Magnetic resonance imaging (MRI) has become arguably the most important clinical imaging modality but it is less well suited for molecular and metabolic imaging because of its inherently low sensitivity. Solution phase nuclear dynamic polarization (DNP) technology can increase the sensitivity of standard NMR experiments by factors of 5000 to 25000. Such increases in sensitivity make it possible to perform molecular/functional imaging of other nuclei than 1H. The signal coming from any hyperpolarized nucleus will decay according to the spin-lattice relaxation time (T1) and one can anticipate having a detectable NMR signal for ~5T1. This poses a limitation on the biochemical processes that could be imaged and motivates the search for long T1 agents. Among the common spin 1/2 NMR active nuclei 89Y(III) has the longest T1 relaxation time (up to 600 seconds) rendering hyperpolarized yttrium-89 attractive as a potential in vivo imaging and spectroscopy probe. Our preliminary data indicated that Y(III)-complexes can be hyperpolarized with currently available commercial hardware. The goal of this project is to demonstrate that imaging of hyperpolarized Y- complexes is possible in vivo. We will first establish the optimal conditions for the DNP hyperpolarization of 89Y (Specific Aim 1). Y(III) complexes of two open chain (DTPA, TTHA) and four macrocyclic ligands, [DOTA, PCTA, DOTP, DOTA(AmP)4] will be prepared and hyperpolarized. Polarization enhancements and T1's of the complexes will be determined (Specific Aim 2). We will build a dual-tuned 89Y/1H coil for rats and develop a protocol to image the biodistribution of hyperpolarized Y(III) chelates. The samples will be hyperpolarized in the Hypersense """""""" DNP polarizer and the in vivo imaging experiments will be performed at 4.7T (Specific Aim 3). The extreme sensitivity of 89Y(III) to its chemical environment could be exploited in the design of sensitive probes to image and map physiological parameters such as pH, temperature, and other indices of metabolism in vivo.

Public Health Relevance

Solution phase nuclear dynamic polarization (DNP) nuclear magnetic resonance (NMR) technology increases the sensitivity of standard NMR experiments by factors of 5000 to 25000 making MRI imaging of nuclei other than 1H feasible. The goal of this proposal is to demonstrate that imaging hyperpolarized yttrium-89-complexes is possible in vivo. Potential applications include the design and synthesis of sensitive probes to image and map physiological parameters such as pH, temperature, redox state and glucose levels in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB009147-02
Application #
7802862
Study Section
Special Emphasis Panel (ZRG1-SBIB-J (90))
Program Officer
Liu, Christina
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$194,288
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lumata, Lloyd L; Martin, Richard; Jindal, Ashish K et al. (2015) Development and performance of a 129-GHz dynamic nuclear polarizer in an ultra-wide bore superconducting magnet. MAGMA 28:195-205
Lumata, Lloyd L; Merritt, Matthew E; Malloy, Craig R et al. (2013) Dissolution DNP-NMR spectroscopy using galvinoxyl as a polarizing agent. J Magn Reson 227:14-9
Lumata, Lloyd; Kovacs, Zoltan; Sherry, A Dean et al. (2013) Electron spin resonance studies of trityl OX063 at a concentration optimal for DNP. Phys Chem Chem Phys 15:9800-7
Lumata, Lloyd; Merritt, Matthew E; Kovacs, Zoltan (2013) Influence of deuteration in the glassing matrix on 13C dynamic nuclear polarization. Phys Chem Chem Phys 15:7032-5
Lumata, Lloyd; Merritt, Matthew E; Malloy, Craig R et al. (2012) Impact of Gd3+ on DNP of [1-13C]pyruvate doped with trityl OX063, BDPA, or 4-oxo-TEMPO. J Phys Chem A 116:5129-38
Lumata, Lloyd; Merritt, Matthew E; Hashami, Zohreh et al. (2012) Production and NMR characterization of hyperpolarized (107,109)Ag complexes. Angew Chem Int Ed Engl 51:525-7
Lumata, Lloyd; Merritt, Matthew; Khemtong, Chalermchai et al. (2012) The efficiency of DPPH as a polarising agent for DNP-NMR spectroscopy. RSC Adv 2:12812-12817
Lumata, Lloyd; Jindal, Ashish K; Merritt, Matthew E et al. (2011) DNP by thermal mixing under optimized conditions yields >60,000-fold enhancement of 89Y NMR signal. J Am Chem Soc 133:8673-80
Lumata, Lloyd; Ratnakar, S James; Jindal, Ashish et al. (2011) BDPA: an efficient polarizing agent for fast dissolution dynamic nuclear polarization NMR spectroscopy. Chemistry 17:10825-7
Doi, Shigehiro; Zou, Yonglong; Togao, Osamu et al. (2011) Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 286:8655-65

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