대한방사성의약품학회지 (Journal of Radiopharmaceuticals and Molecular Probes)

  • 제10권1호
  • /
  • Pages.13-19
  • /
  • 2024
  • /
  • 2384-1583(pISSN)
  • /
  • 2508-3848(eISSN)
대한방사성의약품학회 (Korean Society of Radiopharmaceuticals and Molecular Probes)
권호 표지
DOI QR코드

DOI QR Code

Development of Benzothiazole-Based Boron and Fluorine Complex for Boron Neutron Capture Therapy

  • Soyeon Kim (Leading Research Center of Total Solution for Osteoporosis Treatment, Chonnam National University) ;
  • Iqra Bibi (Division of Applied RI, Korea Institute of Radiological & Medical Sciences (KIRAMS)) ;
  • Jung Young Kim (Division of Applied RI, Korea Institute of Radiological & Medical Sciences (KIRAMS)) ;
  • Ji-Ae Park (Division of Applied RI, Korea Institute of Radiological & Medical Sciences (KIRAMS))
  • 투고 : 2024.04.17
  • 심사 : 2024.05.10
  • 발행 : 2024.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Boron neutron capture therapy (BNCT) represents a cutting-edge approach in cancer treatment, offering a promising avenue to enhance cure rates for patients resistant to conventional therapies. A critical factor for successful BNCT is the development of boron drugs with exceptional tumor selectivity. In this study, we synthesized a novel benzothiazole derivative, potassium (4-(benzo[d]thiazol-2-yl)-2,6-difluorophenyl) trifluoroborate (B13), incorporating boron and fluorine. Following its synthesis, we radiolabeled the drug with 18F via a 19F/18F isotope exchange reaction, producing 18F-B13 with good radiochemical purity and yield. Notably, the radiotracer demonstrated significant uptake in U87MG tumors, as evidenced by PET imaging. Biodistribution analysis revealed a substantial accumulation of boron (4 ppm) in U87MG tumors 1h post-intravenous injection. Moreover, it showcased significant tumor/muscle ratios (2.04) 2 h post-injection. While the tumor selectivity of B13 did not meet the stringent standards for BNCT, its potential as a BNCT tracer remains promising. Notably, the tumor/muscle ratio remained elevated up to two hours post-injection, suggesting future avenues for optimization and clinical translation.

키워드

과제정보

이 논문은 한국연구재단 학문후속세대양성 지원사업(2021R1A6A3A01086709)과 과학기술정보통신부 한국원자력의학원 연구 운영비 지원사업(50462-2024)의 지원에 의하여 이루어졌으며 다른 이해 관계는 없음을 밝힙니다.

