Klaes Golman

Increase in signal-to-noise ratio of > 10,000 times in liquid-state NMR

A method for obtaining strongly polarized nuclear spins in solution has been developed. The method uses low temperature, high magnetic field, and dynamic nuclear polarization (DNP) to strongly polarize nuclear spins in the solid state. The solid sample is subsequently dissolved rapidly in a suitable solvent to create a solution of molecules with hyperpolarized nuclear spins. The polarization is performed in a DNP polarizer, consisting of a super-conducting magnet (3.35 T) and a liquid-helium cooled sample space. The sample is irradiated with microwaves at ≈94 GHz. Subsequent to polarization, the sample is dissolved by an injection system inside the DNP magnet. The dissolution process effectively preserves the nuclear polarization. The resulting hyperpolarized liquid sample can be transferred to a high-resolution NMR spectrometer, where an enhanced NMR signal can be acquired, or it may be used as an agent for in vivo imaging or spectroscopy. In this article we describe the use of the method on aqueous solutions of [13C]urea. Polarizations of 37% for 13C and 7.8% for 15N, respectively, were obtained after the dissolution. These polarizations correspond to an enhancement of 44,400 for 13C and 23,500 for 15N, respectively, compared with thermal equilibrium at 9.4 T and room temperature. The method can be used generally for signal enhancement and reduction of measurement time in liquid-state NMR and opens up for a variety of in vitro and in vivo applications of DNP-enhanced NMR.

Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy.

Measurements of early tumor responses to therapy have been shown, in some cases, to predict treatment outcome. We show in lymphoma-bearing mice injected intravenously with hyperpolarized [1-13C]pyruvate that the lactate dehydrogenase–catalyzed flux of 13C label between the carboxyl groups of pyruvate and lactate in the tumor can be measured using 13C magnetic resonance spectroscopy and spectroscopic imaging, and that this flux is inhibited within 24 h of chemotherapy. The reduction in the measured flux after drug treatment and the induction of tumor cell death can be explained by loss of the coenzyme NAD(H) and decreases in concentrations of lactate and enzyme in the tumors. The technique could provide a new way to assess tumor responses to treatment in the clinic.

Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate.

As alterations in tissue pH underlie many pathological processes, the capability to image tissue pH in the clinic could offer new ways of detecting disease and response to treatment. Dynamic nuclear polarization is an emerging technique for substantially increasing the sensitivity of magnetic resonance imaging experiments. Here we show that tissue pH can be imaged in vivo from the ratio of the signal intensities of hyperpolarized bicarbonate (H13CO3-) and 13CO2 following intravenous injection of hyperpolarized H13CO3-. The technique was demonstrated in a mouse tumour model, which showed that the average tumour interstitial pH was significantly lower than the surrounding tissue. Given that bicarbonate is an endogenous molecule that can be infused in relatively high concentrations into patients, we propose that this technique could be used clinically to image pathological processes that are associated with alterations in tissue pH, such as cancer, ischaemia and inflammation.

Molecular imaging with endogenous substances

Dynamic nuclear polarization has enabled hyperpolarization of nuclei such as 13C and 15N in endogenous substances. The resulting high nuclear polarization makes it possible to perform subsecond 13C MRI. By using the dynamic nuclear polarization hyperpolarization technique, 10% polarization was obtained in an aqueous solution of 100 mM 13C-labeled urea, ready for injection. The in vivo T1 relaxation time of 13C in the urea solution was determined to 20 ± 2 s. Due to the long relaxation time, it is possible to use the hyperpolarized substance for medical imaging. A series of high-resolution (≈1-mm) magnetic resonance images were acquired, each with a scan time of 240 ms, 0-5 s after an i.v. injection of the hyperpolarized aqueous [13C]urea solution in a rat. The results show that it is possible to perform 13C angiography with a signal-to-noise ratio of ≈275 in ≈0.25 s. Perfusion studies with endogenous substances may allow higher spatial and/or temporal resolution than is possible with current proton imaging techniques.

Parahydrogen‐induced polarization in imaging: Subsecond 13C angiography

High nuclear spin polarization of 13C was reached in organic molecules. Enhancements of up to 104, compared to thermal polarization at 1.5 T, were achieved using the parahydrogen‐induced polarization technique in combination with a field cycling method. While parahydrogen has no net polarization, it has a high spin order, which is retained when hydrogen is incorporated into another molecule by a chemical reaction. By subjecting this molecule to a sudden change of the external magnetic field, the spin order is transferred into net polarization. A 13C angiogram of an animal was generated in less than a second. Magn Reson Med 46:1–5, 2001.

Overhauser enhanced magnetic resonance imaging for tumor oximetry: Coregistration of tumor anatomy and tissue oxygen concentration

An efficient noninvasive method for in vivo imaging of tumor oxygenation by using a low-field magnetic resonance scanner and a paramagnetic contrast agent is described. The methodology is based on Overhauser enhanced magnetic resonance imaging (OMRI), a functional imaging technique. OMRI experiments were performed on tumor-bearing mice (squamous cell carcinoma) by i.v. administration of the contrast agent Oxo63 (a highly derivatized triarylmethyl radical) at nontoxic doses in the range of 2–7 mmol/kg either as a bolus or as a continuous infusion. Spatially resolved pO2 (oxygen concentration) images from OMRI experiments of tumor-bearing mice exhibited heterogeneous oxygenation profiles and revealed regions of hypoxia in tumors (<10 mmHg; 1 mmHg = 133 Pa). Oxygenation of tumors was enhanced on carbogen (95% O2/5% CO2) inhalation. The pO2 measurements from OMRI were found to be in agreement with those obtained by independent polarographic measurements using a pO2 Eppendorf electrode. This work illustrates that anatomically coregistered pO2 maps of tumors can be readily obtained by combining the good anatomical resolution of water proton-based MRI, and the superior pO2 sensitivity of EPR. OMRI affords the opportunity to perform noninvasive and repeated pO2 measurements of the same animal with useful spatial (≈1 mm) and temporal (2 min) resolution, making this method a powerful imaging modality for small animal research to understand tumor physiology and potentially for human applications.

