대한임상검사과학회지 (Korean Journal of Clinical Laboratory Science)

  • 제55권4호
  • /
  • Pages.261-268
  • /
  • 2023
  • /
  • 1738-3544(pISSN)
  • /
  • 2288-1662(eISSN)
대한임상검사과학회 (Korean Society for Clinical Laboratory Science)
권호 표지
DOI QR코드

DOI QR Code

고체상 추출법을 기반으로 한 [18F]Fluorocholine 합성법의 최적화 연구

Optimization of Automated Solid Phase Extraction-based Synthesis of [18F]Fluorocholine

  • 박준영 (연세대학교 세브란스병원 핵의학검사실) ;
  • 손정민 (연세대학교 세브란스병원 핵의학검사실) ;
  • 강원준 (연세대학교 세브란스병원 핵의학과)
  • Jun Young PARK (Nuclear Medicine Laboratory, Yonsei University Severance Hospital) ;
  • Jeongmin SON (Nuclear Medicine Laboratory, Yonsei University Severance Hospital) ;
  • Won Jun KANG (Department of Nuclear Medicine, Yonsei University Severance Hospital)
  • 투고 : 2023.10.30
  • 심사 : 2023.11.14
  • 발행 : 2023.12.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

[18F]Fluorocholine은 임상에서 부갑상선 선종, 전립선암 및 간세포암 진단 등에 사용되는 PET용 콜린 방사성의약품이다. 본 연구에서는 고체상 추출 카트리지법을 방사성의약품 자동합성장치에 적용하여 [18F]fluorocholine을 제조하는 방법을 최적화하였다. [18F]Fluorocholine은 하나의 반응용기를 사용하여 두 단계 표지반응으로 합성하였으며, [18F]fluorocholine 합성과정 중 생성되는 불순물을 제거하기 위해 사용하는 SepPakⓇ Silica 카트리지의 개수를 3개로 최적화하였고, 전구 물질인 DMAE를 10%로 희석하였을 때 가장 높은 방사화학적 수율을 획득 할 수 있었다. 또한 최종 생산된 [18F] fluorocholine 주사액은 유럽약전에 명시된 품질관리기준을 모두 만족하였다. 본 연구를 통해 쉽고 간편하게 사용할 수 있는 고체상 추출 카트리지를 사용하여 방사성의약품 자동합성장치에 최적화한 [18F]fluorocholine의 합성법은 임상 현장에 안정적으로 [18F]fluorocholine을 공급하는데 유용하게 사용될 것으로 사료된다.

[18F]Fluorocholine is a radiopharmaceutical used non-invasively in positron emission tomography to diagnose parathyroid adenoma, prostate cancer, and hepatocellular carcinoma by evaluating the choline metabolism. In this study, a radiolabeling method for [18F]fluorocholine was optimized using a solid phase extraction (SPE) cartridge. [18F]Fluorocholine was labeled in two steps using an automated synthesizer. In the first step, dibromomethane was reacted with [18F]KF/K2.2.2/K2CO3 to obtain the intermediate [18F]fluorobromomethane. In the second step, [18F]fluorobromomethane was passed through a Sep-PakⓇ Silica SPE cartridge to remove the impurities and then reacted with N,N-dimethylaminoethanol (DMAE) in a Sep-PakⓇ C18 SPE cartridge to label [18F]fluorocholine. The reaction conditions of [18F]fluorocholine were optimized. The synthesis yield was confirmed according to the number of silica cartridges and DMAE concentration. No statistically significant difference in the synthesis yield of [18F]fluorocholine was observed when using four or three silica cartridges (P>0.05). The labeling yield was 11.5±0.5% (N=4) when DMAE was used as its original solution. On the other hand, when diluted to 10% with dimethyl sulfoxide, the radiochemical yield increased significantly to 30.1±5.2% (N=20). In conclusion, [18F]Fluorocholine for clinical use can be synthesized stably in high yield by applying an optimized synthesis method.

