Toward 19F magnetic resonance thermometry: spin–lattice and spin–spin-relaxation times and temperature dependence of fluorinated drugs at 9.4 T

  • Christian Prinz
  • Paula Ramos Delgado
  • Thomas Wilhelm Eigentler
  • Ludger Starke
  • Thoralf Niendorf
  • Sonia WaicziesEmail author
Research Article



This study examines the influence of the environmental factor temperature on the 19F NMR characteristics of fluorinated compounds in phantom studies and in tissue.

Materials and methods

19F MR mapping and MR spectroscopy techniques were used to characterize the 19F NMR characteristics of perfluoro-crown ether (PFCE), isoflurane, teriflunomide, and flupentixol. T1 and T2 mapping were performed, while temperature in the samples was changed (T = 20–60 °C) and monitored using fiber optic measurements. In tissue, T1 of PFCE nanoparticles was determined at physiological temperatures and compared with the T1-measured at room temperature.


Studies on PFCE, isoflurane, teriflunomide, and flupentixol showed a relationship between temperature and their physicochemical characteristics, namely, chemical shift, T1 and T2. T1 of PFCE nanoparticles was higher at physiological body temperatures compared to room temperature.


The impact of temperature on the 19F NMR parameters of fluorinated compounds demonstrated in this study not only opens a trajectory toward 19F MR-based thermometry, but also indicates the need for adapting MR sequence parameters according to environmental changes such as temperature. This will be an absolute requirement for detecting fluorinated compounds by 19F MR techniques in vivo.


Magnetic resonance Fluorine MR 19F MR Thermometry Spin–lattice relaxation 



CP would like to thank Yiyi Ji for helpful discussions on thermometry. TN wishes to acknowledge the support provided by the European Research Council (ERC advanced Grant, ThermalMR, EU project 743077). SW wishes to acknowledge the support provided by the Germany Research Council (DFG WA2804).

Author contributions

Study conception and design: CP, PR, TE, TN, and SW. Acquisition of data: CP, TE, LS, and SW. Drafting of manuscript: CP, PR, TE, LS, TN, and SW. Critical revision: CP, PR, TE, LS, TN, and SW.


This study was funded (in part) by the Deutsche Forschungsgemeinschaft to SW (DFG WA2804). TN received funding from the European Research Council (ERC advanced Grant, ThermalMR, EU project 743077).

Compliance with ethical standards

Conflict of interest

Thoralf Niendorf is founder and CEO of MRI.TOOLS GmbH, Berlin, Germany.

Statement of human/animal rights

All animal experiments were conducted in accordance with procedures approved by the Animal Welfare Department of the State Office of Health and Social Affairs Berlin (LAGeSo), and conformed to national and international guidelines to minimize discomfort to animals (86/609/EEC).


