Overhauser Enhanced Magnetic Resonance Imaging (OMRI)

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Rational Probe Design: Dynamic nuclear polarization (DNP) is a cutting-edge technique that markedly enhances the detection sensitivity of molecules using nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI). This methodology enables real-time imaging of dynamic metabolic status in vivo using MRI. To expand the targetable metabolic reactions, there is a demand for developing exogenous, i.e., artificially designed, DNP-NMR molecular probes; however, complying with the requirements of practical DNP-NMR molecular probes is challenging because of the lack of established design guidelines. Here, we report Ala-[1-(13)C]Gly-d2-NMe2 as a DNP-NMR molecular probe for in vivo detection of aminopeptidase N activity. We developed this probe rationally through precise structural investigation, calculation, biochemical assessment, and advanced molecular design to achieve rapid and detectable responses to enzyme activity in vivo. With the fabricated probe, we successfully detected enzymatic activity in vivo. This report presents a comprehensive approach for the development of artificially derived, practical DNP-NMR molecular probes through structure-guided molecular design. Low cost hyperpolarizer: Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) is investigated to achieve rapid hyperpolarization of (13) C1 spins of [1-(13) C]pyruvate, using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co-ligation of DMSO and H2 O. Order-unity (13) C (50 %) polarization of catalyst-bound [1-(13) C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1-(13) C]pyruvate at lower temperatures. On the catalyst bound pyruvate, 39 % polarization is measured using a 1.4 T NMR spectrometer, and extrapolated to 50 % at the end of build-up in situ. The highest measured polarization of a 30-mM pyruvate sample, including free and bound pyruvate is 13 % when using 20 mM DMSO and 0.5 M water in CD3 OD. Efficient (13) C polarization is also enabled by favorable relaxation dynamics in sub-microtesla magnetic fields, as indicated by fast polarization buildup rates compared to the T1 spin-relaxation rates (e. g., approximately 0.2 s(-1) versus approximately 0.1 s(-1) , respectively, for a 6 mM catalyst-[1-(13) C]pyruvate sample). Finally, the catalyst-bound hyperpolarized [1-(13) C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water, paving the way to future biomedical applications of hyperpolarized [1-(13) C]pyruvate produced via comparatively fast and simple SABRE-SHEATH-based approaches. Parahydrogen generator: We report on a robust and low-cost parahydrogen generator design employing liquid nitrogen as a coolant. The core of the generator consists of catalyst-filled spiral copper tubing, which can be pressurized to 35 atm. Parahydrogen fraction 48% was obtained at 77 K with three nearly identical generators using paramagnetic hydrated iron oxide catalysts. Parahydrogen quantification was performed on the fly via benchtop NMR spectroscopy to monitor the signal from residual orthohydrogen-parahydrogen is NMR silent. This real-time quantification approach was also used to evaluate catalyst activation at up to 1.0 standard liter per minute flow rate. The reported inexpensive device can be employed for a wide range of studies employing parahydrogen as a source of nuclear spin hyperpolarization. To this end, we demonstrate the utility of this parahydrogen generator for hyperpolarization of concentrated sodium [1-(13)C]pyruvate, a metabolic contrast agent under investigation in numerous clinical trials. The reported pilot optimization of SABRE-SHEATH (signal amplification by reversible exchange-shield enables alignment transfer to heteronuclei) hyperpolarization yielded (13)C signal enhancement of over 14,000-fold at a clinically relevant magnetic field of 1 T corresponding to approximately 1.2% (13)C polarization-if near 100% parahydrogen would have been employed, the reported value would be tripled to (13)C polarization of 3.5%. Imaging markers from MRI using D2O: Purpose: Water is a substrate in many biochemical pathways. Systemic administration of deuterated water (D2O) results in deuterium incorporation into nucleic acids, carbohydrates, proteins, and lipids. Given their relatively high rates of proliferation and resultant deuterium enrichment we hypothesized that tumors would be more easily discerned from healthy tissues via deuterium MRI. Methods: We initiated D2O administration in two xenograft mouse models harboring either human colorectal, HT-29, or pancreatic, MiaPaca2, cancers. Results: After 14 days of in vivo tumor growth and 7 days of systemic labeling with D2O, a clear dMRI contrast was demonstrated between the xenografts and normal tissue. Conclusions: Our novel clinically relevant labeling-imaging approach enables non-radioactive sensitive tumor detection and supports the use of deuterium in cancer imaging.