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Validation of R-2-[18F]Fluoropropionic Acid as a Potential Tracer for PET Imaging of Liver Cancer

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Abstract

Purpose

2-[18F]Fluoropropionic acid (RS-[18F]FPA) has shown potential value as a short-chain fatty acid positron emission tomography (PET) tracer for the detection of liver cancer. However, RS-[18F]FPA is a mixture of 2-R-[18F]fluoropropionic acid (R-[18F]FPA) and 2-S-[18F]fluoropropionic acid (S-[18F]FPA). The aim of this study is to validate the feasibility of R-[18F]FPA in preclinical PET imaging of liver cancer and to compare the use of R-[18F]FPA with that of RS-[18F]FPA and S-[18F]FPA.

Procedures

A comparative study of R-[18F]FPA, RS-[18F]FPA, S-[18F]FPA, and [18F]FDG micro-PET imaging was performed in HepG2 and SK-Hep-1 tumor-bearing mice. A comparison of R-[18F]FPA uptake with that of S-[18F]FPA by HepG2 and SK-Hep-1 cells was made at different time points. Additionally, in vivo blocking experiments in HepG2 and SK-Hep-1 tumor models were conducted with orlistat and 3-nitropropionic acid (3-NP). In vitro blocking experiments with orlistat or 3-NP were performed with HepG2 and SK-Hep-1 cells.

Results

The radioactivity uptake values of R-[18F]FPA were comparable to those of RS-[18F]FPA but were higher than those of S-[18F]FPA and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in HepG2 tumors. The radioactivity uptake values of R-[18F]FPA in large HepG2 tumors were lower than those of [18F]FDG (P < 0.05), while R-[18F]FPA PET was significantly superior to [18F]FDG PET in detecting small tumors (both SK-Hep-1 and HepG2 tumors). The in vivo PET imaging experiments showed that R-[18F]FPA uptake in HepG2 tumor-bearing mice was blocked by 19.3 % and 31.8 % after treatment with orlistat and 3-NP, respectively. The radioactivity uptake values of R-[18F]FPA in SK-Hep-1 tumor-bearing mice was blocked by 39.5 % with orlistat.

Conclusion

R-[18F]FPA seems to be more potential than S-[18F]FPA as an optically pure PET probe, with effective compensation for the deficiencies of [18F]FDG, particularly in PET imaging of small liver cancer. The uptake mechanism of [18F]FPA in liver cancer may be related to fatty acid synthesis and the tricarboxylic acid cycle. However, compared with the racemic RS-[18F]FPA, the possible advantages of R-enantiomer R-[18F]FPA still needs further research.

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References

  1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921

    Article  CAS  PubMed  Google Scholar 

  2. Benson AB 3rd, D’Angelica MI, Abrams TA et al (2014) Hepatobiliary cancers, version 2. 2014. J Natl Compr Cancer Netw 12:1152–1182

    Article  CAS  Google Scholar 

  3. Kremer N, Walther AE, Tiao GM (2014) Management of hepatoblastoma: an update. Curr Opin Pediatr 26:362–369

    Article  PubMed  Google Scholar 

  4. Bolog N, Andreisek G, Oancea I, Mangrau A (2011) CT and MR imaging of hepatocellular carcinoma. J Gastrointestin Liver Dis 20:181–189

    PubMed  Google Scholar 

  5. Chotipanich C, Kunawudhi A, Promteangtrong C, Tungsuppawattanakit P, Sricharunrat T, Wongsa P (2016) Diagnosis of hepatocellular carcinoma using C-11 choline PET/CT: comparison with F-18FDG, contrast-enhanced MRI and MDCT. Asian Pac J Cancer Prev 17:3569–3573

    PubMed  Google Scholar 

  6. Trojan J, Schroeder O, Raedle J, Baum RP, Herrmann G, Jacobi V, Zeuzem S (1999) Fluorine-18 FDG positron emission tomography for imaging of hepatocellular carcinoma. Am J Gastroenterol 94:3314–3319

    Article  CAS  PubMed  Google Scholar 

  7. Wu HB, Wang QS, Li BY, Li HS, Zhou WL, Wang QY (2011) F-18 FDG in conjunction with 11C-choline PET/CT in the diagnosis of hepatocellular carcinoma. Clin Nucl Med 36:1092–1097