  1. 1.
    Schmieder AH, Caruthers SD, Keupp J, Wickline SA, Lanza GM (2015) Recent advances in 19Fluorine magnetic resonance imaging with perfluorocarbon emulsions. Engineering (Beijing, China) 1(4):475–489Google Scholar
  2. 2.
    Ahrens ET, Flores R, Xu H, Morel PA (2005) In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol 23(8):983–987CrossRefPubMedGoogle Scholar
  3. 3.
    Waiczies H, Lepore S, Drechsler S, Qadri F, Purfürst B, Sydow K, Dathe M, Kühne A, Lindel T, Hoffmann W, Pohlmann A, Niendorf T, Waiczies S (2013) Visualizing brain inflammation with a shingled-leg radio-frequency head probe for 19F/1H MRI. Sci Rep 3:1280CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ruiz-Cabello J, Barnett BP, Bottomley PA, Bulte JW (2011) Fluorine (19F) MRS and MRI in biomedicine. NMR Biomed 24(2):114–129CrossRefPubMedGoogle Scholar
  5. 5.
    Karson CN, Newton JE, Livingston R, Jolly JB, Cooper TB, Sprigg J, Komoroski RA (1993) Human brain fluoxetine concentrations. J Neuropsychiatry Clin Neurosci 5(3):322–329CrossRefPubMedGoogle Scholar
  6. 6.
    Karson CN, Newton JE, Mohanakrishnan P, Sprigg J, Komoroski RA (1992) Fluoxetine and trifluoperazine in human brain: a 19F-nuclear magnetic resonance spectroscopy study. Psychiatry Res 45(2):95–104CrossRefPubMedGoogle Scholar
  7. 7.
    Komoroski RA, Newton JE, Cardwell D, Sprigg J, Pearce J, Karson CN (1994) In vivo 19F spin relaxation and localized spectroscopy of fluoxetine in human brain. Magn Reson Med 31(2):204–211CrossRefPubMedGoogle Scholar
  8. 8.
    Bolo NR, Hode Y, Nedelec JF, Laine E, Wagner G, Macher JP (2000) Brain pharmacokinetics and tissue distribution in vivo of fluvoxamine and fluoxetine by fluorine magnetic resonance spectroscopy. Neuropsychopharmacology 23(4):428–438CrossRefPubMedGoogle Scholar
  9. 9.
    Ji Y, Waiczies H, Winter L, Neumanova P, Hofmann D, Rieger J, Mekle R, Waiczies S, Niendorf T (2015) Eight-channel transceiver RF coil array tailored for (1)H/(1)(9)F MR of the human knee and fluorinated drugs at 7.0 T. NMR Biomed 28(6):726–737CrossRefPubMedGoogle Scholar
  10. 10.
    Desmoulin F, Gilard V, Malet-Martino M, Martino R (2002) Metabolism of capecitabine, an oral fluorouracil prodrug: (19)F NMR studies in animal models and human urine. Drug Metab Dispos 30(11):1221–1229CrossRefPubMedGoogle Scholar
  11. 11.
    Doi Y, Shimmura T, Kuribayashi H, Tanaka Y, Kanazawa Y (2009) Quantitative (19)F imaging of nmol-level F-nucleotides/-sides from 5-FU with T(2) mapping in mice at 9.4T. Magn Reson Med 62(5):1129–1139CrossRefPubMedGoogle Scholar
  12. 12.
    Cron GO, Beghein N, Ansiaux R, Martinive P, Feron O, Gallez B (2008) 19F NMR in vivo spectroscopy reflects the effectiveness of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy. Magn Reson Med 59(1):19–27CrossRefPubMedGoogle Scholar
  13. 13.
    Morikawa S, Inubushi T, Morita M, Murakami K, Masuda C, Maki J, Tooyama I (2007) Fluorine-19 fast recovery fast spin echo imaging for mapping 5-fluorouracil. Magn Reson Med Sci 6(4):235–240CrossRefPubMedGoogle Scholar
  14. 14.
    Reid DG, Murphy PS (2008) Fluorine magnetic resonance in vivo: a powerful tool in the study of drug distribution and metabolism. Drug Discov Today 13(11–12):473–480CrossRefPubMedGoogle Scholar
  15. 15.
    Colotti R, Bastiaansen JAM, Wilson A, Flögel U, Gonzales C, Schwitter J, Stuber M, van Heeswijk RB (2017) Characterization of perfluorocarbon relaxation times and their influence on the optimization of fluorine-19 MRI at 3 tesla. Magn Reson Med 77(6):2263–2271CrossRefPubMedGoogle Scholar
  16. 16.
    Berkowitz BA, Handa JT, Wilson CA (1992) Perfluorocarbon temperature measurements using 19F NMR. NMR Biomed 5(2):65–68CrossRefPubMedGoogle Scholar
  17. 17.
    Kadayakkara DK, Damodaran K, Hitchens TK, Bulte JW, Ahrens ET (2014) (19)F spin-lattice relaxation of perfluoropolyethers: dependence on temperature and magnetic field strength (7.0–14.1T). J Magn Reson 242:18–22CrossRefPubMedGoogle Scholar
