for
detecting slow growing tumors that do not have enhanced gly-
colytic activity.3 Therefore, radiotracers targeting other cancer
imaging biomarkers especially receptors of peptide growth factors
such as bombesin and somatostatin are being actively developed
and evaluated in the clinic.4–8
therapy.9 Effective B1R-targeting PET tracers could potentially be
used to select patients who can benefit from emerging anti-B1R
therapies. Previously, our group reported the evaluation of several
potent radiolabeled [des-Arg10]kallidin derivatives for cancer
imaging.15–18 Our data indicate that in vivo stability is crucial as
only radiolabeled [des-Arg10]kallidin derivatives with unnatural
amino acid substitutions in the peptide sequence were effective
in visualizing B1R-expressing tumors.15–18 This is because the
native [des-Arg10]kallidin peptide sequence can be rapidly
degraded in vivo by peptidases.15
In addition to B1R-targeting peptides, a significant number of
potent B1R small molecule antagonists have been developed by
pharmaceutical companies for the treatment of chronic pain,19–23
and could potentially be exploited for the design of B1R-targeting
PET tracers. An advantage of using small molecules as opposed to
peptide sequence is their reduced metabolic lability. Barth et al.
reported a series of 2-[2-[[(4-methoxy-2,6-dimethylphenyl)sul-
fonyl]methylamino]ethoxy]acetamide derivatives that are potent
and selective B1R antagonists.19 Modification of the small N-alkyl
group in some of those compounds was tolerable as 1–4 (Fig. 1)
exhibited comparable high binding affinity to B1R.19 Based on this
observation, we hypothesized that replacing the small N-alkyl
group (methyl, ethyl or 2-propyl) in 1–4 with a 2-fluoroethyl group
to generate Z02035 and Z02165 would retain comparable binding
The bradykinin B1 receptor (B1R), a G-protein coupled receptor,
is overexpressed in
a variety of cancers, but has minimal
expression in normal tissues.9 The endogenous B1R ligands are
[des-Arg9]bradykinin
(Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe)
and
[des-Arg10]kallidin (Lys-[des-Arg9]bradykinin).10 Activation of
B1R has been shown to promote proliferation and invasion of
cancer cells, and to induce angiogenesis.11–14 Therefore, B1R
antagonism has been proposed as a promising strategy for cancer
⇑
Corresponding author. Tel.: +1 604 675 8208; fax: +1 604 675 8218.
E-mail address: klin@bccrc.ca (K.-S. Lin).
http://dx.doi.org/10.1016/j.bmcl.2016.06.066
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

4096
Z. Zhang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4095–4100
O
O
O
O
O
O
S
O
O
S
O
N
N
N
N
O
X
X
18F-Z02035: X = C
N
N
1
: X = C; R = CH3; Ki(hB1R) = 0.7 nM
2: X = C; R = CH(CH3)2; Ki(hB1R) = 0.4 nM
R
18F
18F-Z02165
: X = N
3
: X = N; R = CH3; Ki(hB1R) = 1.6 nM
4: X = N; R = CH2CH3; Ki(hB1R) = 0.2 nM
Figure 1. Design of 18F-labeled B1R-targeting tracers derived from small molecule antagonists.
affinity to B1R. Since the fluorine atom at the 2-fluoroethyl group
could be replaced with a radioactive 18F, the resultant 18F-labeled
Z02035 and Z02165 could be exploited for PET imaging. In fact,
replacing a methyl or ethyl group with a 2-[18F]fluoroethyl group
is a common strategy to convert a potent therapeutic drug into a
potential 18F-labeled PET imaging agent.24,25
cell membranes and [3H][Leu9,des-Arg10]kallidin as the radioli-
gand.15 Both compounds inhibited the binding of [3H][Leu9,
des-Arg10]kallidin to B1R in a dose dependant manner as shown
in Figure 2. The Ki values for Z02035 and Z02165 are 0.9 0.4
and 2.8 0.5 nM, respectively. The low nM binding affinity values
of Z02035 and Z02165 are comparable to those of compounds 1–
4 (Fig. 1).19 This confirms our hypothesis that the small N-alkyl
groups (methyl, ethyl, and 2-propyl) in 1–4 could be replaced with
a 2-fluoroethyl group, and the resultant 2-fluoroethyl derivatives
(Z02035 and Z02165) would still retain good binding affinity to
B1R. As the binding affinities of Z02035 and Z02165 are compara-
ble to those of previously reported radiolabeled B1R-targeting pep-
tides,15–18 we proceeded with radiolabeling and imaging studies
with Z02035 and Z02165.
