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Boosting the sensitivity of nuclear magnetic resonance

Hyperpolarized MRI. Boosting the sensitivity of nuclear magnetic resonance. Yves De Deene. MRI: Basic principles. Molecular imaging with MRI. Hyperpolarized gas MRI. The future of hyperpolarized Xe 129. In this presentation. 2/33. E. Purcell 1946. F. Bloch 1946. I.I. Rabi 1938.

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Boosting the sensitivity of nuclear magnetic resonance

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  1. Hyperpolarized MRI Boosting the sensitivity of nuclear magnetic resonance Yves De Deene

  2. MRI: Basic principles Molecular imaging with MRI Hyperpolarized gas MRI The future of hyperpolarized Xe129 In this presentation ... 2/33

  3. E. Purcell 1946 F. Bloch 1946 I.I. Rabi 1938 Superconducting coil (magnet) Radiofrequency coil Gradient coil The use of MRI: basic principle The advantage of magnetic resonance imaging (MRI) is the absence of any ionizing irradiation to acquire an image. To make an MRI image use is made of a static magnetic field, radiofrequency waves (electromagnetic waves similar to the ones received by a transistor radio) and switched magnetic fields (gradients). No adverse health effects are found with the use of MRI scanners. Unlike any other medical imaging modality, it are the (nuclei of atoms within) molecules themselves that are the signal carriers. The molecular interactions of water molecules with macromolecular structures (proteins, cell membranes, etc.) are responsible for the image contrast. The superior soft tissue contrast originates from the large amount of water molecules that ‘probe’ the cellular microstructure. The water molecules interact with cellular components through diffusion, collision, adhesion, absorption, collision, chemical exchange and magnetization transfer. All these interactions cause changes in the behavior of the received MR signal. 3/33

  4. external magnetic field Cryogenic magnet Hydrogen proton has a magnetic moment Radiofrequency coil Water molecule Gradient coil The use of MRI: basic principle Conventional magnetic resonance imaging (MRI) is based on the radiofrequency signal that is transmitted from the atomic nucleus of hydrogen atoms placed in a magnetic field and after they have been excited by a radiofrequent electromagnetic pulse. Hydrogen proton transmits a radiofrequent electromagnetic wave (yellow) after excitation by an RF pulse (red) The electromagnetic signal transmitted by the hydrogen protons is received by the scanner and processed... Cross-section of an NMR scanner 4/33

  5. Bloembergen Pound Purcell Hydrogen bridges M FREE WATER t M INTERMEDIATE LAYER + t + + - + + - M - O BOUND LAYER + C O - + - - + C + N C + - + t The contrast in NMR is based on the molecular physics of water molecules (e.g. spin-spin relaxation) High mobility Low mobility Protein, polymer, cell membrane 5/33

  6. -1/2 B0 +1/2 MOLECULAR IMAGING WITH MRI Low sensitivity of conventional 1H MRI The sensitivity of conventional MRI is governed by Boltzman statistics. In a magnetic field of 3T, only an excess of one of 100,000 atoms is magnetized in the direction of the applied magnetic field. Boltzmann statistics ( at 3T ) 6/33

  7. NON SPECIFIC CONTRAST AGENTS SPECIFIC CONTRAST AGENTS Blood circulation (MRA) Ligand Perfusion Receptor (Target) Reporter Vector • Cell receptor • Gene sequence • Enzyme MOLECULAR IMAGING WITH MRI Exogeneous contrast agents MR contrast agent 7/33

  8. MOLECULAR IMAGING WITH MRI Molecular specific probes ESSENTIAL PROPERTIES SENSITIVITY SPECIFICITY BIO DISTRIBUTION (Pharmacokinetics) BIO COMPATIBILITY In vivo moleculaire doelwitten: 1 nM – 1 pM Molecular Contrast - = Background Foreground 8/33

  9. t Gd3+ Gd3+ Gd3+ Gd3+ Gd3+ Gd3+ Gd3+ HYDRATION SPHERE Gd3+ Gd3+ MOLECULAR IMAGING WITH MRI The sensitivity problem: molecular specific probes 9/33

