Intermolecular multiple quantum coherences (iMQCs) can provide unique contrast with sub-voxel resolution. However, the characteristic growth rate of iMQCs mostly limits these effects to either hydrogen or hydrogen-coupled systems for thermally polarized samples. Hyperpolarization techniques such as dynamic nuclear polarization (DNP) allow for significant increases in the carbon signal (even more signal than that from hydrogen), making carbon iMQCs achievable. We present the first intermolecular multiple quantum signal between two carbon nuclei

Branca, R.T.

Jenista, E.R.

Warren, W.S.

PubMed

Carolina Digital Repository

Journal of Magnetic Resonance 196 (2009) 74–77Contents lists available at ScienceDirectJournal of Magnetic Resonancejournal homepage: www.elsevier .com/ locate/ jmrCommunicationHyperpolarized carbon–carbon intermolecular multiple quantum coherencesElizabeth R. Jenista *, Rosa T. Branca, Warren S. WarrenCenter for Molecular and Biomolecular Imaging, 2220 French Family Science Center, Duke University, Durham, NC 27708, USAa r t i c l e i n f o a b s t r a c tArticle history:Received 17 July 2008Revised 17 September 2008Available online 2 October 2008Keywords:Intermolecular multiple quantumcoherence13C hyperpolarizationDynamic nuclear polarizationMultiCRAZEDCRAZED1090-7807/$ - see front matter  2008 Elsevier Inc. Adoi:10.1016/j.jmr.2008.09.027* Corresponding author. Fax: +1 919 660 1506.E-mail address: elizabeth.specht@duke.edu (E.R. JeIntermolecular multiple quantum coherences (iMQCs) can provide unique contrast with sub-voxel reso-lution. However, the characteristic growth rate of iMQCs mostly limits these effects to either hydrogen orhydrogen-coupled systems for thermally polarized samples. Hyperpolarization techniques such asdynamic nuclear polarization (DNP) allow for significant increases in the carbon signal (even more signalthan that from hydrogen), making carbon iMQCs achievable. We present the first intermolecular multiplequantum signal between two carbon nuclei. 2008 Elsevier Inc. All rights reserved.1. IntroductionDuring the last decade, dipolar field interactions between differ-ent spins in solution have allowed for the detection of new types ofmagnetic resonance signals, arising from intermolecular multiplequantum coherences (iMQCs). These coherences have unique andfundamentally different properties than conventional signal, inparticular an intrinsic sensitivity to sub-voxel structure. This sensi-tivity makes these signals particularly suitable for a wide range ofapplications, such as temperature imaging [1], novel contrast inhuman brain imaging [2], and detection of molecularanisotropy[3].iMQC experiments in a test tube of water can exhibit strongsignals (within a factor of two of the equilibrium magnetiza-tion). However, applications to water in more complex samples,such as tissue, are limited by relaxation effects resulting in asmaller signal (typically 10–20% of the conventional signal).For other nuclei the drop is even more dramatic, essentially be-cause the signal scales as the square of the magnetization den-sity. For physiologically reasonable concentrations of moleculeswith low c nuclei such as carbon with normal thermal polariza-tion, the low magnetization density makes it nearly impossibleto detect iMQC signals. The solution discussed here is to em-ploy hyperpolarization techniques, which provide even moredramatic gains in iMQC experiments than in conventionalimages. One such technique is dynamic nuclear polarization(DNP) which transfers the large spin polarization present inll rights reserved.nista).the electron spin reservoir to the nuclei. This transfer is rou-tinely done by microwave irradiation at or near the electronLarmor frequency in the presence of a large magnetic field atlow temperatures. DNP techniques have been used to see in-creases in signal to noise of >10,000 [4]. By using hyperpolar-ization to enhance the initial magnetization of the sample, wewere able to acquire the first multi-CRAZED FID of