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Published in final edited form as: Bioorg Med Chem Lett. 2015 Dec 19;26(3):924–927. doi: 10.1016/j.bmcl.2015.12.062

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
PMCID: PMC4728040  NIHMSID: NIHMS749662  PMID: 26778147

Abstract

Design, radiosynthesis, and biological evaluation of two radiotracers (N-(3-[18F]fluoropropyl)-6-(4-(trifluoromethyl)benzoyl)-piperazin-1-yl)pyridazine-3-carboxamide (18F-FPPPT) and (N-(4-[18F]fluoro-aniline)-6-(4-(trifluoromethyl)benzoyl)-piperazin-1-yl)pyridazine-3-carboxamide (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

Graphical Abstract

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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 ubiquitously expressed in the brain, liver, fat, heart and lung.4 Upregulated expression of SCD-1 has been reported in multiple solid tumors (e.g., prostate, breast, lung, and ovarian cancer) with implication 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 preclinical tumor xenograft mouse models.6-8 Given the reported correlation of SCD-1 expression with cancer progression, measurement of SCD-1 level can potentially serve as a biomarker for cancer treatment planning and prognostic evaluation post-treatment.

In clinic, the expression of SCD-1 is often measured by the desaturation index (DI) from plasma and tissue or immunohistochemical analysis on tissue biopsies.5, 9, 10 Suboptimal accuracy of biopsies aside, major drawbacks of both methods include the invasiveness of obtaining biopsies from tissues and long sample processing times. A noninvasive imaging technique would be highly desirable in clinic for the assessment of SCD-1 expression.

To date, numerous SCD-1 inhibitors with sub-μM binding affinities have been reported for cancer treatment.11-15 These inhibitors can potentially serve as lead compounds for SCD-1 targeted radiotracer development.

To enable positron emission tomography (PET) imaging of SCD-1, the design of radiotracers labeled with 18F (t1/2 = 109.8 minutes; β+ 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-(trifluoromethyl)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]fluoro-aniline)-6-(4-(trifluoromethyl)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-toluenesulfonyl 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 on a C-18 Sep-Pak cartridge, which was eluted into a vial and dried under a nitrogen flow. Compound 4 was then deprotected by trifluoroacetic acid (TFA, neat) for 8 min generating 18F-fluoro-propylamine (5) in 51% radiochemical yield (RCY). After removal of TFA, the silica Sep-Pak cartridge trapped 5 was eluted with acetonitrile for further radiochemistry. For the synthesis of 18F-FPPPT and 18F-FAPPT, 6-(4-(2-(trifluoromethyl)benzoyl)piperazine-1-yl)-pyridazine-3-carboxylate (6) was prepared according to a published procedure, from which the amine reactive acid chloride analogue 7 was obtained by reacting with thionyl chloride. Compound 7 is the common precursor to make both 18F-FPPPT and 18F-FAPPT by reacting with synthons 5 and 1, respectively. The coupling reaction between 5 and 720 was carried out at room temperature (r.t.) for 15 min, followed by HPLC purification of 18F-FPPPT on a semi-preparative C-18 column. The decay corrected radiochemical yield at the end of synthesis (EOS) was 21%. The radiochemical purity of the obtained 18F-FPPPT was 99%. The synthesis of 18F-FAPPT was accomplished in a similar way by reacting 1 with 7.21 The decay corrected RCY of 18F-FAPPT was lower at 3% at the EOS, due to the poor reactivity of aromatic amines as opposed to the aliphatic in 18F-FPPPT synthesis, and its radiochemical purity was 99%. The average (n = 3) specific radioactivity for 18F-FPPPT and 18F-FAPPT was 507 ± 148 MBq·μmol−1 and 61 ± 28 MBq·μmol−1, respectively. The reference standard compounds, the 19F counterparts of 18F-FPPPT and 18F-FAPPT, were synthesized by reacting 6 with 3-fluoro-propylamine or 4-fluoro-aniline in the presence of N,N-diisopropylethylamine (DIPEA) using O-(benzotriazo-1-yl)-N,N,N’N’-tetramethyluronium hexafluorophosphate (HBTU) as the coupling agent at yields of 85% and 80%, respectively as shown in Scheme 1.22, 23

Scheme 1.

