Skip to main content

Advertisement

Log in

In vivo preclinical PET/CT imaging of carbon-11-labeled aminoglycerol probe for the diagnosis of liver fibrosis

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Objective

As an important membrane protein, aquaglyceroporin involves liver glycerol metabolism, which can be used to stage liver fibrosis. In this study, we synthesized a novel molecular probe carbon-11-labeled AR ([11C]AR) with aminoglycerol (AR), and evaluated its preclinical performance for liver fibrosis diagnosis by positron emission tomography/computed tomography (PET/CT) imaging in vivo.

Methods

We developed a fully automatic synthesis procedure for the preparation of [11C]AR by radiolabeling glycerol analogue precursor AR with carbon-11. The liver uptake kinetics of [11C]AR was investigated using a rat model by the PET/CT scanner. The dynamic PET/CT scans were performed between the control group (n = 5) and experimental group (n = 25), which was divided into three subgroups (S1, S2 + S3, S4) based on the stages of liver fibrosis. The regions of interest (ROIs) of 20 pixels were drawn in the liver area on the reconstructed images. One-way analysis of variance and independent sample t test were used to analyze the statistical difference of the maximum standardized uptake value (SUVmax) among the groups at series of scanning time points (20 s, 60 s, 90 s, 150 s, 5 min, 10 min, 20 min and 25 min).

Results

The fully automatic synthesis of [11C]AR was successfully achieved with high synthesis efficiency (above 50%). The uptake of [11C]AR in progressive liver fibrosis tissues was significantly lower than that in healthy livers at all the imaging time points (P < 0.05), especially at early time points (before 10 min p.i.). A cut-off SUVmax value (1.1) at 150 s p.i. was set for discrimination progressive fibrosis from healthy liver. More experimental and healthy rats were tested with this new threshold to evaluate fibrosis situation. The sensitivity of detecting progressive fibrosis with [11C]AR was 100% in the second cohort.

Conclusion

We demonstrated a new carbon-11-radiolabeled aminoglycerol PET/CT imaging probe [11C]AR for liver fibrosis diagnosis and staging, which may allow potential assessment of liver fibrosis stages in a rapid and noninvasive method.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Zhao J, Zhai F, Cheng J, He Q, Luo J, Yang X, et al. Evaluating the significance of viscoelasticity in diagnosing early-stage liver fibrosis with transient elastography. PLoS ONE. 2017;12(1):e0170073.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jensen L, Kupcova V, Arold G, Pettersson J, Hjerpsted JB. Pharmacokinetics and tolerability of semaglutide in people with hepatic impairment. Diabetes Obes Metab. 2018;20(4):998–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology. 2015;61(3):1066–79.

    Article  PubMed  Google Scholar 

  4. Atta HM. Reversibility and heritability of liver fibrosis: implications for research and therapy. World J Gastroenterol. 2015;21(17):5138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Elpek GO. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: an update. World J Gastroenterol. 2014;20(23):7260–76.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rodriguez A, Gena P, Mendez-Gimenez L, Rosito A, Valenti V, Rotellar F, et al. Reduced hepatic aquaporin-9 and glycerol permeability are related to insulin resistance in non-alcoholic fatty liver disease. Int J Obes (Lond). 2014;38(9):1213–20.

    Article  CAS  Google Scholar 

  7. Schiavon Lde L, Narciso-Schiavon JL, de Carvalho-Filho RJ. Non-invasive diagnosis of liver fibrosis in chronic hepatitis C. World J Gastroenterol. 2014;20(11):2854–66.

    Article  PubMed  Google Scholar 

  8. Baues M, Dasgupta A, Ehling J, Prakash J, Boor P, Tacke F, et al. Fibrosis imaging: current concepts and future directions. Adv Drug Deliv Rev. 2017;121:9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Han TT, Du M, Zhang X, Cao L, Li H, Zhao ZS, et al. Quantitative assessment of early liver fibrosis in rats using 13N-NH3∙H2O PET/CT. Nucl Med Commun. 2016;37(1):92–8.

    CAS  PubMed  Google Scholar 

  10. Zhang X, Guo Q, Shi Y, Xu W, Yu S, Yang Z, et al. (99m)Tc-3PRGD2 scintigraphy to stage liver fibrosis and evaluate reversal after fibrotic stimulus withdrawn. Nucl Med Biol. 2017;49:44–9.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang X, Xin J, Shi Y, Xu W, Yu S, Yang Z, et al. Assessing activation of hepatic stellate cells by (99m)Tc-3PRGD2 scintigraphy targeting integrin alphavbeta3: a feasibility study. Nucl Med Biol. 2015;42(3):250–5.

