Research Article
BibTex RIS Cite

Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-

Year 2023, Volume: 27 Issue: 5, 2058 - 2066, 28.06.2025

Maja Chochevska Katerina Kolevska Marija Atanasova Lazareva Maja Velichkovska Filip Jolevski Toni Tripunovski Emilija Janevik Ivanovska Ana Ugrinska Bistra Angelovska

Abstract

The increasing number of fluorinated pharmaceuticals in pharmaceutical chemistry and fluorine radiopharmaceuticals in radiochemistry highlights the importance of optimizing their synthesis processes. [18F]Fluoromisonidazole ([18F]FMISO) radiopharmaceutical synthesized using aqueous [18F]F- and 1-(2'-nitro-1'-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulfonylpropanediol precursor (NITTP), is one such example. This radiolabeled compound is used for imaging tumor hypoxia by positron emission tomography (PET). When working with ionizing radiation, ensuring the operator's safety is crucial. As a result, the synthesis process for [18F]FMISO takes place within automated modules in closed lead-shielded hot cells. This protective measure prohibits the collection of control samples during the synthesis process. Our experiments involved utilizing the stable isotope [19F]F- instead of [18F]F- to examine various aspects. These included analyzing the intermediate compound produced after the fluorination reaction, assessing unhydrolyzed/hydrolyzed intermediates, and detecting unexpected or unknown chemical impurities in both the unpurified and final purified products. HPLC analysis was employed to analyze the collected samples. The results obtained from these experiments proved invaluable in addressing the challenge of unwanted chemical impurities during the radiosynthesis of [18F]FMISO. They provided valuable insights that aided in the further development of the synthesis process. Overall, this study demonstrates the significance of utilizing non-radioactive chemistry to optimize radiosynthesis, allowing for the safe and efficient production of [18F]FMISO without the need for radiation exposure.

Keywords

[18F]Fluoromisonidazole [19F]F- synthesis fluorinated intermediate impurity

References

  • [1] Müller K, Faeh C, Diederich F. Fluorine in pharmaceuticals: looking beyond intuition. Science. 2007; 317(5846): 1881-6. https://doi.org/10.1126/science.1131943
  • [2] Cai L, Lu S, Pike VW, Chemistry with [18F]fluoride ion. Eur. J. Org. Chem. 2008; 2008(17):2853–2873. https://doi.org/10.1002/ejoc.200800114
  • [3] Jacobson O, Chen X. PET designated fluoride-18 production and chemistry. Curr. Top. Med. Chem. 2010; 10: 1048–1059. https://doi.org/10.2174/156802610791384298
  • [4] Halder R, Ritter T. 18F-Fluorination: Challenge and Opportunity for Organic Chemists, The Journal of Organic Chemistry. 2021; 86 (20): 13873-13884, https://doi.org/10.1021/acs.joc.1c01474
  • [5] Wang Y, Lin Q, Shi H, Cheng D. Fluorine-18: Radiochemistry and Target-Specific PET Molecular Probes Design. Front Chem. 2022; 10: 884517. https://doi.org/10.3389/fchem.2022.884517
  • [6] Mason NS, Mathis AC, Radiohalogens for PET Imaging. Springer-Verlag London Ltd 2003; 217–236.
  • [7] Schirrmacher R., Wängler C., Schirrmacher E. Recent developments and trends in 18F-radiochemistry: syntheses and applications. Mini Rev Org Chem. 2007; 4: 317–329. https://doi.org/10.2174/157019307782411699
  • [8] Ross TL, Wester HJ. 18F: Labeling chemistry and labeled compounds. Handbook of Nuclear Chemsitry. Springer; New York: 2011; 2021
  • [9] Littich R, Scott P.J.H. Novel strategies for fluorine-18 radiochemistry. Angew Chem Int Ed. 2012; 51: 1106–1109. https://doi.org/10.1002/anie.201106785
  • [10] Kumar P, Bacchu V, Irving WL, Semin, The Chemistry and Radiochemistry of Hypoxia-Specific, Radiohalogenated Nitroaromatic Imaging Probes., Nucl Med 2015; 45: 122-135. https://doi.org/10.1053/j.semnuclmed.2014.10.005
  • [11] Cole EL, Stewart MN, Littich R, Hoareau R, Scott PJ. Radiosyntheses using fluorine-18: the art and science of late stage fluorination. Curr Top Med Chem. 2014; 14(7): 875-900. https://doi.org/10.2174/1568026614666140202205035
  • [12] Keng PY, Esterby M, van Dam RM. Emerging Technologies for Decentralized Production of PET Tracers. In: Hsieh C-H, editor. Positron Emission Tomography - Current Clinical and Research Aspects. London, UK: InTechOpen; 2012; 10:153–182. https://doi.org/10.5772/31390
  • [13] Claggett SB., Quinn KM., Lazari M, Moore MD., van Dam RM. Simplified programming and control of automated radiosynthesizers through unit operations. European Journal of Nuclear Medicine and Molecular Imaging (EJNMMI) Research. 2013; 3: 53. https://doi.org/10.1186/2191-219X-3-53
  • [14] Schopf E, Waldmann CM, Collins J, Drake C, Slavik R, van Dam R.M. Automation of a Positron-emission Tomography (PET) Radiotracer Synthesis Protocol for Clinical Production. J Vis Exp. 2018; 140:58428. https://doi.org/10.3791/58428
  • [15] Barnes-Seeman D, Beck J. Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analyses. Curr. Top. Med. Chem. 2014; 14:855–864. https://doi.org/10.2174/1568026614666140202204242
  • [16] Daruich de Souza C, Joo Kim J, Tae HJ., Start Here When Performing Radiochemical Reactions. IntechOpen. 2022; Chapter 2. https://doi.org/10.5772/intechopen.98766
  • [17] Kim DW, Jeong HJ, Lim ST, Sohn MH. Recent Trends in the Nucleophilic [(18)F]-radiolabeling Method with No-carrier-added [(18)F]fluoride. Nucl Med Mol Imaging. 2010; 44(1):25-32. https://doi.org/10.1007/s13139-009-0008-1
  • [18] Rong J, Ahmed H, Steven L. Precision Radiochemistry for Fluorine‐18 Labeling of PET Tracers. WILEY‐VCH GmbH., Organofluorine Chemistry: Synthesis, Modeling, and Applications. 2021; Chapter 12., 397-425. https://doi.org/10.1002/9783527825158.ch12
  • [19] Lemaire CF, Aerts JJ, Voccia S, Libert LC, Mercier F, Goblet D, Plenevaux AR, Luxen AJ. Fast Production of Highly Reactive No-Carrier-Added [18F]Fluoride for the Labeling of Radiopharmaceuticals. Angew. Chem. Int. Ed. 2010; 49: 3161–3164. https://doi.org/10.1002/anie.200906341
  • [20] Sergeev M, Lazari M, Morgia F, Collins J, Javed MR, Sergeeva O, Jones J, Phelps ME, Lee JT, Keng PY, Dam RM. Performing radiosynthesis in microvolumes to maximize molar activity of tracers for positron emission tomography. Commun. Chem. 2018; 1(1): 10. https://doi.org/10.1038/s42004-018-0009-z
  • [21] Blom E, Koziorowski J. Automated synthesis of [18F]FMISO on IBA Synthera®. Journal of Radioanalytical and Nuclear Chemistry. 2014; 299: 265-270. https://doi.org/10.1007/s10967-013-2753-y
There are 21 citations in total.