carbon–car-bon coherences.2. Results and discussionThe first demonstrations of iMQCs were over a decade ago,and so the theory behind the CRAZED experiment [5,6] willnot be explained here. The multi-CRAZED experiment, which ac-quires multiple iMQCs, was first outlined in [7] but it is impor-tant to briefly revisit that theory to better understand whyiMQCs between low c nuclei (with thermal polarization) isimpractical.To understand why low c nuclei give very weak multiple quan-tum signals, it is important to look at the expression for the signalgenerated by the multi-CRAZED experiment. The pulse sequencefor the multi-CRAZED experiment is shown in Fig. 1. The standardpulse sequence for acquiring the signal from n-quantum intermo-lecular coherences is the ‘‘CRAZED” sequence 90  {delays}  {gradient pulse  area GT}  h  {gradient pulse areanGT}  {delay TE}  180  {delay TE  ns}  acquire. The multi-CRAZED sequence takes advantage of differences in echo timingsof the various coherences to acquire multiple echoes [7,8]. Neglect-ing diffusion and T1 relaxation effects, the signal for a multi-CRAZED experiment is [7,9]:+DQC -DQC-SQCZQC+SQCGt GtGtGtGt GtGt180φ3τ TE/2 TE/2-nτ(θ1)φ1(θ2)φ2Fig. 1. The multi-CRAZED sequence takes advantage of differences in the echo timing to separate the different echoes at full intensity. The +DQC, DQC and ZQC (+2,2 and 0quantum coherences, respectively) have contrast from sub-voxel variations in the magnetization density or resonance frequency. The +SQC and –SQC (+1 and 1 quantumcoherences, respectively) signals have conventional contrast.Communication / Journal of Magnetic Resonance 196 (2009) 74–77 75Mþðs;TEÞ¼ in1eiDxTEeTE=T2 einDxsein/1 eiðnþ1Þ/2e2i/3 M0 sinðh1ÞnsdTEDs sinðh1Þsinðh2ÞJnTEDs sinðh1Þsinðh2Þsd cosðh2Þ2Jnþ1TEDs sinðh1Þsinðh2Þsd þcosðh2Þ2Jn1TEDs sinðh1Þsinðh2Þsd ð1Þwhere Dx is the resonance offset, sd = (cl0M0)1 is the dipolardemagnetizing time, Ds = 3((sz)21)/2 where s is the direction ofthe gradient pulse, h1 and h2 are the flip angles of the first twopulses, u1 is the phase of the first (excitation) pulse, u2 is the phaseof the mixing pulse, and u3 is the phase of the refocusing pulse.Note that the argument of the Bessel functions is proportionalto TE/sd, which can be made large in a test tube of water, but whichis limited by the relaxation time T2 to small values in tissue (Table1 below). For x<<1, Jn(x) is proportional to xn. This implies that themultiple quantum terms (n = 2, 0, 2) grow in linearly with TE. Ta-ble 1 compares these values for water in tissue (80 M) and water inthe brain, to thermally polarized 1 M 13C urea with at T2 of 36 ms(measured using a spin echo sequence, with the echo time varied),and the same urea sample hyperpolarized (20% polarization) at 7 T.From these values it is clear that for reasonable values of T2, we ex-pect essentially no iMQC signal from a thermally polarized carbonsample, since by the time the multiple quantum signal has grownin, T2 has dephased the spins.Using the Hypersense hyperpolarizer from Oxford Instruments,we polarized a sample of urea (13C labeled, 1 M). The sample waspolarized for 4 h at a microwave frequency of 94.105 GHz. The dis-solution was done in 3 mL of DI water with a 25 mM EDTA. Thissample was inserted in a 7 T small animal imager using a Brukerconsole. The experimental parameters were: TE = 7.232 ms,h1 = 90, h2 = 135, 45–180 delay = 19.080 ms, 1228 points,SW = 90090.09 Hz.In Fig. 2 the carbon–carbon multi-CRAZED fid shows both dou-ble quantum (DQC) and zero quantum (ZQC) signal, demonstratingthat hyperpolarization techniques can be used to acquire multipleTable 1Comparison of predicted iMQC signal for protons, thermally polarized carbon andhyperpolarized carbon.1H, 80 Mwater, 7 T1H water,in the brain(T2 = 25 ms)13C, 1 M,thermallypolarized, 7 T13C, 1 M,hyperpolarized,7 Tsd 185 ms 185 ms 933,976 ms 298 msT2/sd 10.81 .135 .00003854 .123M0*T2/sd 1 .0249 2.8  109 .3859quantum signal between low c nuclei. For comparison, a multi-CRAZED fid of water is shown in the top corner