  18. 18.
    Dolbier WR (2016) Guide to fluorine NMR for organic chemists. Wiley, New YorkCrossRefGoogle Scholar
  19. 19.
    Waiczies S, Lepore S, Sydow K, Drechsler S, Ku MC, Martin C, Lorenz D, Schutz I, Reimann HM, Purfurst B, Dieringer MA, Waiczies H, Dathe M, Pohlmann A, Niendorf T (2015) Anchoring dipalmitoyl phosphoethanolamine to nanoparticles boosts cellular uptake and fluorine-19 magnetic resonance signal. Sci Rep 5:8427CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, Tinevez JY, White DJ, Hartenstein V, Eliceiri K, Tomancak P, Cardona A (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9(7):676–682CrossRefGoogle Scholar
  21. 21.
    Henkelman RM (1985) Measurement of signal intensities in the presence of noise in MR images. Med Phys 12(2):232–233CrossRefPubMedGoogle Scholar
  22. 22.
    Haacke E (1999) Magnetic resonance imaging: physical principles and sequence design. Wiley-Liss, New YorkGoogle Scholar
  23. 23.
    Ben-Eliezer N, Sodickson DK, Block KT (2015) Rapid and accurate T 2 mapping from multi-spin-echo data using Bloch-simulation-based reconstruction. Magn Reson Med 73(2):809–817CrossRefPubMedGoogle Scholar
  24. 24.
    National Electrical Manufacturers A (2001) Determination of signal-to-noise ratio (SNR) in diagnostic magnetic resonance imaging. NEMA Standards Publication MS 1-2001Google Scholar
  25. 25.
    Niendorf T, Ji Y, Waiczies S (2016) Fluorinated natural compounds and synthetic drugs. In: Ahrens ET, Flögel U (eds) Fluorine magnetic resonance imaging. Pan Stanford Publishing, Singapore, pp 311–344CrossRefGoogle Scholar
  26. 26.
    Gerig J (2001) Fluorine NMRGoogle Scholar
  27. 27.
    Bushberg JT (2002) The essential physics of medical imaging. lippincott. Williams & Wilkins, PhiladelphiaGoogle Scholar
  28. 28.
    Sinnecker T, Kuchling J, Dusek P, Dörr J, Niendorf T, Paul F, Wuerfel J (2015) Ultrahigh field MRI in clinical neuroimmunology: a potential contribution to improved diagnostics and personalised disease management. EPMA J 6(1):16CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Niendorf T, Schulz-Menger J, Paul K, Huelnhagen T, Ferrari VA, Hodge R (2017) High field cardiac magnetic resonance imaging: a case for ultrahigh field cardiac magnetic resonance. Circ Cardiovasc Imaging 10:(6)CrossRefGoogle Scholar
  30. 30.
    Niendorf T, Barth M, Kober F, Trattnig S (2016) From ultrahigh to extreme field magnetic resonance: where physics, biology and medicine meet. Magma (New York, NY) 29(3):309–311Google Scholar
  31. 31.
    Waiczies S, Millward JM, Starke L, Delgado PR, Huelnhagen T, Prinz C, Marek D, Wecker D, Wissmann R, Koch SP, Boehm-Sturm P, Waiczies H, Niendorf T, Pohlmann A (2017) Enhanced fluorine-19 MRI sensitivity using a cryogenic radiofrequency probe: technical developments and ex vivo demonstration in a mouse model of neuroinflammation. Sci Rep 7(1):9808CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Faber C, Schmid F (2016) Pulse sequence considerations and schemes. In: Ahrens ET, Flögel U (eds) Fluorine magnetic resonance imaging. Pan Stanford Publishing, Singapore, pp 3–27Google Scholar
  33. 33.
    Zhong J, Mills PH, Hitchens TK, Ahrens ET (2013) Accelerated fluorine-19 MRI cell tracking using compressed sensing. Magn Reson Med 69(6):1683–1690CrossRefPubMedGoogle Scholar

Copyright information

© European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) 2018

Authors and Affiliations

  1. 1.Berlin Ultrahigh Field Facility (B.U.F.F.)Max Delbrueck Center for Molecular Medicine in the Helmholtz AssociationBerlinGermany
  2. 2.Experimental and Clinical Research CenterA Joint Cooperation Between the Charité Medical Faculty and the Max Delbrueck Center for Molecular Medicine in the Helmholtz AssociationBerlinGermany

Personalised recommendations