    Article  PubMed  Google Scholar 

  8. Plathow C, Weber WA (2008) Tumor cell metabolism imaging. J Nucl Med 49(Suppl 2):43S–63S

    Article  CAS  PubMed  Google Scholar 

  9. Yoshii Y, Furukawa T, Oyama N, Hasegawa Y, Kiyono Y, Nishii R, Waki A, Tsuji AB, Sogawa C, Wakizaka H, Fukumura T, Yoshii H, Fujibayashi Y, Lewis JS, Saga T (2013) Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome. PLoS One 8:e64570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Deford-Watts LM, Mintz A, Kridel SJ (2013) The potential of 11C-acetate PET for monitoring the fatty acid synthesis pathway in tumors. Curr Pharm Biotechnol 14:300–312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yoshii Y, Furukawa T, Saga T, Fujibayashi Y (2015) Acetate/acetyl-CoA metabolism associated with cancer fatty acid synthesis: overview and application. Cancer Lett 356:211–216

    Article  CAS  PubMed  Google Scholar 

  12. Ho CL, Yu SC, Yeung DW et al (2003) 11C-acetate PET imaging in hepatocellular carcinoma and other liver masses. J Nucl Med 44:213–221

    PubMed  Google Scholar 

  13. Hwang KH, Choi DJ, Lee SY, Lee MK, Choe W (2009) Evaluation of patients with hepatocellular carcinomas using [11C]acetate and [18F]FDG PET/CT: a preliminary study. Appl Radiat Isot 67:1195–1198

    Article  CAS  PubMed  Google Scholar 

  14. Salem N, Kuang Y, Wang F, Maclennan GT, Lee Z (2009) [(Methyl)1-11C]-acetate metabolism in hepatocellular carcinoma. Q J Nucl Med Mol Imaging 53:144–156

    CAS  PubMed  Google Scholar 

  15. Bertagna F, Bertoli M, Bosio G, Biasiotto G, Sadeghi R, Giubbini R, Treglia G (2014) Diagnostic role of radiolabelled choline PET or PET/CT in hepatocellular carcinoma: a systematic review and meta-analysis. Hepatol Int 8:493–500

    Article  PubMed  Google Scholar 

  16. Takemoto K, Hatano E, Nishii R, Kagawa S, Kishibe Y, Takahashi M, Yamauchi H, Matsumura K, Zaima M, Toriguchi K, Tanabe K, Kitamura K, Seo S, Taura K, Endo K, Uemoto S, Higashi T (2014) Assessment of [18F]-fluoroacetate PET/CT as a tumor-imaging modality: preclinical study in healthy volunteers and clinical evaluation in patients with liver tumor. Ann Nucl Med 28:371–380

    Article  CAS  PubMed  Google Scholar 

  17. Yamamoto Y, Nishiyama Y, Kameyama R, Okano K, Kashiwagi H, Deguchi A, Kaji M, Ohkawa M (2008) Detection of hepatocellular carcinoma using 11C- choline PET: comparison with 18F-FDG PET. J Nucl Med 49:1245–1248

    Article  PubMed  Google Scholar 

  18. Talbot JN, Gutman F, Fartoux L, Grange JD, Ganne N, Kerrou K, Grahek D, Montravers F, Poupon R, Rosmorduc O (2006) PET/CT in patients with hepatocellular carcinoma using [18F] fluorocholine: preliminary comparison with [18F]FDG PET/CT. Eur J Nucl Med Mol Imaging 33:1285–1289

    Article  PubMed  Google Scholar 

  19. Ho CL, Cheung MK, Chen S, Cheung TT, Leung YL, Cheng KC, Yeung WD (2012) [18F]fluoroacetate positron emission tomography for hepatocellular carcinoma and metastases: an alternative tracer for [11C]acetate? Mol Imaging 11:229–239

    Article  CAS  PubMed  Google Scholar 

  20. Kuang Y, Salem N, Tian H, Kolthammer JA, Corn DJ, Wu C, Wang F, Wang Y, Lee Z (2011) Imaging lipid synthesis in hepatocellular carcinoma with [methyl-11C]choline: correlation with in vivo metabolic studies. J Nucl Med 52:98–106

