Timothy J. Scholl

Design of field-cycled magnetic resonance systems for small animal imaging

This paper presents a design study for a field-cycled magnetic resonance imaging (MRI) system directed at small animal imaging applications. A field-cycled MRI system is different from a conventional MRI system in that it uses two separate and dynamically controllable magnetic fields. A strong magnetic field is used to polarize the object, and a relatively weak magnetic field is used during signal acquisition. The potential benefits of field-cycled MRI are described. The theoretical dependences of field-cycled MRI performance on system design are introduced and investigated. Electromagnetic, mechanical and thermal performances of the system were considered in this design study. A system design for imaging 10 cm diameter objects is presented as an example, capable of producing high-duty-cycle polarizing magnetic fields of 0.5 T and readout magnetic fields corresponding to a proton Larmor frequency of 5 MHz. The specifications of the final design are presented along with its expected electromagnetic and thermal performance.

Delta relaxation enhanced MR: improving activation-specificity of molecular probes through R1 dispersion imaging.

MR molecular imaging enables high‐resolution, in vivo study of molecular processes frequently utilizing gadolinium‐based probes that specifically bind to a particular biological molecule or tissue. While some MR probes are inactive when unbound and produce enhancement only after binding, the majority are less specific and cause enhancement in either state. Accumulation processes are then required to increase probe concentration in regions of the target molecule/tissue. Herein, a method is described for creating specificity for traditionally nonspecific probes. This method utilizes MR field‐cycling methods to produce MRI contrast related to the dependence of R1 upon magnetic field. It is shown that the partial derivative of R1 with respect to magnetic field strength, R1′, can be used as an unambiguous measure of probe binding. T1‐weighted images and R1′ images were produced for samples of albumin and buffer both enhanced with the albumin‐binding agent Vasovist. For T1 images, samples with low concentrations of Vasovist in an albumin solution could not be differentiated from samples with higher concentrations of Vasovist in buffer. Conversely, the R1′ images showed high specificity to albumin. Albumin samples with a 10‐μM concentration of Vasovist were enhanced over buffer samples containing up to 16 times more Vasovist. Magn Reson Med, 2009.

Field dependence of T1 for hyperpolarized [1-13C]pyruvate

In vivo metabolism of hyperpolarized pyruvate has been demonstrated to be an important probe of cellular glycolysis in diseases such as cancer. The usefulness of hyperpolarized (13)C imaging is dependent on the relaxation rates of the (13)C-enriched substrates, which in turn depend on chemical conformation and properties of the dissolution media such as buffer composition, solution pH, temperature and magnetic field. We have measured the magnetic field dependence of the spin-lattice relaxation time of hyperpolarized [1-(13)C]pyruvate using field-cycled relaxometry. [1-(13)C]pyruvate was hyperpolarized using dynamic nuclear polarization and then rapidly thawed and dissolved in a buffered solution to a concentration of 80 mmol l(-1) and a pH of ~7.8. The hyperpolarized liquid was transferred within 8 s to a fast field-cycling relaxometer with a probe tuned for detection of (13)C at a field strength of ~0.75 T. The magnetic field of the relaxometer was rapidly varied between relaxation and acquisition fields where the sample magnetization was periodically measured using a small flip angle. Data were recorded for relaxation fields varying between 0.237 mT and 0.705 T to map the T(1) dispersion of the C-1 of pyruvate. Using similar methods, we also determined the relaxivity of the triarylmethyl radical (OX063; used for dynamic nuclear polarization) on the C-1 of pyruvate at field strengths of 0.001, 0.01, 0.1 and 0.5 T using 0.075, 1.0 and 2.0 mmol l(-1) concentrations of OX063 in the hyperpolarized pyruvate solution.