Scheme 1

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Synthesis of 18F-FPPPT, 18F-FAPPT, synthons 1 and 5, FPPPT, and FAPPT. Reagents and conditions: (i) p-toluenesulfonyl chloride, DMAP, Et3N, dichloromethane (DCM); (ii) K2,2,2/K2CO3, acetonitrile (ACN), 110 °C, 15 min.; (iii) TFA, r.t., 8 min.; (iv) thionyl chloride, DCM, 50 °C, overnight; (v) 5, Et3N, ACN, r.t., 15 min.; (vi) 1, Et3N, ACN, r.t., 15 min.; (vii) 3-fluoropropylamine hydrochloride, HBTU, DIPA, dimethylformamide (DMF); (viii) 4-fluoroanline, HBTU, DIPEA, DMF.

The lipophilicity of 18F-FPPPT and 18F-FAPPT measured by partition coefficient (log P) was assessed in a biphasic mixture of n-octanol and water.24 The logP values of 18F-FPPPT and 18F-FAPPT were determined to be 1.23 and 2.08, respectively. The lipophilicity difference of 18F-FPPPT and 18F-FAPPT can be attributed to the fact that different linkers, phenyl and propyl, were used for their construction. The stability of 18F-FPPPT and 18F-FAPPT in fetal bovine serum (FBS) was assessed by radio-HPLC after 3 h of incubation at 37° C. Both radiotracers were found nearly 100% intact.

The SCD-1 mediated retention of 18F-FPPPT and 18F-FAPPT was assayed in SCD-1 positive prostate cancer cells (C4-2; Figure 1a), where a commercially available SCD-1 inhibitor, 4-(2-chlorophenoxy)-N-[3-[(methylamino) carbonyl]phenyl]-1-piperidinecarboxamide (IC50 = 37 nM for human SCD-1) (Figure 1b).25, 26 Briefly, ~2.0 μCi of each radiotracer was incubated with or without the inhibitor in C4-2 cells for 30 min, followed by rinsing with fresh media to remove non-specifically bound radiotracer. The cells were later trypsinized and the activity was measured and normalized to the cell numbers. Shown in Figure 1b, the SCD-1 mediated C4-2 cell uptake reduced by 40% and 39% for 18F-FPPPT and 18F-FAPPT, respectively, by the blockade with the inhibitor, which indicates the specific binding of the radiotracers to SCD-1. Further, 18F-FPPPT and 18F-FAPPT showed 2.2-fold and 1.5-fold higher uptake in C4-2 cells than in a low SCD-1 expressing MDA-MB-231 cell line (Figure 1a), respectively.

Figure 1.

Figure 1

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In vitro evaluation of 18F-FPPPT and 18F-FAPPT in cancer cells. (a) Western blot showing protein expression of SCD-1 in C4-2 and MDA-MB-231 cells with GAPDH as loading control. (b) SCD-1 mediated retention of 18F-FPPPT and 18F-FAPPT in C4-2 cells with and without co-incubation of an SCD-1 inhibitor and MDAMB-231 cells.

Given its higher SCD-1 specific uptake, 18F-FPPPT was selected to test the feasibility of imaging SCD-1 in vivo in mouse models bearing tumor xenografts with high (PC-3) and low (MDA-MB-231) SCD-1 expression as determined by western blot (Figure 2a). Each mouse was injected with ~100 μCi and underwent PET imaging at 1 h post-injection (p.i.).27 As shown in Figure 2b, the tumor with high SCD-1 expression, PC-3, was clearly visualized, while the one with low SCD-1 expression, MDA-MB-231, showed an uptake level barely above the background. Further quantitative analysis revealed that the uptake of 18F-FPPPT in the PC-3 tumor was 1.8-fold higher than in the MDA-MB-231 tumor, which is consistent with the in vitro result presented in Figure 1. Of note, high bone uptake was observed in the scans of both animal models, likely due to defluorination of 18F from the alkyl subunit. Other 18F-labeled synthons with higher stability will be employed to minimize or overcome the problem of defluorination in future.

Figure 2.