of the figure, illus-trating the standard multi-CRAZED fid. Control experiments weredone on a sample of water, with the correlation gradients alongthe z-axis and along the magic angle. When the correlation gradi-ents are on the magic angle, the distant dipolar field is disabled,and no iMQC signals should appear. The experiments with the cor-relation gradient along the magic angle show a dramatic decreasein the amount of +iDQC signal (the signal seen in the first acquisi-tion, the +iDQC acquisition period, is .8% of the signal seen with thegradients just along z). A similar decrease is seen for the iDQCacquisition window. The drop in iZQC signal is less dramatic, whichis also expected because some contamination arises from pulseimperfections.In the case of hyperpolarized urea, the enhancement of theiMQC signal is hampered by the short T2 of the sample as illus-trated in Fig. 3. It is also clear from the Table 2, which comparessignal intensities, that the T2 of the carbon sample is short enoughto significantly hamper even the SQC signal intensity. In the caseof water (inset on Fig. 2) the SQC signal is 23.6% of the +SQC sig-nal. Fig. 3 compares the calculated signal intensity (from Eq. (1))for SQC and ZQC signals for water, and two hyperpolarized carbonsamples with a short (36 ms) T2 and a long (300 ms) T2. The ZQCsignal intensity is hurt much more by the shortening of T2 thanthe intensity of the SQC signal. It is clear from the figures thatthe short T2 of the carbon nuclei has a profound effect on theamount of iMQC signal that can be obtained. An increase of T2 from36 to 300 ms results in a seven fold increase in maximum signalintensity. Unfortunately, T2 for urea and radical is quite short(approximately 36 ms), severely limiting the amount of iMQC sig-nal possible from this molecule. Nonetheless, the demonstration ofobservable multi-CRAZED signal even under these unfavorableconditions bodes well for imaging applications.3. ConclusionIn summary, we have demonstrated that carbon hyperpolariza-tion permits intermolecular multiple quantum signals with inten-sities comparable to those previously seen in water. In general,hyperpolarized techniques can give useful metabolic informationcomplementary to the anatomical information obtainable withstandard proton MR. One pitfall of these techniques is the inher-ently short acquisition time, which limits the spatial resolutionin MR images and the spectral resolution in NMR spectra. It hasbeen previously demonstrated that iMQC experiments can providesubvoxel resolution and inhomgeneity compensation in MRI andMRS of thermally polarized proton samples. Experiments that arecurrently done using single quantum coherences, could be done—200—1000100200300400500600700800—2—1.5—1—0.500.511.52x 10 4+DQC+SQC-SQCZQCIntensity (a.u.)Acquisition Number1 2 3 4 5 6 7 8Fig. 2. Multi-CRAZED FID of hyperpolarized urea compared to the multi-CRAZED FID of water (top corner). It is important to note that this is not one long FID, but a series ofconsecutive FIDs separated by a gradient pulse.Hyperpolarized carbon T2 = 300 msHyperpolarized carbon T2 = 36 msWater T2 = 2sTE (ms)TE (ms)Hyperpolarized carbon T2 = 300 msHyperpolarized carbon T2 = 36 msWater  T2 = 2s200 400 600 800 10000.51.01.52.0200 400 600 800 10000.050.100.150.200.250.30Expected Signal Intensityin units of M0Expected Signal Intensityin units of M0Fig. 3. Comparison of the calculated signal (from Eq. (1)) for a ZQC (left) experiment with an SQC (right) experiment for water (T2 = 2 s), and two hyperpolarized carbonsamples with T2 s of 300 and 36 ms with the following parameters: Dx = 0, s = 7 ms, u1 = u2 = u3 = 0, M0 (hyperpolarized carbon) = 2.5, M0 (water) = 1, h1 = p/2, h2 = 3p/4,sd = 298 ms (hyperpolarized carbon), sd = 185 ms (water) and Ds = 1.Table 2Signal intensities for the coherences observed in the multi-CRAZED experiment.