  10. vector FexOy vector MOLECULAR IMAGING WITH MRI Increasing sensitivity by increasing the number of reporter molecules Magnetic nanoparticles Liposomes / Micelles contrastagent Lecithine/cholesterol Perfluoro- octylbromide nanoparticle phospholipid Gd-DTPA lipid Gd-DTPA-PE Biotinylated DPPE phospholipide avidin (Ultra-)Small-Particle Iron-Oxide SPIO, USPIO Size: 30 nm - 300 nm r1 ≈ 25 s-1.mM-1 PEG 10/33 antibody Antibody

  11. β-galactosidase Enzym-mediated contrast agent CLIO Ca2+ mediated contrastagent Gen-sequence specific contrastagent (also for Zn2+ en pH) MOLECULAR IMAGING WITH MRI ‘Smart’ contrastagents H2O T « Switch-on / switch-off » probes Liposome membrane Temperature sensitive contrastagent 11/33

  12. Gd-DTPA-PE Perfluoro- octylbromide nanoparticle Lecithine/cholesterol anti αvβ3- integrine MOLECULAR IMAGING WITH MRI In vivo experiments Artherosclerose 12/33

  13. Loss of specificity Disturbance of the de pharmacokinetics MOLECULAR IMAGING WITH MRI Dilemma for molecular imaging with 1H paramagnetic contrastagents SENSITIVITY ENHANCEMENT WITH BIGGER CONTRAST AGENTS 13/33

  14. PET SPECT MRI MRS X-ray MOLECULAR IMAGING Increasing the sensitivity of MRI Sensitivity 1 pM In vivo molecular targets 1 nM 1 μM MRI (‘pushing the limits’) 1 mM 10 μm 1 cm 1 μm 1 mm 1 dm 100 μm 14/33 Spatial resolution

  15. HYPERPOLARISATION OUTSIDE THE SCANNER INJECTION OF HYPERPOLARIZED AGENT SCANNING THE PATIENT MOLECULAR IMAGING WITH MRI HYPERPOLARIZATION: A possible alternative for boosting NMR sensitivity 15/33

  16. Parahydrogen Optical pumping ‘Brute Force’  Dynamic Nuclear Polarization 94 GHz 13C 13C B0 room temperature cooling (P = 10-5) How to obtain HYPERPOLARIZATION ? 16/33

  17. Hyperpolarized gas NMR by optical pumping Bouchiat M.A., Carver T.R. And Varnum C.M. “Nuclear Polarization in He3 Gas Induced by Optical Pumping and Dipolar Exchange” Physical Review Letters, 5, 373-375, 1960. Philips G.C., Perry R.R., Windham P.M., “Demonstration of a Polarized He3 Target for Nuclear Reactions” Physical Review Letters, 9, 502-504, 1962. Walters G.K., Colegrove F.D. and Schearer L.D. “Nuclear Polarization of He3 Gas by Metastability Exchange with Optically Pumped Metastable He3 Atoms”, Physical Review Letters, 9, 502-504, 1962. 17/33

  18. Fine splitting 794.7 nm Hyperfine structure Hyperpolarized gas NMR by optical pumpingPrinciple Rb 18/33

  19. Hyperpolarized gases: Spin exchange Rb He3 Laser- beam OPTICAL PUMPING SPIN EXCHANGE H = a(r).I.S

  20. Fine interaction (spin – orbital momentum coupling) e- e- e- Hyperfine interaction (nucleus – angular momentum) e- e- n Zeeman splitting Hyperfine structure Fine structure B Hyperpolarized gas NMR by optical pumpingPrinciple: Electron energy states of Rubidium Bohr model 20/33

  21. Hyperpolarized gas NMR by optical pumpingPrinciple: Optical pumping of Rubidium photon (S = 1) e- e- electron = trapped 21/33

  22. Hyperpolarized gas NMR by optical pumpingRubidium-Xenon Spin-Exchange Rb Xe Hyperfine coupling (Rb) Hyperfine coupling (Rb electron – Xe nucleus) Spin rotation 22/33

