Bioorganic & Medicinal Chemistry Letters
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,
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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
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Corresponding author. Tel.: +1 604 675 8208; fax: +1 604 675 8218.
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.