Mapping metabolic changes associated with early Radiation Induced Lung Injury post conformal radiotherapy using hyperpolarized 13C-pyruvate Magnetic Resonance Spectroscopic Imaging

PURPOSE Radiation Pneumonitis (RP) limits radiotherapy. Detection of early metabolic changes in the lungs associated with RP may provide an opportunity to adjust treatment before substantial toxicities occur. In this work, regional lactate-to-pyruvate signal ratio (lac/pyr) was quantified in rat lungs and heart following administration of hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) at day 5, 10, 15 and 25-post conformal radiotherapy. These results were also compared to histology and blood analyses. METHODS The lower right lungs of 12 Sprague Dawley rats were irradiated in 2 fractions with a total dose of 18.5 Gy using a modified micro-CT system. Regional lactate and pyruvate data were acquired from three irradiated and three age-matched healthy rats at each time point on days 5, 10, 15 and 25-post radiotherapy. Arterial blood was collected from each animal prior to the (13)C-pyruvate injection and was analyzed for blood lactate concentration and arterial oxygen concentration (paO₂). Macrophage count was computed from the histology of all rat lungs. RESULTS A significant increase in lac/pyr was observed in both right and left lungs of the irradiated cohort compared to the healthy cohort for all time points. No increase in lac/pyr was observed in the hearts of the irradiated cohort compared to the hearts of the healthy cohorts. Blood lactate concentration and paO2 did not show a significant change between the irradiated and the healthy cohorts. Macrophage count in both right and left lungs was elevated for the irradiated cohort compared to the healthy cohort. CONCLUSIONS Metabolic changes associated with RP may be mapped as early as five days post conformal radiotherapy. Over the small sample size in each cohort, elevated macrophage count, consistent with early phase of inflammation was highly correlated to increases in lac/pyr in both the irradiated and unirradiated lungs. Further experiments with larger sample size may improve the confidence of this finding.

Detection of radiation-induced lung injury using hyperpolarized 13C magnetic resonance spectroscopy and imaging

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.

Polymer cross-linking: a nanogel approach to enhancing the relaxivity of MRI contrast agents

Polymer cross-linking was explored as an approach for increasing the relaxivity of macromolecular contrast agents for magnetic resonance imaging. Poly(ethylene glycol) methyl ether methacrylate, N-(2-aminoethyl)methacrylamide hydrochloride, and the cross-linker ethylene glycol dimethacrylate were copolymerized under free radical conditions. By tuning the cross-linker content and reaction concentration, it was possible to obtain 10 nm nanogels in a single synthetic step. The pendant amine moieties were functionalized with an isothiocyanate derivative of diethylenetriaminepentaacetic acid (DTPA) and Gd(iii) was chelated. In comparison with a linear control polymer prepared under the same conditions in the absence of the cross-linking agent, the nanogel contrast agent did exhibit enhanced relaxivity with an r1 of 20.8 ± 0.2 at 20 MHz and 17.5 ± 0.4 at 60 MHz (corresponding to the clinical field strength of 1.5 T). The nuclear magnetic resonance dispersion profile was modeled to demonstrate that the enhanced relaxivity was a result of the nanogel agents increased rotational correlation time, that is proposed to result from the constraint on motion imparted by the cross-linking. T1 weighted imaging in mice showed enhanced contrast and vascular circulation for the nanogel relative to Gd(iii)-DTPA (Magnevist) demonstrating the future promise of these new agents.

Structure-guided directed evolution of highly selective p450-based magnetic resonance imaging sensors for dopamine and serotonin.

New tools that allow dynamic visualization of molecular neural events are important for studying the basis of brain activity and disease. Sensors that permit ligand-sensitive magnetic resonance imaging (MRI) are useful reagents due to the noninvasive nature and good temporal and spatial resolution of MR methods. Paramagnetic metalloproteins can be effective MRI sensors due to the selectivity imparted by the protein active site and the ability to tune protein properties using techniques such as directed evolution. Here, we show that structure-guided directed evolution of the active site of the cytochrome P450-BM3 heme domain produces highly selective MRI probes with submicromolar affinities for small molecules. We report a new, high-affinity dopamine sensor as well as the first MRI reporter for serotonin, with which we demonstrate quantification of neurotransmitter release in vitro. We also present a detailed structural analysis of evolved cytochrome P450-BM3 heme domain lineages to systematically dissect the molecular basis of neurotransmitter binding affinity, selectivity, and enhanced MRI contrast activity in these engineered proteins.