  23. Hyperpolarization generator Polarisation optics Laser unit Coil for static magnetic field (~ 5 mT) Cooling circuit Glass cell (Xe-129, N2, He) NMR-acquisition Circulation bath (cooling liquid) Pre amplifier PA 100 W To Spectrometer or scanner Rb Oil bath (~ 140 °C) Xe-129 He Pinhole Circulation bath oil (~ 140 °C) N2 Optical spectrometer Laser power meter Vacuumpump Semi-transparant mirror 23/33

  24. T1 0.8 33 h 0.6 • Rb density • collision rate 10 h Polarization 0.4 5 h 2.5 h 0.2 t [h] 0 0 h 5 h 10 h 15 h Hyperpolarized gases: Spin exchange Example: From: Leawoods et al, Concepts in Magnetic Resonance, 13(5): 277-293, (2001).

  25. Hyperpolarized gases: Sequences and Applications In H1-imaging: T1 is needed for recovery of signal In Xe129-imaging: All imaging has to be performed within a time T1 Small flip angles should be used (FLASH, FISP) • Static He3 density images (during breath-hold) • Diffusion images (Optimized Interleaved-Spiral): • Restricted diffusion by alveolar walls (emphysema) • Xe129 transport into tissue (Compartimental analysis) • He3 and Xe129 Spectroscopy • Tagging for monitoring lung ventilation • Dynamic studies with EPI sequences 25/33

  26. HYPERPOLARISED GAS NMR: Some immediate applications Dynamic MRI of the lung MR ventilation images of the lung asthma studies with He-3 Hyperpolarized Xe-129 imaging 3D rendered MRI of the lung 26/33 SOURCE: University of Virginia Health Systems

  27. HYPERPOLARISED GAS NMR: Lung imaging Diffusion imaging reveals lung microstructure Tagging reveals lung motion 20-year old non-smoker 62-year old smoker Inhalation Exhalation Displacement vectors Fain et al, J. Magn. Reson. Imaging. 25, 910-23, 2007 Cai et al, Int. J. Radiation Oncology Biol. Phys. 68, 650-3, 2007 27/33

  28. HYPERPOLARISED GAS NMR: No need for high-field strength scanners ... 28/33

  29. T1 HYPERPOLARISED GAS Decay time T1 relaxation decay is determined by T1-decay the Intra-molecular environment the solvent Magnetic spin polarization the temperature the degree of acidity (pH) 60 s t Injection 29/33

  30. Xe-129 as a smart molecular contrast agent spectrum NMR spectrum Molecular probe Polair peptide Cryptophane-A cage biotin polar peptide Not bound bound SOURCE: Spence MM et al 2001, PNAS 98, 10654-7 30/33

  31. M T1 t T1 HYPERPOLARISED Xe-129 as a molecular marker The problem Xe Loss of magnetization before tracer at site Science 314: 446-9, 2006 31/33

  32. Hyperpolarized Xe-129 CHEMICAL EXCHANGE HYPERPOLARISED Xe-129 as a molecular marker 50 ppm 200 ppm 100 ppm 100 ppm Chemical shift Schröder et al, Science 314: 446-9, 2006 32/33

  33. Hyperpolarized gases: Objectives of the UGent research group Construction of a hyperpolarizer for Xe129 MRI Implementation of clinical applications for pneumology / oncology Investigation of the possible use of hyperpolarized MRI for molecular imaging Hyperpolarization of other nuclei (SPINOE) 33/33

  34. I visited Copenhagen frequently after the war. At one point, I gave a talk in Copenhagen, and then afterwards we met with Bjerrum. Bjerrum was a chemist and a great friend of Niels Bohr… Bohr said to him: “You know, what these people do is really very clever. They put little spies into the molecules and send radio signals to them, and they have to radio back what they are seeing.” I thought that was a very nice way of formulating it. That was exactly how they were used. It was not anymore the protons as such. But from the way they reacted, you wanted to know in what kind of environment they are, just like spies that you send out. That was a nice formulation. - Felix Bloch -

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