    Article  PubMed  Google Scholar 

  21. Kwee SA, Sato MM, Kuang Y, Franke A, Custer L, Miyazaki K, Wong LL (2017) [18F]fluorocholine PET/CT imaging of liver cancer: radiopathologic correlation with tissue phospholipid profiling. Mol Imaging Biol 19:446–455

  22. Li L, Che L, Wang CM, Blecha JE, Li X, VanBrocklin HF, Calvisi DF, Puchowicz M, Chen X, Seo Y (2016) [11C]acetate PET imaging is not always associated with increased lipogenesis in hepatocellular carcinoma in mice. Mol Imaging Biol 18:360–367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Park JW, Kim JH, Kim SK, Kang KW, Park KW, Choi JI, Lee WJ, Kim CM, Nam BH (2008) A prospective evaluation of 18F-FDG and 11C-acetate PET/CT for detection of primary and metastatic hepatocellular carcinoma. J Nucl Med 49:1912–1921

    Article  PubMed  Google Scholar 

  24. Vāvere AL, Kridel SJ, Wheeler FB et al (2008) 1-11C-acetate as a PET radiopharmaceutical for imaging fatty acid synthase expression in prostate Cancer. J Nucl Med 49:327–334

    Article  CAS  PubMed  Google Scholar 

  25. Pillarsetty N, Punzalan B, Larson SM (2009) 2-18F-Fluoropropionic acid as a PET imaging agent for prostate cancer. J Nucl Med 50:1709–1714

    Article  CAS  PubMed  Google Scholar 

  26. Kasumov T, Cendrowski AV, David F, Jobbins KA, Anderson VE, Brunengraber H (2007) Mass isotopomer study of anaplerosis from propionate in the perfused rat heart. Arch Biochem Biophys 463:110–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kridel SJ, Lowther WT, Pemble CW (2007) Fatty acid synthase inhibitors: new directions for oncology. Expert Opin Investig Drugs 16:1817–1829

    Article  CAS  PubMed  Google Scholar 

  28. Bastiaansen JA, Cheng T, Mishkovsky M et al (2013) In vivo enzymatic activity of acetylCoA synthetase in skeletal muscle revealed by 13C turnover from hyperpolarized [1-13C]acetate to [1-13C]acetylcarnitine. Biochim Biophys Acta 1830:4171–4178

    Article  CAS  PubMed  Google Scholar 

  29. Zhang ZW, Liu SY, Tang XL, Nie D, Tang G, Sun A, Xiong Y, Ma H, Wen F, Hu P (2018) Radiosynthesis and preliminary biological evaluation of the 2-[18F]fluoropropionic acid enantiomers for tumor PET imaging. J Radi Nucl Chem 316:153–159

    Article  CAS  Google Scholar 

  30. Zhao J, Zhang ZW, Nie DH et al (2019) PET imaging of hepatocellular carcinomas:18F-fluoropropionic acid as a complementary radiotracer for 18F-fluorodeoxyglucose. Mol Imaging 18:1–8

    Article  CAS  Google Scholar 

  31. Wang HL, Hu KZ, Tang GH et al (2012) Simple and efficient automated radiosynthesis of 2-18F-fluoropropionic acid using solid-phase extraction cartridges purification. J Label Compd Radiopharm 55:366–370

    Article  CAS  Google Scholar 

  32. Olsen C, Rustad A, Fonnum F, Paulsen RE, Hassel B (1999) 3-Nitropropionic acid: an astrocyte-sparing neurotoxin in vitro. Brain Res 850:144–149

    Article  CAS  PubMed  Google Scholar 

  33. Khan MA, Combs CS, Brunt EM, Lowe VJ, Wolverson MK, Solomon H, Collins BT, Bisceglie AMD (2000) Positron emission tomography scanning in the evaluation of hepatocellular carcinoma. J Hepatol 32:792–797

    Article  CAS  PubMed  Google Scholar 

  34. Yen TC, See LC, Lai CH, Yah-Huei CW, Ng KK, Ma SY, Lin WJ, Chen JT, Chen WJ, Lai CR, Hsueh S (2004) 18F-FDG uptake in squamous cell carcinoma of the cervix is correlated with glucose transporter 1 expression. J Nucl Med 45:22–29

