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Molecular Imaging and Biology

, Volume 20, Issue 6, pp 1001–1007 | Cite as

PET Imaging Analysis of Vitamin B1 Kinetics with [11C]Thiamine and its Derivative [11C]Thiamine Tetrahydrofurfuryl Disulfide in Rats

  • Satoshi Nozaki
  • Aya Mawatari
  • Yuka Nakatani
  • Emi Hayashinaka
  • Yasuhiro Wada
  • Yukihiro Nomura
  • Takahito Kitayoshi
  • Kouji Akimoto
  • Shinji Ninomiya
  • Hisashi Doi
  • Yasuyoshi WatanabeEmail author
Research Article
  • 312 Downloads

Abstract

Purpose

Thiamine is an essential component of glucose metabolism and energy production. The disulfide derivative, thiamine tetrahydrofurfuryl disulfide (TTFD), is better absorbed than readily-available water-soluble thiamine salts because it does not require the rate-limiting transport system required for thiamine absorption. However, the detailed pharmacokinetics of thiamine and TTFD under normal and pathological conditions have not yet been clarified. C-11-labeled thiamine and TTFD were recently synthesized by our group. In this study, to clarify the differences in pharmacokinetics and metabolism of these probes, a quantitative PET imaging study and radiometabolite analysis of C-11-labeled thiamine and TTFD were performed in the rat heart.

Procedures

Positron emission tomography (PET) imaging with [11C]thiamine and [11C]TTFD was performed in normal rats to determine the pharmacokinetics of these probes, and the radiometabolites of both probes from the blood and heart tissue were analyzed by thin-layer chromatography.

Results

Accumulation of [11C]TTFD was significantly higher than that of [11C]thiamine in the rat heart. Moreover, as a result of the radiometabolite analysis of heart tissue at 15 min after the injection of [11C]TTFD, thiamine pyrophosphate, which serves as a cofactor for the enzymes involved in glucose metabolism, was found as the major radiometabolite and at a significantly higher level than in the [11C]thiamine-injected group.

Conclusions

PET imaging techniques for visualizing the kinetics and metabolism of thiamine using [11C]thiamine and [11C]TTFD were developed in this study. Consequently, noninvasive PET imaging for the pathophysiology of thiamine-related cardiac function may provide novel information about heart failure and related disorders.

Key words

Vitamin B1 Thiamine Fursultiamine Thiamine tetrahydrofurfuryl disulfide Positron emission tomography 

Notes

Acknowledgements

The authors would like to thank Mr. M. Kurahashi (Sumitomo Heavy Industry Accelerator Service Ltd.) for operating the cyclotron.

Compliance with Ethical Standards

All experimental protocols were approved by the Animal Care and Use Committee of RIKEN Kobe Institute and were performed in accordance with the National Institutes of Health Principles of Laboratory Animal Care. All applicable institutional and/or national guidelines for the care and use of animals were followed.

Conflict of Interest

This work was supported in part by an extramural research grant from Takeda Pharmaceutical Company Limited (Tokyo, Japan) to Yasuyoshi Watanabe. Yukihiro Nomura, Takahito Kitayoshi, Kouji Akimoto, and Shinji Nomura were employees of Takeda Pharmaceutical Company Limited. Other authors declare that there are no conflicts of interest.