The syntheses of Z02035 and Z02165 are depicted in Scheme 1.
For
the
synthesis
of
Z02035,
2-[2-[[(4-methoxy-2,6-
dimethylphenyl)sulfonyl]methylamino]ethoxy]acetyl chloride 526
was first reacted with N-Boc-4,40-bipiperidine 627 in dichloro-
methane with triethylamine as the base to obtain 7 in 95% yield.
The Boc protecting group was subsequently removed by treating
7 with trifluoroacetic acid, and the free amine 8 was isolated quan-
titatively. Coupling amine 8 with 2-fluoroethyl tosylate 928 in ace-
tonitrile with potassium carbonate as the base gave the cold
standard Z02035 in 27% yield. The synthesis of Z02165 followed
the same procedures for the synthesis of Z02035 but replacing N-
Boc-4,40-bipiperidine 6 with tert-butyl 4-piperazinotetrahydro-1
(2H)-pyridinecarboxylate 10. The Boc-protected intermediate 11,
free amine 12 and Z02165 were isolated in 83%, 100%, and 71%
yields, respectively.
18F-labeled Z02035 and Z02165 were prepared in two steps as
shown in Scheme 2. The two-step approach was adopted to avoid
the possibility of forming aziridinium in a one-step 18F-nucle-
ophilic substitution reaction. First,
synthon was prepared followed by a coupling reaction with the
a
2-[18F]fluoroethylation
respective amine precursors
8 and 12 to give the desired
18F-labeled Z02035 and Z02165, respectively. 2-[18F]Fluoroethyl
tosylate ([18F]9) was chosen as it is the most widely used synthon
for the 2-[18F]fluoroethylation reaction, and could be prepared
The binding affinities of Z02035 and Z02165 were measured via
in vitro competition binding assays using B1R-expressing CHO-K1
(A)
O
O
HN
O
O
TEA
O
O
+
S
O
O
S
O
N
Cl
N
N
N
DCM
O
N
Boc
F
5
6
7
NBoc
O
O
O
O
O
O
OTs
TFA, DCM
9
S
O
S
O
N
N
N
O
K2CO3, CH3CN
NH
O
8
Z02035
N
F
(B)
O
O
HN
O
O
O
O
N
TEA
+
S
O
O
S
S
O
O
N
Cl
N
N
N
DCM
Boc
N
5
10
11
NBoc
O
O
F
TFA, DCM
O
O
OTs
9
O
O
O
S
O
O
N
N
K2CO3, CH3CN
O
N
N
N
N
Z02165
12
NH
N
F
Scheme 1. Synthesis of (A) Z02035 and its radiolabeling precursor 8; and (B) Z02165 and its radiolabeling precursor 12.

Z. Zhang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4095–4100
4097
18F-Z02165, it was isolated in 22 14% (n = 3) decay-corrected
radiochemical yield with >99% radiochemical purity and
54 33 GBq/lmol specific activity at the end of synthesis.
The stability of 18F-Z02035 and 18F-Z02165 were evaluated in
mouse plasma, and monitored by radio-HPLC. As shown in Figure 3,
both 18F-Z02035 and 18F-Z02165 were relatively stable with 86%
and 97% of the radiotracers remaining intact after being incubated
in mouse plasma for 60 min. LogD7.4 measurement was conducted
using the shake flask method as previously reported to estimate
tracer lipophilicity.15 Both tracers are moderately lipophilic and
the LogD7.4 values (n = 3) for 18F-Z02035 and 18F-Z02165 are
1.10 0.08 and 0.59 0.01, respectively. Previously tested B1R-tar-
geting peptides did not cross the blood–brain barrier due to their
bulky size (>1500 Da) and high hydrophilicity (LogD7.4 < ꢀ2.50).
With a smaller size (ꢁ500 Da) and moderate lipophilicity, 18F-
Z02035 and 18F-Z02165 could potentially cross the blood–brain
barrier and be used for imaging B1R expression in neurological
disorders.30,31
Figure 2. Representative displacement curves of [3H]-[Leu9,des-Arg10]kallidin by
Z02035 and Z02165.