참고문헌

  1. Coghi P, Li J, Hosmane NS, Zhu Y. Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment. Med Res Rev 2023;43(5):1809-30. 
  2. Barth RF, Mi P, Yang W. Boron delivery agents for neutron capture therapy of cancer. Cancer Commun 2018;38:1-5. 
  3. Dymova MA, Taskaev SY, Richter VA, Kuligina EV. Boron neutron capture therapy: Current status and future perspectives. Cancer Commun 2020;40(9):406-21. 
  4. Barth RF, Coderre JA, Vicente MG, Blue TE. Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects. Clin Cancer Res 2005;11(11):3987-4002. 
  5. Kankaanranta L,Seppala T, Koivunoro H, Saarilahti K, Atula T, Collan J, Salli E, Kortesniemi M, Uusi-Simola J, Valimaki P, Makitie A, M. Seppanen, Minn H, Revitzer H, Kouri M, Kotiluoto P, Seren T, Auterinen I, Savolainen S, Joensuu H. Boron neutron capture therapy in the treatment of locally recurred head-and-neck cancer: final analysis of a phase I/II trial. Int J Radiat Oncol Biol Phys 2012;82(1):e67-75. 
  6. Nedunchezhian K, Aswath N, Thiruppathy M, Thiru-gnanamurthy S. Boron neutron capture therapy-a literature review. JCDR 2016;10(12):ZE01. 
  7. Barth RF, H Vicente M, Harling OK, Kiger WS, Riley KJ, Binns PJ, Wagner FM, Suzuki M, Aihara T, Kato I, Kawabata S. Current status of boron neutron capture therapy of high-grade gliomas and recurrent head and neck cancer. Radiat Oncol 2012;7:1-21. 
  8. Wittig A, Sauerwein WA, Coderre JA, Coderre JA. Mechanisms of transport of p-borono-phenylalanine through the cell membrane in vitro. Radiat Res 2000;153(2):173-80. 
  9. Detta A, Cruickshank GS. L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors. Cancer Res 2009;69(5):2126-32. 
  10. Ishiwata K. 4-Borono-2-18F-fluoro-L-phenylalanine PET for boron neutron capture therapy-oriented diagnosis: Overview of a quarter century of research. Ann Nucl Med 2019;33(4):223-36. 
  11. Ishiwata K, Ido T, Mejia AA, Ichihashi M, Mishima Y. Synthesis and radiation dosimetry of 4-borono-2-[18F] fluoro-D, L-phenylalanine: a target compound for PET and boron neutron capture therapy. Int J Radiat Appl Instrum A 1991;42(4):325-8. 
  12. Li J, Shi Y, Zhang Z, Liu H, Lang L, Liu T, Chen X, Liu Z. A metabolically stable boron-derived tyrosine serves as a theranostic agent for positron emission tomography guided boron neutron capture therapy. Bioconjugate Chem 2019;30(11):2870-8. 
  13. Kuivila HG, Armour AG. Electrophilic displacement reactions. IX. Effects of substituents on rates of reactions between hydrogen peroxide and benzeneboronic acid1-3. J Am Chem Soc 1957;79(21):5659-62. 
  14. Mortimer CG, Wells G, Crochard JP, Stone EL, Bradshaw TD, Stevens MF, Westwell AD. Antitumor benzothiazoles. 26. 2-(3, 4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a simple fluorinated 2-arylbenzothiazole, shows potent and selective inhibitory activity against lung, colon, and breast cancer cell lines. J Med Chem 2006;49(1):179-85. 
  15. Hutchinson I, Jennings SA, Vishnuvajjala BR, Westwell AD, Stevens MF. Antitumor benzothiazoles. 16. Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl) benzothiazole amino acid prodrugs. J Med Chem 2002;45(3):744-7. 
  16. Li Z, Chansaenpak K, Liu S, Wade CR, Conti PS, Gabbai FP. Harvesting 18F-fluoride ions in water via direct 18F-19F isotopic exchange: radiofluorination of zwitterionic aryltrifluoroborates and in vivo stability studies. Med Chem Comm 2012;3(10):1305-8. 
  17. Liu Z, Lin KS, Benard F, Pourghiasian M, Kiesewetter DO, Perrin DM, Chen X. One-step 18F labeling of biomolecules using organotrifluoroborates. Nat Protoc 2015;10(9):1423-32. 
  18. Kato I, Ono K, Sakurai Y, Ohmae M, Maruhashi A, Imahori Y, Kirihata M, Nakazawa M, Yura Y. Effectiveness of BNCT for recurrent head and neck malignancies. Appl Radiat Isot 2004;61(5):1069-73. 
  19. Balcerzyk M, De-Miguel M, Guerrero C, Fernandez B. Quantification of Boron Compound Concentration for BNCT Using Positron Emission Tomography. Cells 2020;9(9):2084. 
  20. Lee JW, Park JA, Lee YJ, Shin UC, Kim SW, Kim BI, Lim SM, An GI, Kim JY, Lee KC. New Glucocyclic RGD Dimers for Positron Emission Tomography Imaging of Tumor Integrin Receptors. Cancer Biother Radiopharm 2016;31(6): 209-16. 
  21. Lee JW, Lee YJ, Shin UC, Kim SW, Kim BI, Lee KC, Kim JY, Park JA. Improved pharmacokinetics following PEGylation and dimerization of ac (RGD-ACH-K) conjugate used for tumor positron emission tomography imaging. Cancer Biother Radiopharm 2016;31(8):295-301. 
  22. Dubey R, Shrivastava PK, Basniwal PK, Bhattacharya S, Narayana Moorthy NS. 2-(4-aminophenyl) benzothiazole: A potent and selective pharmacophore with novel mechanistic action towards various tumour cell lines. Mini-Rev Med Chem 2006;6(6):633-7. 
  23. Chun JH, Lee M, Jun S, Son J. Organometallic fluorine-18 bonds in 18F-radiochemistry. J Radiopharm Mol Probes 2021;7(1):22-32. 
  24. Burke BP, Clemente GS, Archibald SJ. Boron-18F containing positron emission tomography radiotracers: advances and opportunities. Contrast Media Mol Imaging 2015;10(2):96-110. 
  25. Wilson TC, Cailly T, Gouverneur V. Boron reagents for divergent radiochemistry. Chem Soc Rev 2018;47(18):6990-7005. 
  26. Kim S, Yang J-u, Lee KC, Kim JY, Lee YJ, Park J-A. Preliminary research on the development of boron neutron capture therapy drugs. J Radiopharm Mol Probes 2021;7(1):3-10. 
  27. Yang JU, Kim S. Lee KC, Lee YJ, Kim JY, Park JA. Development of evaluation of B/F benzothiazole analogues for boron neutron capture therapy. J Radiopharm Mol Probes 2022;8(1):17-23. 
  28. Yang JU, Kim S, Lee KC, Lee YJ, Kim JY, Park JA. Development of Brain-Tumor-Targeted Benzothiazole-Based Boron Complex for Boron Neutron Capture Therapy. ACS Med Chem Lett 2022;13(10):1615-20.