References

  1. 1.
    Batifoulier F, Verny MA, Besson C, Demigné C, Rémésy C (2005) Determination of thiamine and its phosphate esters in rat tissues analyzed as thiochromes on a RP-amide C16 column. J Chromatogr B Analyt Technol Biomed Life Sci 816:67–72CrossRefGoogle Scholar
  2. 2.
    Gaitonde MK, Fayein NA, Johnson AL (1975) Decreased metabolism in vivo of glucose into amino acids of the brain of thiamine-deficient rats after treatment with pyriThiamine. J Neurochem 24:1215–1223CrossRefGoogle Scholar
  3. 3.
    Holowach J, Kauffman F, Ikossi MG, Thomas C, McDougal DB (1968) The effects of a thiamine antagonist, pyriThiamine, on levels of selected metabolic intermediates and on activities of thiamine-dependent enzymes in the brain and liver. J Neurochem 15:621–631CrossRefGoogle Scholar
  4. 4.
    Zubaran C, Fernandes JG, Rodnight R (1997) Wernicke-Korsakoff syndrome. Postgrad Med J 73:27–31CrossRefGoogle Scholar
  5. 5.
    Kawano H, Hayashi T, Koide Y, Toda G, Yano K (2005) Histopathological changes of biopsied myocardium in Shoshin beriberi. Int Heart J 46:751–759CrossRefGoogle Scholar
  6. 6.
    Takeda A, Sakano M, Mizoguchi Y et al (2004) Vitamin B1 nutritional status assessed by blood vitamin B1 values of middle-aged Japanese men and woman. Trace Nutr Res 23:124–127Google Scholar
  7. 7.
    Smidt LJ, Cremin FM, Grivetti LE, Clifford AJ (1991) Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency. J Gerontol 46:M16–M22CrossRefGoogle Scholar
  8. 8.
    Chen MF, Chen LT, Gold M, Boyce HW Jr (1996) Plasma and erythrocyte thiamin concentrations in geriatric outpatients. J Am Coll Nutr 15:231–236CrossRefGoogle Scholar
  9. 9.
    Wilkinson TJ, Hanger HC, Elmslie J, George PM, Sainsbury R (1997) The response to treatment of subclinical thiamine deficiency in the elderly. Am J Clin Nutr 66:925–928CrossRefGoogle Scholar
  10. 10.
    Vognar L, Stoukides J (2009) The role of low plasma thiamin levels in cognitively impaired elderly patients presenting with acute behavioral disturbances. J Am Geriatr Soc 57:2166–2168CrossRefGoogle Scholar
  11. 11.
    Butterworth RF (2009) Thiamine deficiency-related brain dysfunction in chronic liver failure. Metab Brain Dis 24:189–196CrossRefGoogle Scholar
  12. 12.
    Shimomura T, Mori E, Hirono N, Imamura T, Yamashita H (1998) Development of Wernicke-Korsakoff syndrome after long intervals following gastrectomy. Arch Neurol 55:1242–1245CrossRefGoogle Scholar
  13. 13.
    Lonsdale D (1987) Thiamine and its fat-soluble derivatives as therapeutic agents. Int Clin Nutr Rev 7:114–125Google Scholar
  14. 14.
    Sen I, Cooper JR (1976) The turnover of thiamine and its phosphate esters in rat organs. Neurochem Res 1:65–71CrossRefGoogle Scholar
  15. 15.
    Nozaki S, Mizuma H, Tanaka M, Jin G, Tahara T, Mizuno K, Yamato M, Okuyama K, Eguchi A, Akimoto K, Kitayoshi T, Mochizuki-Oda N, Kataoka Y, Watanabe Y (2009) Thiamine tetrahydrofurfuryl disulfide improves energy metabolism and physical performance during physical-fatigue loading in rats. Nutr Res 29:867–872CrossRefGoogle Scholar
  16. 16.
    Djoenaidi W, Notermans SL, Dunda G (1992) Beriberi cardiomyopathy. Eur J Clin Nutr 46:227–234PubMedGoogle Scholar
  17. 17.
    Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, Ganapathy V, Prasad PD (1999) Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem 274:31925–31929CrossRefGoogle Scholar
  18. 18.
    Reidling JC, Subramanian VS, Dudeja PK, Said HM (2002) Expression and promoter analysis of SLC19A2 in the human intestine. Biochim Biophys Acta 1561:180–187CrossRefGoogle Scholar
  19. 19.
    Said HM, Balamurugan K, Subramanian VS, Marchant JS (2004) Expression and functional contribution of hTHTR-2 in thiamin absorption in human intestine. Am J Physiol Gastrointest Liver Physiol 286:G491–G498CrossRefGoogle Scholar
  20. 20.
    Reidling JC, Said HM (2005) Adaptive regulation of intestinal thiamin uptake: molecular mechanism using wild-type and transgenic mice carrying hTHTR-1 and -2 promoters. Am J Physiol Gastrointest Liver Physiol 288:G1127–G1134CrossRefGoogle Scholar
  21. 21.
