Bioorganic & Medicinal Chemistry Letters
Design, radiosynthesis, and evaluation of radiotracers for positron
emission tomography imaging of stearoyl-CoA desaturase-1
William C. Silvers a, Hancheng Cai a,b, Orhan K. Öz a, Xiankai Sun a,b,
⇑
a Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
b Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
a r t i c l e i n f o
a b s t r a c t
Design, radiosynthesis, and biological evaluation of two radiotracers (N-(3-[18F]fluoropropyl)-6-(4-
Article history:
(trifluoromethyl)benzoyl)-piperazin-1-yl)pyridazine-3-carboxamide
fluoroaniline)-6-(4-(trifluoromethyl)benzoyl)-piperazin-1-yl)pyridazine-3-carboxamide
(
18F-FPPPT)
and
(N-(4-[18F]
Received 11 December 2015
Revised 17 December 2015
Accepted 18 December 2015
Available online 19 December 2015
(
18F-FAPPT))
are described for noninvasive assessment of stearoyl-CoA desaturase-1 (SCD-1). The overexpression of
SCD-1 in multiple solid tumors associates with poor survival in cancer patients. The two radiotracers,
18F-FPPPT and 18F-FAPPT, were each prepared in three steps in radiochemical yields of 21% and 3%,
respectively. The practicality of imaging SCD-1 with 18F-FPPPT was tested in two mouse models bearing
xenograft tumors with different levels of SCD-1 expression, which afforded a 1.8-fold uptake difference
correspondingly. Our work indicates that it is possible to develop SCD-1 specific imaging probes from
previously reported SCD-1 inhibitors.
Keywords:
Stearoyl-CoA desaturase
De novo lipid metabolism
Radiosynthesis
PET
18F-FPPPT
Ó 2015 Elsevier Ltd. All rights reserved.
The family of stearoyl-CoA desaturase (SCD) enzymes catalyzes
the formation of a double bond at the C9 position in saturated fatty
acids (SFAs) to create monounsaturated fatty acids (MUFAs).1–3 Of
the two isoforms in humans, SCD-1 is predominant and ubiqui-
tously expressed in the brain, liver, fat, heart and lung.4 Upregu-
lated expression of SCD-1 has been reported in multiple solid
tumors (e.g., prostate, breast, lung, and ovarian cancer) with impli-
cations in cancer progression, which is indicative of poor prognosis
in cancer patients.5,6 The important role of SCD-1 in de novo fatty
acid (FA) metabolism, a pathway elevated across all cancer types,
makes it an ideal target for cancer therapy. To date, small organic
inhibitors of SCD-1 have shown desired anti-cancer effects by
inducing cancer cell apoptosis and slowing tumor-growth in pre-
clinical tumor xenograft mouse models.6–8 Given the reported cor-
relation of SCD-1 expression with cancer progression,
measurement of SCD-1 levels can potentially serve as a biomarker
for cancer treatment planning and prognostic evaluation post-
treatment.
highly desirable in the clinic for the assessment of SCD-1
expression.
To date, numerous SCD-1 inhibitors with sub-lM binding affini-
ties have been reported for cancer treatment.11–15 These inhibitors
can potentially serve as lead compounds for SCD-1 targeted radio-
tracer development.
To enable positron emission tomography (PET) imaging of SCD-
1, the design of radiotracers labeled with 18F (t1/2 = 109.8 minutes;
b+ 0.63 MeV, 97%) was based on two previously reported SCD-1
inhibitors, N-pentyl-6-(4-(2-(trifluoromethyl)benzoyl)piperazin-
1-yl)pyrazine-3-carboxamide and N-phenethyl-6-(4-(2-(trifluo-
romethyl)benzoyl)piperazin-1-yl)pyrazine-3-carboxamide.15 Their
half maximal inhibitory concentrations (IC50) were measured at 25
and 18 nM, respectively, for human SCD-1. Shown in Scheme 1, the
18F synthon (1) for 18F-FAPPT (N-(4-[18F]fluoroaniline)-6-(4-(triflu-
oromethyl)benzoyl)-piperazin-1-yl)pyridazine-3-carboxamide)
was synthesized as previously described.16 To make the synthon
(5) for 18F-FPPPT (N-(3-[18F]fluoropropyl)-6-(4-(trifluoromethyl)
benzoyl)-piperazin-1-yl)pyridazine-3-carboxamide), the desired
tosylated precursor (3) was first prepared through reacting N-
(tert-butoxycarbonyl)-3-hydroxypropylamine (2)17 with p-tolue-
nesulfonyl chloride in the presence of triethylamine (Et3N) (63%
yield).18 Synthesis of 18F-FPPPT was accomplished in 3 steps within
120 min, as outlined in Scheme 1.19 Radiolabeling of 3 with 18F was
performed under basic conditions in the presence of kryptofix 2,2,2
(K2,2,2)/K2CO3 and the reaction was carried out at 110 °C for 15 min.
The resulting protected 3-[18F]fluoro-propylamine 4 was isolated
Clinically, the expression of SCD-1 is often measured by the
desaturation index (DI) from plasma and tissue or immunohisto-
chemical analysis on tissue biopsies.5,9,10 Suboptimal accuracy of
biopsies aside, major drawbacks of both methods include the inva-
siveness of obtaining biopsies from tissues and long sample
processing times. A noninvasive imaging technique would be
⇑
Corresponding author.
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.