+DQC +SQC ZQC SQCMaximum signal intensity, 13C urea 25 700 50 10Percent of +SQC maximum signal intensity, 13C urea 3.59% 100% 7.14% 1.43%Maximum signal intensity, 1H water 1920 16,150 3720 3815Percent of +SQC maximum signal intensity, 1H water 11.9% 100% 23.0% 23.6%76 Communication / Journal of Magnetic Resonance 196 (2009) 74–77with iMQCs to achieve better spatial and spectral resolution. A par-ticular example of this is that the iMQC signal could be tuned to de-tect intracellular and extracellular compounds. For lowconcentration thermally polarized samples of low c nuclei suchas carbon, the exceedingly small magnetization makes iMQCdetection nearly impossible; however, for hyperpolarized samples,the demagnetization time becomes reasonably short, and in factthe theoretical signal gain is vastly larger for iMQC sequences thanfor conventional imaging. The demonstration that carbon–carboniMQC signal can be observed has been shown in this paper, andopens the door to the possibility of future applications of non-pro-ton iMQC experiments. For example, fast 2D NMR spectroscopy hasbeen demonstrated for iMQCs [10], and for hyperpolarized samples[11], and the combination of these types of experiments would al-Communication / Journal of Magnetic Resonance 196 (2009) 74–77 77low for inhomogeneity compensated 2D spectra. In addition, iMQCsignals are proportional to M20 instead of M0, as in standard exper-iments, and this difference could be used to amplify the concentra-tion variation of different metabolites in vivo. Since this signal isintrinsically different than the standard MRI signal, we expect thisapproach will enhance the utility of hyperpolarized experiments.AcknowledgmentThis work was funded by NIH Grant R01 EB2122.References[1] G. Galiana, R.T. Branca, E.R. Jenista, W.S. Warren, Accurate temperatureimaging using intermolecular coherences, Proceedings of the InternationalSociety for Magnetic Resonance in Medicine (2007).[2] R.R. Rizi, S. Ahn, D.C. Alsop, S. Garrett-Roe, M. Mescher, W. Richter, M.D.Schnall, J.S. Leigh, W.S. Warren, Intermolecular zero-quantum coherenceimaging of the human brain, Magnetic Resonance in Medicine 43 (2000)627–632.[3] L.S. Bouchard, W.S. Warren, Multiple-quantum vector field imaging bymagnetic resonance, Journal of Magnetic Resonance 177 (2005) 9–21.[4] J.H. Ardenkjaer-Larsen, B. Fridlund, A. Gram, G. Hansson, L. Hansson, M.H.Lerche, R. Servin, M. Thaning, K. Golman, Increase in signal-to-noise ratio of>10,000 times in liquid-state NMR, Proceedings of the National Academy ofSciences of the United States of America 100 (2003) 10158–10163.[5] W.S. Warren, W. Richter, A.H. Andreotti, B.T. Farmer, Generation of impossiblecross-peaks between bulk water and biomolecules in solution NMR, Science262 (1993) 2005–2009.[6] W.S. Warren, W. Richter, S. Qiuhong He, Imaging with intermolecularmultiple-quantum coherences in solution nuclear magnetic resonance,Science 267 (1995) 654–657.[7] X.P. Tang, H. Ong, K. Shannon, W.S. Warren, Simultaneous acquisition ofmultiple orders of intermolecular multiple-quantum coherence images,Magnetic Resonance Imaging 21 (2003) 1141–1149.[8] K.L. Shannon, R.T. Branca, G. Galiana, S. Cenzano, L.S. Bouchard, W. Soboyejo,W.S. Warren, Simultaneous acquisition of multiple orders of intermolecularmultiple-quantum coherence images in vivo, Magnetic Resonance Imaging 22(2004) 1407–1412.[9] J.H. Cho, S. Ahn, C. Lee, K.S. Hong, K.C. Chung, S.K. Chang, C. Cheong, W.S.Warren, Magnetic resonance microscopic imaging based on high-orderintermolecular multiple-quantum coherences, Magnetic Resonance Imaging25 (2007) 626–633.[10] G. Galiana, R.T. Branca, W.S. Warren, Ultrafast intermolecular zero quantumspectroscopy, Journal of the American Chemical Society 127 (2005) 17574–17575.[11] L. Frydman, D. Blazina, Ultrafast two-dimensional nuclear magnetic resonancespectroscopy of hyperpolarized solutions, Nature Physics 3 (2007) 415–419.

Hyperpolarized carbon-carbon intermolecular multiple quantum coherences

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Hyperpolarized carbon-carbon intermolecular multiple quantum coherences

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