Figure 2

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(a) Western blot showing protein expression of SCD-1 in PC-3 and MDA-MB-231 cells with actin as loading control. (b) Transaxial PET images of PC-3 and MDA-MB-231 tumors with 18F-FPPPT in NODSCID mice (1 h p.i.). Tumors marked with white arrows.

In summary, we have successfully synthesized two PET radiotracers (18F-FPPPT and 18FPPPT) for noninvasive imaging of SCD-1. The synthesis of each radiotracer was achieved with low to high RCY with high specific radioactivity and radiochemical purity. Both radiotracers were found to exhibit SCD-1 mediated retention in SCD-1 expressing prostate cancer cells in vitro, with 18F-FPPPT having higher specific retention. In vivo evaluation in mouse xenograft models demonstrated the ability of PET with 18F-FPPPT to differentiate tumors with high and low SCD-1 expression.

Supplementary Material

Acknowledgments

This study was partially supported by a grant from the National Institutes of Health (R01 DK092163) and the Dr. Jack Krohmer Professorship Funds.

Footnotes

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18

Synthesis of 3: N-(tert-butoxycarbonyl)-3-hydroxypropylamine (2.4 g, 13.7 mmol) was dissolved in 60 mL DCM under nitrogen. To the reaction was added 2.23 mL (16 mmol) Et3N, followed by 3.12 g (16.4 mmol) p-toluenesulfonyl chloride and 100 mg DMAP in 20 mL DCM. The reaction was stirred overnight and solvent removed. The reaction was purified on a silica column with a mobile phase of 2:1 Hexanes:EtOAc. The product was dried under high vacuum, giving 2.82 g (63% yield) of a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, 2H), 7.37 (d, 2H), 4.09 (t, 2H), 3.17 (d, 2H), 2.45 (s, 3H), 1.86 (q, 2H) 1.42 (s, 9H). m/z (ESI-TOF): 174.11 [M+H]+, calcd. 174.14.

19

Radiosynthesis of 18F-FPPPT (8): Radiosynthesis of 4 was carried out in a GE FXN module. Approximately 7.0 mg of 3 in 0.7 mL dry ACN was added to dried 18F in 1.0 mg K2,2,2 and 1.0 mg K2CO3 and the reaction mixture was heated for 15 min at 110 °C. After cooling to r.t., the crude mixture was diluted with 10 mL water and flushed through a C-18 Sep-Pak cartridge, trapping the Boc protected 3-[18F]fluoro-propylamine 4. The product was eluted with 1.5 mL ACN into a reaction vial and dried by heating to 70 °C and flowing nitrogen. When dry, the product was Boc deprotected by adding 0.8 mL TFA (neat). After 8 min. at r.t. the reaction was diluted with 20 mL DCM and flushed through a silica Sep-Pak cartridge trapping 5. The product was eluted with 1.5 mL ACN into a round bottom flash with a stir bar and dried by heating to 70 °C and flowing nitrogen. Approximately 20 mg of 7 in 1.0 mL ACN was added to the flask followed with 200 μL Et3N. After 15 min., the reaction was diluted with 3.0 mL water and the reaction was purified with a semi preparative RP-HPLC (Phenomenex C18, 10 × 250 mm) and a mobile phase of 40% ACN in water containing 0.01% TFA at a flow rate of 4 mL/min. The fractions containing the product (retention time of 14 – 16 min.) based on γ-detector was collected, diluted to 50 mL with water, and passed through a C-18 Sep-Pak cartridge to trap 18F-FPPPT. 18F-FPPPT was eluted with 1.5 mL of 85% absolute ethanol in saline. Radiochemical purity was determined by analyzing the portion of the eluent with an analytical RP-HPLC column.

20

Synthesis of 7: Approximately 20 mg (0.05 mmol) of 6 was dissolved in 2 mL dry chloroform in a round bottom flask and heated to 50 °C. To the flask was added 2 drops of DMF and 150 μL thionyl chloride and the solution was left to stir overnight. Solvent was removed with flowing nitrogen and the flask was placed under high-vacuum to dry. Compound 7 was used without purification.