Details

Primary Language English
Subjects Radiopharmacy
Journal Section Articles
Authors

Maja Chochevska 0000-0002-8720-342X

Katerina Kolevska 0000-0002-8312-218X

Marija Atanasova Lazareva 0000-0002-1516-8303

Maja Velichkovska 0000-0003-2806-3436

Filip Jolevski 0000-0002-3554-6746

Toni Tripunovski 0000-0001-6388-4139

Emilija Janevik Ivanovska 0000-0002-8493-5481

Ana Ugrinska 0000-0001-6558-3890

Bistra Angelovska 0009-0003-9074-0490

Publication Date June 28, 2025
Published in Issue Year 2023 Volume: 27 Issue: 5

Cite

APA Chochevska, M., Kolevska, K., Atanasova Lazareva, M., Velichkovska, M., et al. (2025). Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-. Journal of Research in Pharmacy, 27(5), 2058-2066.
AMA Chochevska M, Kolevska K, Atanasova Lazareva M, Velichkovska M, Jolevski F, Tripunovski T, Janevik Ivanovska E, Ugrinska A, Angelovska B. Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-. J. Res. Pharm. July 2025;27(5):2058-2066.
Chicago Chochevska, Maja, Katerina Kolevska, Marija Atanasova Lazareva, Maja Velichkovska, Filip Jolevski, Toni Tripunovski, Emilija Janevik Ivanovska, Ana Ugrinska, and Bistra Angelovska. “Optimization of Reaction Conditions for Synthesis of [18F]FMISO Using Stable [19F]F-”. Journal of Research in Pharmacy 27, no. 5 (July 2025): 2058-66.
EndNote Chochevska M, Kolevska K, Atanasova Lazareva M, Velichkovska M, Jolevski F, Tripunovski T, Janevik Ivanovska E, Ugrinska A, Angelovska B (July 1, 2025) Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-. Journal of Research in Pharmacy 27 5 2058–2066.
IEEE M. Chochevska, K. Kolevska, M. Atanasova Lazareva, M. Velichkovska, F. Jolevski, T. Tripunovski, E. Janevik Ivanovska, A. Ugrinska, and B. Angelovska, “Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-”, J. Res. Pharm., vol. 27, no. 5, pp. 2058–2066, 2025.
ISNAD Chochevska, Maja et al. “Optimization of Reaction Conditions for Synthesis of [18F]FMISO Using Stable [19F]F-”. Journal of Research in Pharmacy 27/5 (July 2025), 2058-2066.
JAMA Chochevska M, Kolevska K, Atanasova Lazareva M, Velichkovska M, Jolevski F, Tripunovski T, Janevik Ivanovska E, Ugrinska A, Angelovska B. Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-. J. Res. Pharm. 2025;27:2058–2066.
MLA Chochevska, Maja et al. “Optimization of Reaction Conditions for Synthesis of [18F]FMISO Using Stable [19F]F-”. Journal of Research in Pharmacy, vol. 27, no. 5, 2025, pp. 2058-66.
Vancouver Chochevska M, Kolevska K, Atanasova Lazareva M, Velichkovska M, Jolevski F, Tripunovski T, Janevik Ivanovska E, Ugrinska A, Angelovska B. Optimization of reaction conditions for synthesis of [18F]FMISO using stable [19F]F-. J. Res. Pharm. 2025;27(5):2058-66.