Some methods of dynamic nuclear polarization for use in metabolic imaging

It has been suggested already more than 60 years ago to use polarized nuclei in particle scattering experiments1, but only with the discovery of the solid effect dynamic nuclear polarization process2 the realisation of polarized solid targets became possible in the early sixties. In parallel to the technical development of these instruments, the theoretical basis for the understanding of the various dynamic nuclear polarization (DNP) processes has been established3. The knowledge accumulated in all these years has not been of immediate interest for NMR/MRI applications until recently, when an experiment of Golman, Ardenkjær-Larsen and colleagues has put it into a new context4. They demonstrated that it is actually possible to transform a dynamically polarized organic sample from its initial frozen state into a liquid room temperature solution, while retaining a big part of the nuclear polarization, by rapidly dissolving it in superheated water. The nuclear relaxation times in such polarized liquid solutions are long enough to open the possibility of injecting them into biological subjects to investigate (e.g. in vivo) metabolic processes in a nearby MRI installation. With this approach an amplification of NMR signals in the order of 10,000 can be achieved for 13C nuclei in labelled compounds, thus opening a breath of new experimental possibilities. The well-established DNP techniques, where the electron polarization from paramagnetic impurities is transferred to the surrounding nuclei in an external field at low temperature (∼1 K), need now to be adapted to the requirements of NMR/MRI/MRS. A main challenge is to find biologically compatible solutions containing a small concentration of an efficient paramagnetic centre well suited for DNP in which the labelled molecule of biological interest, e.g. metabolic precursors, can be easily dissolved. The DNP process in such samples has to be thoroughly studied and optimized and therefore suitable hardware for this specific application needs to be developed (polarizer, dissolution and injection set-ups etc.). These are problems which are addressed in the presented thesis work. Extensive DNP studies have been performed on frozen solutions of several compounds of biological interest with 13C (Na acetate, Na pyruvate, Na bicarbonate, urea, glycine, glucose), 15N (urea, choline chloride) and 6Li (Li chloride) nuclei in water-ethanol and water-glycerol solvents doped with TEMPO free radicals. Two different W-band DNP set-ups operating around 3.5 T and 1.2 K were used: one at PSI Villigen and second at EPFL Lausanne specially developed for dissolution experiments. The main mechanism of DNP processes in all frozen samples was found to be dynamic cooling where spin temperatures of ∼10 mK were routinely reached which corresponds to a polarization level of 40 %, 8 %, 5 % and 3 % for protons, 13C, 6Li and 15N nuclei respectively5. The obtained solid state data were treated within existing theoretical models (Provotorov-thermal spin mixing equations), which were expanded to allow a multinuclear (1H/13C/23Na/2H) analysis. This allowed to explain some newly observed experimental results, namely the linear polarization increase with a higher degree of sample deuteration and the difference in the polarization build-up and relaxation rates, as well as to choose the criteria for the optimum sample composition and DNP process. Fast dissolution experiments on the EPFL polarizer have shown that 70-80 % of the initial solid state polarization can be retained for all studied nuclei (13C, 6Li, 15N) while the liquid state NMR amplification factor reaches the order of 10,000 and mainly depends on the relaxation speed of the specific nuclei after the dissolution6. Optimum samples are now routinely used in metabolic/MRI experiments at CIBM Lausanne employing the developed DNP and dissolution apparatus operated according to established protocols. ______________________________ 1 C.J. Gorter, Physica 14 (1948) 504; M.E. Rose, Phys. Rev. 75 (1949) 213. 2 A. Abragam, W. G. Proctor, Compt. Rend. 246 (1958) 2253. 3 A. Abragam, M. Goldman, Rep. Prog. Phys. 41 (1978) 395. 4 J.H. Ardenkjaer-Larsen et al, PNAS. 100 No 18 (2003) 10158. 5 F. Kurdzesau et al, J. Phys. D: Appl. Phys., 41 (2008) 155506. 6 A. Comment et al, Conc. Magn. Res. B, 31B (2007) 255.