PET Imaging Analysis of Vitamin B1 Kinetics with [11C]Thiamine and its Derivative [11C]Thiamine Tetrahydrofurfuryl Disulfide in Rats
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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.
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.
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.
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 wordsVitamin B1 Thiamine Fursultiamine Thiamine tetrahydrofurfuryl disulfide Positron emission tomography
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.
- 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
- 13.Lonsdale D (1987) Thiamine and its fat-soluble derivatives as therapeutic agents. Int Clin Nutr Rev 7:114–125Google Scholar
- 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
- 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
- 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.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
- 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
- 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.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.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
- 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
- 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