Cardiac metabolism measured noninvasively by hyperpolarized (13)C MRI.

Pyruvate is included in the energy production of the heart muscle and is metabolized into lactate, alanine, and CO2 in equilibrium with HCO  3− . The aim of this study was to evaluate the feasibility of using 13C hyperpolarization enhanced MRI to monitor pyruvate metabolism in the heart during an ischemic episode. The left circumflex artery of pigs (4 months, male, 29–34 kg) was occluded for 15 or 45 min followed by 2 hr of reperfusion. Pigs were examined by 13C chemical shift imaging following intravenous injection of 1‐13C pyruvate. 13C chemical shift MR imaging was used in order to visualize the local concentrations of the metabolites. After a 15‐min occlusion (no infarct) the bicarbonate signal level in the affected area was reduced (25–44%) compared with the normal myocardium. Alanine signal level was normal. After a 45‐min occlusion (infarction) the bicarbonate signal was almost absent (0.2–11%) and the alanine signal was reduced (27–51%). Due to image‐folding artifacts the data obtained for lactate were inconclusive. These studies demonstrate that cardiac metabolic imaging with hyperpolarized 1‐13C‐pyruvate is feasible. The changes in concentrations of the metabolites within a minute after injection can be detected and metabolic maps constructed. Magn Reson Med 59:1005–1013, 2008.

13C imaging-a new diagnostic platform.

The evolution of magnetic resonance imaging (MRI) has been astounding since the early 1980s, and a broad range of applications has emerged. To date, clinical imaging of nuclei other than protons has been precluded for reasons of sensitivity. However, with the recent development of hyperpolarization techniques, the signal from a given number of nuclei can be increased as much as 100,000 times, sufficient to enable imaging of nonproton nuclei. Technically, imaging of hyperpolarized nuclei offers several unique properties, such as complete lack of background signal and possibility for local and permanent destruction of the signal by means of radio frequency (RF) pulses. These properties allow for improved as well as new techniques within several application areas. Diagnostically, the injected compounds can visualize information about flow, perfusion, excretory function, and metabolic status. In this review article, we explain the concept of hyperpolarization and the techniques to hyperpolarize 13C. An overview of results obtained within angiography, perfusion, and catheter tracking is given, together with a discussion of the particular advantages and limitations. Finally, possible future directions of hyperpolarized 13C MRI are pointed out.

Quantitative measurement of regional lung ventilation using 3He MRI.

A new strategy for a quantitative measurement of regional pulmonary ventilation using hyperpolarized helium‐3 (3He) MRI has been developed. The method employs the build‐up of the signal intensity after a variable number of 3He breaths. A mathematical model of the signal dynamics is presented, from which the local ventilation, defined as the fraction of gas exchanged per breath within a given volume, is calculated. The model was used to create ventilation maps of coronal slices of guinea pig lungs. Ventilation values very close to 1 were found in the trachea and the major airways. In the lung parenchyma, regions adjacent to the hilum showed values of 0.6–0.8, whereas 0.2–0.4 was measured in peripheral regions. Monte Carlo simulations were used to investigate the accuracy of the method and its limitations. The simulations revealed that, at presently attainable signal‐to‐noise ratios, the ventilation parameter can be determined with a relative uncertainty of <5% over a wide range of values. Magn Reson Med 48:223–232, 2002.

Characterization of diffusing capacity and perfusion of the rat lung in a lipopolysaccaride disease model using hyperpolarized 129Xe

The ability to quantify pulmonary diffusing capacity and perfusion using dynamic hyperpolarized 129Xe NMR spectroscopy is demonstrated. A model of alveolar gas exchange was developed, which, in conjunction with 129Xe NMR, enables quantification of average alveolar wall thickness, pulmonary perfusion, capillary diffusion length, and mean transit time. The technique was employed to compare a group of naïve rats (n = 10) with a group of rats with acute inflammatory lung injury (n = 10), caused by instillation of lipopolysaccaride (LPS). The measured structural and perfusion‐related parameters were in agreement with reported values from studies using non‐NMR methods. Significant differences between the groups were found in total diffusion length (control 8.5 ± 0.5 μm, LPS 9.9 ± 0.6 μm, P < 0.001), in capillary diffusion length (control 2.9 ± 0.4 μm, LPS 3.9 ± 1.0 μm, P < 0.05), and in pulmonary hematocrit (control 0.55 ± 0.06, LPS 0.43 ± 0.08, P < 0.01), whereas no differences were observed in alveolar wall thickness, pulmonary perfusion, and mean transit time. These results demonstrate the ability of the method to distinguish two main aspects of lung function, namely, diffusing capacity and pulmonary perfusion. Magn Reson Med 50:1170–1179, 2003.