    Doi H, Mawatari A, Kanazawa M, Nozaki S, Nomura Y, Kitayoshi T, Akimoto K, Suzuki M, Ninomiya S, Watanabe Y (2015) Synthesis of 11C-labeled thiamine and Fursultiamine for in vivo molecular imaging of vitamin B1 and its prodrug using positron emission tomography. J Org Chem 80:6250–6258CrossRefGoogle Scholar
  22. 22.
    Suzuki M, Takashima-Hirano M, Ishii H, Watanabe C, Sumi K, Koyama H, Doi H (2014) Synthesis of 11C-labeled retinoic acid, [11C]ATRA, via an alkenylboron precursor by Pd(0)-mediated rapid C-[11C]methylation. Bioorg Med Chem Lett 24:3622–3625CrossRefGoogle Scholar
  23. 23.
    Schieferstein H, Ross TL (2013) 18F-labeled folic acid derivatives for imaging of the folate receptor via positron emission tomography. J Label Compd Radiopharm 56:432–440CrossRefGoogle Scholar
  24. 24.
    Aljammaz I, Al-Otaibi B, Al-Hokbany N et al (2014) Development and pre-clinical evaluation of new 68Ga-NOTA-folate conjugates for PET imaging of folate receptor-positive tumors. Anticancer Res 34:6547–6556PubMedGoogle Scholar
  25. 25.
    AlJammaz I, Al-Otaibi B, Al-Rumayan F et al (2014) Development and preclinical evaluation of new 124I-folate conjugates for PET imaging of folate receptor-positive tumors. Nucl Med Biol 41:457–463CrossRefGoogle Scholar
  26. 26.
    Ikotun OF, Marquez BV, Fazen CH et al (2014) Investigation of a vitamin B12 conjugate as a PET imaging probe. ChemMedChem 9:1244–1251CrossRefGoogle Scholar
  27. 27.
    Slobbe P, Windhorst AD, Stigter-van Walsum M et al (2014) Development of [18F]afatinib as new TKI-PET tracer for EGFR positive tumors. Nucl Med Biol 41:749–757CrossRefGoogle Scholar
  28. 28.
    Tamura K, Kurihara H (2013) Yonemori K, et al. (2013) 64Cu-DOTA-trastuzumab PET imaging in patients with HER2-positive breast cancer. J Nucl Med 54:1869–1875CrossRefGoogle Scholar
  29. 29.
    Oosting SF, Brouwers AH, van Es SC, Nagengast WB, Oude Munnink TH, Lub-de Hooge MN, Hollema H, de Jong JR, de Jong IJ, de Haas S, Scherer SJ, Sluiter WJ, Dierckx RA, Bongaerts AHH, Gietema JA, de Vries EGE (2015) 89Zr-bevacizumab PET visualizes heterogeneous tracer accumulation in tumor lesions of renal cell carcinoma patients and differential effects of antiangiogenic treatment. J Nucl Med 56:63–69CrossRefGoogle Scholar
  30. 30.
    Takashima T, Nagata H, Nakae T, Cui Y, Wada Y, Kitamura S, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y (2010) Positron emission tomography studies using (15R)-16-m-[11C]tolyl-17,18,19,20-tetranorisocarbacyclin methyl ester for the evaluation of hepatobiliary transport. J Pharmacol Exp Ther 335:314–323CrossRefGoogle Scholar
  31. 31.
    Yamashita S, Takashima T, Kataoka M, Oh H, Sakuma S, Takahashi M, Suzuki N, Hayashinaka E, Wada Y, Cui Y, Watanabe Y (2011) PET imaging of the gastrointestinal absorption of orally administered drugs in conscious and anesthetized rats. J Nucl Med 52:249–256CrossRefGoogle Scholar
  32. 32.
    Takashima T, Yokoyama C, Mizuma H, Yamanaka H, Wada Y, Onoe K, Nagata H, Tazawa S, Doi H, Takahashi K, Morita M, Kanai M, Shibasaki M, Kusuhara H, Sugiyama Y, Onoe H, Watanabe Y (2011) Developmental changes in P-glycoprotein function in the blood-brain barrier of nonhuman primates: PET study with R-11C-verapamil and 11C-oseltamivir. J Nucl Med 52:950–957CrossRefGoogle Scholar
  33. 33.
    Takashima T, Hashizume Y, Katayama Y, Murai M, Wada Y, Maeda K, Sugiyama Y, Watanabe Y (2011) The involvement of organic anion transporting polypeptide in the hepatic uptake of telmisartan in rats: PET studies with [11C]telmisartan. Mol Pharm 8:1789–1798CrossRefGoogle Scholar
  34. 34.
    Shingaki T, Takashima T, Wada Y, Tanaka M, Kataoka M, Ishii A, Shigihara Y, Sugiyama Y, Yamashita S, Watanabe Y (2012) Imaging of gastrointestinal absorption and biodistribution of orally administered probe of positron emission tomography in human. Clin Pharmacol Ther 91:653–659CrossRefGoogle Scholar
  35. 35.
    Takashima T, Shingaki T, Katayama Y, Hayashinaka E, Wada Y, Kataoka M, Ozaki D, Doi H, Suzuki M, Ishida S, Hatanaka K, Sugiyama Y, Akai S, Oku N, Yamashita S, Watanabe Y (2013) Dynamic analysis of fluid distribution in the gastrointestinal tract in rats: positron emission tomography imaging after oral administration of nonabsorbable marker, [18F]deoxyfluoropoly(ethylene glycol). Mol Pharm 10:2261–2269CrossRefGoogle Scholar