키워드

참고문헌

  1. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr. 1994;14:269-296. https://doi.org/10.1146/annurev.nu.14.070194.001413
  2. Shim E, Park JH, Lee Y, Park E. Literature review and future tasks necessary to establish of Korean Dietary Reference Intake for choline. J Nutr Health. 2022;55:211-226. https://doi.org/10.4163/jnh.2022.55.2.211
  3. Zeisel SH. Choline phospholipids: signal transduction and carcinogenesis. FASEB J. 1993;7:551-557. https://doi.org/10.1096/fasebj.7.6.8472893
  4. Mehedint MG, Zeisel SH. Choline's role in maintaining liver function: new evidence for epigenetic mechanisms. Curr Opin Clin Nutr Metab Care. 2013;16:339-345. https://doi.org/10.1097/mco.0b013e3283600d46
  5. Michel V, Yuan Z, Ramsubir S, Bakovic M. Choline transport for phospholipid synthesis. Exp Biol Med (Maywood). 2006;231: 490-504. https://doi.org/10.1177/153537020623100503
  6. Blusztajn JK, Liscovitch M, Mauron C, Richardson UI, Wurtman RJ. Phosphatidylcholine as a precursor of choline for acetylcholine synthesis. J Neural Transm Suppl. 1987;24:247-259.
  7. Plathow C, Weber WA. Tumor cell metabolism imaging. J Nucl Med. 2008;49 Suppl 2:43S-63S. https://doi.org/10.2967/jnumed.107.045930
  8. Tian M, Zhang H, Oriuchi N, Higuchi T, Endo K. Comparison of 11C-choline PET and FDG PET for the differential diagnosis of malignant tumors. Eur J Nucl Med Mol Imaging. 2004;31:1064-1072. https://doi.org/10.1007/s00259-004-1496-y
  9. Hara T. 18F-fluorocholine: a new oncologic PET tracer. J Nucl Med. 2001;42:1815-1817.
  10. Roivainen A, Forsback S, Gronroos T, Lehikoinen P, Kahkonen M, Sutinen E, et al. Blood metabolism of [methyl-11C]choline; implications for in vivo imaging with positron emission tomography. Eur J Nucl Med. 2000;27:25-32. https://doi.org/10.1007/pl00006658
  11. DeGrado TR, Baldwin SW, Wang S, Orr MD, Liao RP, Friedman HS, et al. Synthesis and evaluation of (18)F-labeled choline analogs as oncologic PET tracers. J Nucl Med. 2001;42:1805-1814.
  12. Schmid DT, John H, Zweifel R, Cservenyak T, Westera G, Goerres GW, et al. Fluorocholine PET/CT in patients with prostate cancer: initial experience. Radiology. 2005;235:623-628. https://doi.org/10.1148/radiol.2352040494
  13. Talbot JN, Fartoux L, Balogova S, Nataf V, Kerrou K, Gutman F, et al. Detection of hepatocellular carcinoma with PET/CT: a prospective comparison of 18F-fluorocholine and 18F-FDG in patients with cirrhosis or chronic liver disease. J Nucl Med. 2010;51:1699-1706. https://doi.org/10.2967/jnumed.110.075507
  14. DeGrado TR, Coleman RE, Wang S, Baldwin SW, Orr MD, Robertson CN, et al. Synthesis and evaluation of 18F-labeled choline as an oncologic tracer for positron emission tomography: initial findings in prostate cancer. Cancer Res. 2001;61:110-117.
  15. Iwata R, Pascali C, Bogni A, Furumoto S, Terasaki K, Yanai K. [18F]fluoromethyl triflate, a novel and reactive [18F]fluoromethylating agent: preparation and application to the on-column preparation of [18F]fluorocholine. Appl Radiat Isot. 2002; 57:347-352. https://doi.org/10.1016/s0969-8043(02)00123-9
  16. Zhang MR, Ogawa M, Furutsuka K, Yoshida Y, Suzuki K. [18F]Fluoromethyl iodide ([18F]FCH2I): preparation and reactions with phenol, thiophenol, amide and amine functional groups. J Fluor Chem. 2004;125:1879-1886. https://doi.org/10.1016/j.jfluchem.2004.06.017
  17. Neal TR, Apana S, Berridge MS. Improved synthesis of [18F]fluoromethyl tosylate, a convenient reagent for radiofluoromethylations. J Label Compd Radiopharm. 2005;48:557-568. https://doi.org/10.1002/jlcr.949
  18. Kryza D, Tadino V, Filannino MA, Villeret G, Lemoucheux L. Fully automated [18F]fluorocholine synthesis in the TracerLab MX FDG Coincidence synthesizer. Nucl Med Biol. 2008;35:255-260. https://doi.org/10.1016/j.nucmedbio.2007.11.008
  19. Rodnick ME, Brooks AF, Hockley BG, Henderson BD, Scott PJ. A fully-automated one-pot synthesis of [18F]fluoromethylcholine with reduced dimethylaminoethanol contamination via [18F]fluoromethyl tosylate. Appl Radiat Isot. 2013;78:26-32. https://doi.org/10.1016/j.apradiso.2013.04.017
  20. Huang YY, Tsai CL, Wen HP, Tzen KY, Yen RF, Shiue CY. High yield one-pot production of [18F]FCH via a modified TRACERlab FxFN module. Appl Radiat Isot. 2017;128:190-198. https://doi.org/10.1016/j.apradiso.2017.07.029
  21. Kobayashi K, Bhargava P, Raja S, Nasseri F, Al-Balas HA, Smith DD, et al. Image-guided biopsy: what the interventional radiologist needs to know about PET/CT. Radiographics. 2012;32:1483-1501. https://doi.org/10.1148/rg.325115159
  22. Slaets D, De Bruyne S, Dumolyn C, Moerman L, Mertens K, De Vos F. Reduced dimethylaminoethanol in [(18)F]fluoromethylcholine: an important step towards enhanced tumour visualization. Eur J Nucl Med Mol Imaging. 2010;37:2136-2145. https://doi.org/10. 1007/s00259-010-1508-z https://doi.org/10.1007/s00259-010-1508-z
  23. Cornford EM, Braun LD, Oldendorf WH. Carrier mediated blood-brain barrier transport of choline and certain choline analogs. J Neurochem. 1978;30:299-308. https://doi.org/10.1111/j.1471-4159.1978.tb06530.x
  24. Dodia C, Fisher AB, Chander A, Kleinzeller A. Inhibitors of choline transport in alveolar type II epithelial cells. Am J Respir Cell Mol Biol. 1992;6:426-429. https://doi.org/10.1165/ajrcmb/6.4.426
  25. Kwee S, Turner H, Lim J, Wakano C, Coel M. Dimethylaminoethanol reduces 18F-fluoroethylcholine uptake in prostate cancer cells. J Nucl Med. 2006;47(Suppl 1):425P.
  26. Costa CLS, Santos LM, Castro ACF, Nascimento LTC, Silva JB, Silveira MB. Chromatographic method development using multivariate approaches for organic solvents optimized analysis in [18F]fluorocholine. Appl Radiat Isot. 2023;195:110736. https://doi.org/10.1016/j.apradiso.2023.110736