Optimisation of dynamic nuclear polarisation of [1-13C] pyruvate by addition of gadolinium-based contrast agents

Dynamic nuclear polarisation (DNP) of carbon-13 ((13)C) enriched endogenous compounds provides a novel means for magnetic resonance imaging and spectroscopy of biological processes. Adding small amounts of gadolinium-based contrast agents (GBCAs) to the (13)C-enriched substrate matrix increases the amount of hyperpolarisation that can be achieved, but also may decrease the longitudinal relaxation time (T(1)) of the (13)C nucleus in solution. This study examined the effects of five different GBCA at concentrations of 0.5, 1, 2, and 3 mM on [1-(13)C]-enriched pyruvic acid. It was found that contrast agents with an open chain structure (Gadobenate dimeglumine, Gadopentetate dimeglumine, Gadodiamide) caused the largest enhancement (up to 82%) in solid state polarisation relative to solutions without GBCA. In the liquid state, T(1) of pyruvate decreased by as much as 62% and polarisation was much lower (70%) relative to solutions without GBCA added. Conversely, for GBCA with macrocyclic structures (Gadoterate meglumine, Gadoteridol), the solid state polarisation enhancement was only slightly less than the open chain GBCA, but enhanced polarisation was retained much better in the liquid state with minimal decrease in T(1) (25% at the highest GBCA concentrations). Near maximum polarisation in the solid state was obtained at a GBCA concentration of 2 mM, with a higher concentration of 3 mM producing minimal improvement. These results indicate that the macrocyclic contrast agents provide the best combination of high solid state and liquid state polarisations with minimal loss of T(1) in experiments with hyperpolarised (13)C-enriched pyruvate. This suggests that macrocyclic contrast agents should be the GBCA of choice for maximising signal in experiments with hyperpolarised (13)C-enriched pyruvate, particularly for in vivo measurements where shortened substrate T(1) is especially problematic.

Complementary Strategies for Developing Gd-Free High-Field T1 MRI Contrast Agents Based on MnIII Porphyrins

Mn(III) porphyrin (MnP) holds the promise of addressing the emerging challenges associated with Gd-based clinical MRI contrast agents (CAs), namely, Gd-related adverse effect and decreasing sensitivity at high clinical magnetic fields. Two complementary strategies for developing new MnPs as Gd-free CAs with optimized biocompatibility were established to improve relaxivity or clearance rate. MnPs with distinct and tunable pharmacokinetic properties can consequently be constructed for different in vivo applications at clinical field of 3 T.

Detection of radiation-induced lung injury using hyperpolarized (13)C magnetic resonance spectroscopy and imaging.

Radiation‐induced lung injury limits radiotherapy of thoracic cancers. Detection of radiation pneumonitis associated with early radiation‐induced lung injury (2–4 weeks postirradiation) may provide an opportunity to adjust treatment, before the onset of acute pneumonitis and/or irreversible fibrosis. In this study, localized magnetic resonance (MR) spectroscopy and imaging of hyperpolarized 13C‐pyruvate (pyruvate) and 13C‐lactate (lactate) were performed in the thorax and kidney regions of rats 2 weeks following whole‐thorax irradiation (14 Gy). Lactate‐to‐pyruvate signal ratio was observed to increase by 110% (P < 0.01), 57% (P < 0.02), and 107% (P < 0.01), respectively, in the thorax, lung, and heart tissues of the radiated rats compared with healthy age‐matched rats. This was consistent with lung inflammation confirmed using cell micrographs of bronchioalveolar lavage specimens and decreases in arterial oxygen partial pressure (paO2), indicative of hypoxia. No statistically significant difference was observed in either lactate‐to‐pyruvate signal ratios in the kidney region (P = 0.50) between the healthy (0.215 ± 0.100) and radiated cohorts (0.215 ± 0.054) or in blood lactate levels (P = 0.69) in the healthy (1.255 ± 0.247 mmol/L) and the radiated cohorts (1.325 ± 0.214 mmol/L), confirming that the injury is localized to the thorax. This work demonstrates the feasibility of hyperpolarized 13C metabolic MR spectroscopy and imaging for detection of early radiation‐induced lung injury. Magn Reson Med 70:601–609, 2013.