  36. 36.
    Takashima T, Kitamura S, Wada Y, Tanaka M, Shigihara Y, Ishii H, Ijuin R, Shiomi S, Nakae T, Watanabe Y, Cui Y, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y (2012) PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-me. J Nucl Med 53:741–748CrossRefGoogle Scholar
  37. 37.
    Takashima T, Wu C, Takashima-Hirano M, Katayama Y, Wada Y, Suzuki M, Kusuhara H, Sugiyama Y, Watanabe Y (2013) Evaluation of breast cancer resistance protein function in hepatobiliary and renal excretion using PET with [11C]SC-62807. J Nucl Med 54:267–276CrossRefGoogle Scholar
  38. 38.
    Shingaki T, Takashima T, Ijuin R, Zhang X, Onoue T, Katayama Y, Okauchi T, Hayashinaka E, Cui Y, Wada Y, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y (2013) Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats. J Pharmacol Exp Ther 347:193–202CrossRefGoogle Scholar
  39. 39.
    Shingaki T, Hume EW, Takashima T et al (2015) Quantitative evaluation of mOcts and mMate1 function based on minimally invasive measurement of tissue concentration using PET with [11C]metformin in mouse. Pharm Res 32:2538–2547PubMedGoogle Scholar
  40. 40.
    DiNicolantonio JJ, Niazi AK, Lavie CJ et al (2013) Thiamine supplementation for the treatment of heart failure: a review of the literature. Congest Heart Fail 19:214–222CrossRefGoogle Scholar
  41. 41.
    Page GL, Laight D, Cummings MH (2011) Thiamine deficiency in diabetes mellitus and the impact of thiamine replacement on glucose metabolism and vascular disease. Int J Clin Pract 65:684–690CrossRefGoogle Scholar
  42. 42.
    Kv L'o'n, Nguyen LT (2011) Role of thiamine in Alzheimer's disease. Am J Alzheimers Dis Other Demen 26:588–598CrossRefGoogle Scholar
  43. 43.
    Lonsdale D, Shamberger RJ, Audhya T (2002) Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuro Endocrinol Lett 23:303–308PubMedGoogle Scholar
  44. 44.
    Gangolf M, Czerniecki J, Radermecker M, Detry O, Nisolle M, Jouan C, Martin D, Chantraine F, Lakaye B, Wins P, Grisar T, Bettendorff L (2010) Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells. PLoS One 5:e13616CrossRefGoogle Scholar
  45. 45.
    Bettendorff L (1995) Thiamine homeostasis in neuroblastoma cells. Neurochem Int 26:295–302CrossRefGoogle Scholar
  46. 46.
    Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625CrossRefGoogle Scholar
  47. 47.
    Bajotto G, Murakami T, Nagasaki M, Tamura T, Tamura N, Harris RA, Shimomura Y, Sato Y (2004) Downregulation of the skeletal muscle pyruvate dehydrogenase complex in the Otsuka long-Evans Tokushima fatty rat both before and after the onset of diabetes mellitus. Life Sci 75:2117–2130CrossRefGoogle Scholar
  48. 48.
    Babaei-Jadidi R, Karachalias N, Kupich C, Ahmed N, Thornalley PJ (2004) High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats. Diabetologia 47:2235–2246CrossRefGoogle Scholar
  49. 49.
    Beltramo E, Berrone E, Tarallo S, Porta M (2008) Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol 45:131–141CrossRefGoogle Scholar
  50. 50.
    Hammes HP, Du X, Edelstein D et al (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294–299CrossRefGoogle Scholar
  51. 51.
    Thornalley PJ (2005) The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev 1:287–298CrossRefGoogle Scholar
  52. 52.
    Berrone E, Beltramo E, Solimine C, Ape AU, Porta M (2006) Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem 281:9307–9313CrossRefGoogle Scholar
  53. 53.
    Schmid U, Stopper H, Heidland A, Schupp N (2008) Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro. Diabetes Metab Res Rev 24:371–377CrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2018

Authors and Affiliations

  • Satoshi Nozaki
    • 1
  • Aya Mawatari
    • 1
  • Yuka Nakatani
    • 1
  • Emi Hayashinaka
    • 1
  • Yasuhiro Wada
    • 1
  • Yukihiro Nomura
    • 2
  • Takahito Kitayoshi
    • 2
  • Kouji Akimoto
    • 2
  • Shinji Ninomiya
    • 2
  • Hisashi Doi
    • 1
  • Yasuyoshi Watanabe
    • 1
    Email author
  1. 1.Division of Bio-Function Dynamics ImagingRIKEN Center for Life Science Technologies (CLST)KobeJapan
  2. 2.Takeda Pharmaceutical Company LimitedTokyoJapan

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