    Article  CAS  PubMed  Google Scholar 

  12. Liu J, Li W, Limbu MH, Li Y, Wang Z, Cheng Z, et al. Effects of simultaneous downregulation of PHD1 and keap1 on prevention and reversal of liver fibrosis in mice. Front Pharmacol. 2018;9:555.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Rodriguez A, Marinelli RA, Tesse A, Fruhbeck G, Calamita G. Sexual dimorphism of adipose and hepatic aquaglyceroporins in health and metabolic disorders. Front Endocrinol (Lausanne). 2015;6:171.

    Article  Google Scholar 

  14. Sanchez-Valle V, Chavez-Tapia NC, Uribe M, Mendez-Sanchez N. Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem. 2012;19(28):4850–60.

    Article  CAS  PubMed  Google Scholar 

  15. Lakner AM, Walling TL, McKillop IH, Schrum LW. Altered aquaporin expression and role in apoptosis during hepatic stellate cell activation. Liver Int. 2011;31(1):42–51.

    Article  CAS  PubMed  Google Scholar 

  16. Jelen S, Wacker S, Aponte-Santamaria C, Skott M, Rojek A, Johanson U, et al. Aquaporin-9 protein is the primary route of hepatocyte glycerol uptake for glycerol gluconeogenesis in mice. J Biol Chem. 2011;286(52):44319–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Calamita G, Gena P, Ferri D, Rosito A, Rojek A, Nielsen S, et al. Biophysical assessment of aquaporin-9 as principal facilitative pathway in mouse liver import of glucogenetic glycerol. Biol Cell. 2012;104(6):342–51.

    Article  CAS  PubMed  Google Scholar 

  18. Gena P, Mastrodonato M, Portincasa P, Fanelli E, Mentino D, Rodriguez A, et al. Liver glycerol permeability and aquaporin-9 are dysregulated in a murine model of non-alcoholic fatty liver disease. PLoS ONE. 2013;8(10):e78139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Golbar HM, Izawa T, Wijesundera KK, Bondoc A, Tennakoon AH, Kuwamura M, et al. Depletion of hepatic macrophages aggravates liver lesions induced in rats by thioacetamide (TAA). Toxicol Pathol. 2016;44(2):246–58.

    Article  CAS  PubMed  Google Scholar 

  20. Tardelli M, Moreno-Viedma V, Zeyda M, Itariu BK, Langer FB, Prager G, et al. Adiponectin regulates aquaglyceroporin expression in hepatic stellate cells altering their functional state. J Gastroenterol Hepatol. 2017;32(1):253–60.

    Article  CAS  PubMed  Google Scholar 

  21. Rodriguez A, Catalan V, Gomez-Ambrosi J, Garcia-Navarro S, Rotellar F, Valenti V, et al. Insulin- and leptin-mediated control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR signaling cascade. J Clin Endocrinol Metab. 2011;96(4):E586–97.

    Article  CAS  PubMed  Google Scholar 

  22. Lindskog C, Asplund A, Catrina A, Nielsen S, Rutzler M. A systematic characterization of aquaporin-9 expression in human normal and pathological tissues. J Histochem Cytochem. 2016;64(5):287–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bulik S, Holzhutter HG, Berndt N. The relative importance of kinetic mechanisms and variable enzyme abundances for the regulation of hepatic glucose metabolism—insights from mathematical modeling. BMC Biol. 2016;14:15.

    Article  PubMed  PubMed Central  Google Scholar 

  24. da Silva IV, Rodrigues JS, Rebelo I, Miranda JPG, Soveral G. Revisiting the metabolic syndrome: the emerging role of aquaglyceroporins. Cell Mol Life Sci. 2018;75(11):1973–88.

    Article  PubMed  Google Scholar 

  25. Pfeifer L, Adler W, Zopf S, Siebler J, Wildner D, Goertz RS, et al. Acoustic radiation force impulse elastography: comparison and combination with other noninvasive tests for the diagnosis of compensated liver cirrhosis. Eur J Gastroenterol Hepatol. 2017;29(5):524–30.

    Article  CAS  PubMed  Google Scholar 

  26. Raichle ME, Martin WR, Herscovitch P, Mintun MA, Markham J. Brain blood flow measured with intravenous H2(15)O. II. Implementation and validation. J Nucl Med. 1983;24(9):790–8.

    CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by grants from Natural Science Foundation of Liaoning Province (2017225030) and Shenyang science and technology program (18014423).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jun Xin.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All animal experiments were performed approved by the Institutional Animal Care and Use Committee at Shengjing Hospital of China Medical University.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Zhang, X., Du, M. et al. In vivo preclinical PET/CT imaging of carbon-11-labeled aminoglycerol probe for the diagnosis of liver fibrosis. Ann Nucl Med 33, 806–812 (2019). https://doi.org/10.1007/s12149-019-01391-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-019-01391-4

Keywords

Navigation