    CAS  PubMed  Google Scholar 

  35. Lee JD, Yang WI, Park YN, Kim KS, Choi JS, Yun M, Ko D, Kim TS, Cho AE, Kim HM, Han KH, Im SS, Ahn YH, Choi CW, Park JH (2005) Different glucose uptake and glycolytic mechanisms between hepatocellular carcinoma and intrahepatic mass-forming cholangiocarcinoma with increased 18F-FDG uptake. J Nucl Med 46:1753–1759

    CAS  PubMed  Google Scholar 

  36. Brito AF, Abrantes AM, Ribeiro M, Oliveira R, Casalta-Lopes J, Gonçalves AC, Sarmento-Ribeiro AB, Tralhão JG, Botelho MF (2015) Fluorine-18 fluorodeoxyglucose uptake in hepatocellular carcinoma: correlation with glucose transporters and p53 expression. J Clin Exp Hepatol 5:183–189

    Article  PubMed  PubMed Central  Google Scholar 

  37. Impheng H, Pongcharoen S, Richert L, Pekthong D, Srisawang P (2014) The selective target of capsaicin on FASN expression and de novo fatty acid synthesis mediated through ROS generation triggers apoptosis in HepG2 cells. PLoS One 9:e107842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang H, Tang G, Hu K, Huang T, Liang X, Wu Z, Li S (2016) Comparison of three 18F-labeled carboxylic acids with 18F-FDG of the differentiation tumor from inflammation in model mice. BMC Med Imaging 16:2

    Article  PubMed  PubMed Central  Google Scholar 

  39. Henry PG, Lebon V, Vaufrey F, Brouillet E, Hantraye P, Bloch G (2002) Decreased TCA cycle rate in the rat brain after acute 3-NP treatment measured by in vivo 1H-{13C} NMR spectroscopy. J Neurochem 82:857–866

    Article  CAS  PubMed  Google Scholar 

  40. Impheng H, Richert L, Pekthong D, Scholfield CN, Pongcharoen S, Pungpetchara I, Srisawang P (2015) [6]-Gingerol inhibits de novo fatty acid synthesis and carnitine palmitoyltransferase-1 activity which triggers apoptosis in HepG2. Am J Cancer Res 5:1319–1336

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hao Q, Li T, Zhang X et al (2014) Expression and roles of fatty acid synthase in hepatocellular carcinoma. Oncol Rep 32:2471–2476

    Article  CAS  PubMed  Google Scholar 

  42. Esslimani-Sahla M, Thezenas S, Simony-Lafontaine J, Kramar A, Lavaill R, Chalbos D, Rochefort H (2007) Increased expression of fatty acid synthase and progesterone receptor in early steps of human mammary carcinogenesis. Int J Cancer 120:224–229

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by the National Natural Science Foundation of China (No. 81571704, No. 81371584), the Science and Technology Foundation of Guangdong Province (No. 2016B090920087, No. 2014A020210008), the Science and Technology Planning Project Foundation of Guangzhou (No. 201604020169), and the China Postdoctoral Science Foundation (CPSF) (No.2018M631029 to S Liu).

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Author notes

  1. Zhanwen Zhang and Shaoyu Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine and Medical Imaging, Guangdong Engineering Research Center for Translational Application of Medical Radiopharmaceuticals, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China

    Zhanwen Zhang, Shaoyu Liu, Hui Ma, Dahong Nie, Fuhua Wen, Jing Zhao, Aixia Sun, Gongjun Yuan, Shu Su, Xianhong Xiang & Ganghua Tang

  2. Department of Nuclear Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, China

    Zhanwen Zhang & Ping Hu

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  1. Zhanwen Zhang
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Correspondence to Ping Hu or Ganghua Tang.

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The experiments were approved by the Institutional Animal Care and Utilization Committee (IACUU) of the First Affiliated Hospital, Sun Yat-sen University (approval no. 2016058).

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Zhang, Z., Liu, S., Ma, H. et al. Validation of R-2-[18F]Fluoropropionic Acid as a Potential Tracer for PET Imaging of Liver Cancer. Mol Imaging Biol 21, 1127–1137 (2019). https://doi.org/10.1007/s11307-019-01346-1

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