21

Radiosynthesis of 18F-FAPPT (9): Synthesis of 1 was carried out in a GE FXN module under conditions previously described.[18] After synthesis, 1 (in methanol) was added to a round bottom flask and dreid with flowing nitrogen and heatign to 70 °C. Approximately 20 mg of 7 in 1.0 mL ACN was added to the flask followed with 200 μL Et3N. After 15 min., the reaction was diluted with 3.0 mL water and purified using a semi preparative RP-HPLC (Phenomenex C18, 10 × 250 mm) and a mobile phase of 50% ACN in water containing 0.01% TFA at a flow rate of 4 mL/min. The fractions containing the product (retention time of 16 - 18 min.) based on γ-detector were collected, diluted to 50 mL with water, and passed through a C-18 Sep-Pak cartridge to trap 18F-FAPPT. 18F-FAPPT was eluted with 1.5 mL of 85% absolute ethanol in saline. Radiochemical purity was determined by analyzing the portion of the eluent with an analytical RP-HPLC column.

22

Synthesis of FPPPT (10): 6-(4-(2-(trifluoromethyl)benzoyl)piperazine-1-yl)-pyridazine-3-carboxylate (200 mg, 0.53 mmol) and 92 mg (0.81 mmol) 3-fluoropropylamine hydrochloride were dissolved in 4 mL DMF under nitrogen. To the reaction was added 301 mg (0.79 mmol) HBTU, followed by 113 μL DIPEA. The reaction was left to stir overnight and the solvent was removed under vacuum. The reaction was purified using a silica column with a mobile phase of 5% MeOH in EtOAc. Fractions containing the product were collected and solvent was removed. The product was dried under high vacuum, yielding 197 mg (85% yield) of a colorless solid. m/z (ESI-TOF): 440.19 [M+H]+, calcd. 440.17.

23

Synthesis of FAPPT (11): 6-(4-(2-(trifluoromethyl)benzoyl)piperazine-1-yl)-pyridazine-3-carboxylate (30 mg, 0.079 mmol) and 11.3 mg (0.1 mmol) 4-fluoroanline were dissolved in 2 mL DMF under nitrogen. To the reaction was added 29 mg (0.1 mmol) HBTU, followed by 27.5 DIPEA. The reaction was left to stir overnight and the solvent was removed under vacuum. The reaction was purified on a silica column with a mobile phase of 2:1 EtOAc:hexanes. Fractions containing the product were collected and solvent removed. The product was dried under high vacuum yielding 197 mg (85% yield) of a colorless solid. m/z (ESI-TOF): 474.04 [M+H]+, calcd. 474.05.

24

Determination of the partition coefficient (log P): 10 uL of 18F-FPPPT was added to a solution containing 0.5 mL of Milli-Q water and 0.5 mL of n-octanol. The sample vials were vortexed for 1 minute at r.t. and allowed to sit for 30 minutes to allow complete separation of phases. Aliquots of 100 μL from each phase were removed and activity counted separately by a Perkin–Elmer γ-counter. The partition coefficient was calculated as the ratio of counts in the octanol fraction to the counts in the water fraction. Each LogP determination was performed in triplicate. .

25

Western blot analysis. Cell lysates were separated on a 4-12% Bis-Tris (NuPAGE) gel and transferred to a nitrocellulose membranes using an iBlot (Thermo Fisher Scientific) transfer system. Membranes were blocked with 5% milk in TBST for 1 hour and incubated overnight with the appropriate primary antibody. After washing the membrane, it was incubated with the secondary HRP-conjugated antibody, and developed with Supersignal West Pico ECL substrate (Thermo Fisher Scientific). The following antibodies were used: anti-SCD-1 (abcam, ab19862) and anti-Actin(abcam, ab3280), anti-GAPDH (ab181602), HRP donkey anti-rabbit (ab6802) and HRP donkey anti-mouse (ab6820).

27

PET/CT imaging procedures: PET/CT imaging was performed on a small animal Siemens Inveon PET/CT imaging system. Approximately 100 μCi of 18F-FPPPT in saline was injected through the tail vein into NOD-SCID mice bearing subcutaneous PC-3 or MDA-MB-231 tumors on the front shoulder. Each mouse underwent a static scan 1.0 hour p.i.

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