To evaluate the potential of 18F-Z02035 and 18F-Z02165 for
imaging B1R expression, static/dynamic imaging and biodistribu-
tion studies were conducted in mice bearing both B1R-positive
(B1R+) HEK293T::hB1R and B1R-negative (B1Rꢀ) HEK293T wild-
type tumors. The B1R+ HEK293T::hB1R cells were created by
transduction of the hB1R gene into wild-type HEK293T cells.15
Imaging mice bearing both B1Rꢀ HEK293T and B1R over-express-
ing HEK293T::hB1R tumors offers the advantage of verifying if the
uptake in tumors is B1R mediated in a single study. This could be
efficiently as reported by incubating commercially available 1,2-bis
(tosyloxy)ethane with K[18F]F/K222 in acetonitrile.29 The subse-
quent coupling with the amine precursor 8 and 12 was conducted
in N,N-dimethylformamide with potassium carbonate as the
base. 18F-Z02035 was isolated in 10 5% (n = 4) decay-corrected
radiochemical yield with >99% radiochemical purity and
38 22 GBq/
l
mol specific activity at the end of synthesis. For
K[18F]F/K222
18F
TsO
OTs
OTs
O
CH3CN
[
18F]9
O
O
K2CO3
DMF
S
O
O
O
N
N
O
O
X
S
O
18F-Z02035
18F-Z02165
N
N
: X = C
: X = N
O
N
X
18F
8
: X = C
12: X = N
NH
Scheme 2. Radiosynthesis of 18F-Z02035 and 18F-Z02165.
Figure 3. Radio-HPLC chromatograms of 18F-Z02035 and 18F-Z02165. Upper chromatograms: purified QC samples; lower chromatograms: extracted samples after being
incubated with mouse plasma for 60 min.

4098
Z. Zhang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4095–4100
Figure 4. 18F-Z02035 and 18F-Z02165 were excreted via both renal
and hepatobiliary pathways as high radioactivity accumulation
was found in kidneys, bladder, liver and gut. Both tracers enabled
visualization of the B1R+ HEK293T::hB1R tumors with better con-
trast than the B1Rꢀ HEK293T tumors. Uptake in some joints was
detected especially when 18F-Z02035 was used, indicating the
occurrence of in vivo defluorination. The clear background (low
muscle uptake) suggests no apparent defluoethylation occurred
as the 18F-labeled defluoroethylated metabolites could signifi-
cantly increase background activity level.32–34 An unexpected find-
ing was the high uptake of 18F-Z02165 in thyroid. However, this
may not be B1R mediated because B1R expression level is low in
normal tissues and no significant thyroid uptake was observed
from our previous imaging studies using radiolabeled B1R-target-
ing [des-Arg10]kallidin derivatives.15–18 It is well documented that
radiolabeled lipophilic cations such as 99mTc-sestamibi and 18F-
labeled phosphonium derivatives can be taken up by thyroid.35–37
With the amino group(s) in their structures 18F-Z02035 and 18F-
Z02165 can form cationic protonated species at the physiological
pH. It is, therefore, possible that the uptake of 18F-Z02035 and 18F-
Z02165 in thyroid was due to the formation of their protonated
species.
Figure 4. Maximum intensity projection images of 18F-Z02035 (left) and 18F-
Z02165 (right) in mice bearing B1R+ HEK293T::B1R tumor (red arrow) and B1Rꢀ
HEK293T wild-type tumor (yellow arrow). Thyroid is indicated by a white arrow.
The 10-min static images were taken at 50–60 min post-injection.
The time–activity curves of 18F-Z02035 and 18F-Z02165 derived
from the dynamic imaging data are shown in Figure 5. The heart
uptake (open blue circle) of both tracers peaked within the first
two minutes to reach ꢁ18%ID/g, and dropped down to <3%ID/g
after 4-min post-injection, indicating fast clearance from the blood.
The uptake in B1R+ tumors (solid red circle) was higher than that
of B1Rꢀ tumors (open black triangle) at all time points, confirming
specific binding of both tracers to B1R. High thyroid uptake (ꢁ7%
performed by directly comparing the uptake difference between
B1Rꢀ HEK293T and B1R+ HEK293T::hB1R tumors, and without
blocking studies.
Representative static images of 18F-Z02035 and 18F-Z02165
acquired at 50–60 min post-injection interval are shown in
Figure 5. Time–activity curves of 18F-Z02035 (A and B) and 18F-Z02165 (C and D) in mice bearing B1R+ HEK293T::B1R tumor and B1Rꢀ HEK293T wild-type tumor.

Z. Zhang et al. / Bioorg. Med. Chem. Lett. 26 (2016) 4095–4100
4099
Table 1
1.78 0.17, 2.26 0.35 and 3.38 1.05, respectively for
18F-Z02035, and 1.65 0.20, 1.99 0.22 and 2.74 0.33, respec-
tively for 18F-Z02165. No significant difference was observed by
comparing the uptake in B1R+ tumor as well as the uptake ratios
of tumor(B1R+)-to-tumor(B1Rꢀ), tumor(B1R+)-to-blood and
tumor(B1R+)-to-muscle between 18F-Z02035 and 18F-Z02165
(Table 1). This implies that both tracers perform equally well for
the detection of B1R expression in tumors.
In conclusion, we took a novel approach for imaging B1R
expression by exploiting the potential of two 18F-labeled small
molecules, 18F-Z02035 and 18F-Z02165. Although tumor-to-back-
ground contrast ratios are lower than those of reported B1R tracers
derived from peptide sequences, both 18F-Z02035 and 18F-Z02165
were able to differentiate between B1R expressing and non-
expressing tumor xenografts. Due to advantages of brain pene-
trance and in vivo stability against peptidase degradation, small
molecule pharmacophores are promising for use for the design of
B1R-targeting PET tracers. Optimization to enhance tumor
uptake/contrast and to reduce in vivo defluorination and non-
specific binding is currently underway.
Biodistribution data (mean SD, 1-h post-injection) of 18F-Z02035 and 18F-Z02165 in
mice bearing both B1R+ HEK293T::hB1R and B1Rꢀ HEK293T tumors
Tissues/organs (%ID/g)
18F-Z02035 (n = 6)
18F-Z02165 (n = 5)
Blood
Fat
Testes
Intestine
Stomach
Spleen
1.67 0.23
0.60 0.09
1.00 0.11
8.84 1.12
4.75 1.56
3.10 0.81
10.1 1.63
7.58 1.76
1.68 0.26
4.71 1.32
2.01 0.29
1.67 0.23
3.77 0.79
2.11 0.37
1.17 0.28
4.63 0.65
0.80 0.08
1.62 0.11
0.29 0.11⁄⁄⁄
1.11 0.15
10.0 1.12
3.29 1.22
5.64 0.97⁄⁄⁄
8.17 0.55⁄
2.67 0.59⁄⁄⁄
1.73 0.50
4.41 1.43
2.84 0.36⁄⁄
1.65 0.14
3.21 0.21
1.98 0.17
1.19 0.16⁄⁄⁄
2.56 0.35
1.06 0.08⁄⁄⁄
Liver
Pancreas
Adrenal gland
Kidney
Lung
Heart
Tumor(B1R+)
Tumor(B1Rꢀ)
Muscle
Bone
Brain
Tumor(B1R+)/tumor(B1Rꢀ)
Tumor/blood
Tumor/muscle
1.78 0.17
2.26 0.35
3.38 1.05
1.65 0.20
1.99 0.22
2.74 0.33
Acknowledgements
⁄
⁄⁄
⁄⁄⁄
and indicate that the p value is <0.05, <0.01, or <0.001, respectively.
,
This work was supported by the Canadian Institutes of Health
Research (MOP-126121). The authors would like to thank Milan
Vuckovic, Wade English, Julius Klug, Nadine Colpo and Navjit Hun-
dal-Jabal for their technical assistance.
ID/g, solid orange square) was observed for both tracers. However,
in static images (Fig. 4) it was more apparent by using 18F-Z02165
due to the higher bone uptake level (solid beige diamond) of
18F-Z02035. The bone uptake of 18F-Z02035 increased continuously
at later time points at a faster rate than that of 18F-Z02165, sug-
gesting 18F-Z02035 is less stable against in vivo defluorination.
The brain uptake (solid green triangle) of both tracers reached
ꢁ1%ID/g after 20 min post-injection. However, the observed slow
increase of brain uptake for both tracers at later time points needs
to be further verified. This could be simply due to the signal inter-
ference from the increasing skull uptake at later time points.
The results of biodistribution studies at 1-h post-injection are
summarized in Table 1, and the data are consistent with observa-
tions from static images and time-activity curves. Higher uptake
(ꢁ8–10%ID/g) of both tracers was observed in intestines and livers.
The high uptake (7.58 1.76%ID/g) of 18F-Z02035 in pancreas was
unexpected, and may not be B1R-mediated as no significant pan-
creas uptake was observed previously using radiolabeled pep-
tide-based B1R-targeting tracers.15–18 Currently, the most widely
used tracers for imaging pancreatic b-cell mass are radiolabeled
dihydrotetrabenazine (DTBZ) derivatives targeting vesicular
monoamine transporter 2 (VMAT2).38,39 There are some similari-
ties between DTBZ and the core structure of 18F-Z02035, and there-
fore the possibility for the uptake of 18F-Z02035 into pancreas via
VMAT2 cannot be ruled out. However, further studies are needed
to confirm if the uptake of 18F-Z02035 into pancreas is indeed
mediated by VMAT2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.06.
066.
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