@article{macculloch_browning_bedoya_mcbride_abdulmojeed_dedesma_goodson_rosen_chekmenev_yen_et al._2023, title={Facile hyperpolarization chemistry for molecular imaging and metabolic tracking of [1-13C]pyruvate in vivo}, volume={16-17}, ISSN={["2666-4410"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85168097895&partnerID=MN8TOARS}, DOI={10.1016/j.jmro.2023.100129}, abstractNote={Hyperpolarization chemistry based on reversible exchange of parahydrogen, also known as Signal Amplification By Reversible Exchange (SABRE), is a particularly simple approach to attain high levels of nuclear spin hyperpolarization, which can enhance NMR and MRI signals by many orders of magnitude. SABRE has received significant attention in the scientific community since its inception because of its relative experimental simplicity and its broad applicability to a wide range of molecules, however in vivo detection of molecular probes hyperpolarized by SABRE has remained elusive. Here we describe a first demonstration of SABRE-hyperpolarized contrast detected in vivo, specifically using hyperpolarized [1-13C]pyruvate. Biocompatible formulations of hyperpolarized [1-13C]pyruvate in, both, methanol-water mixtures, and ethanol-water mixtures followed by dilution with saline and catalyst filtration were prepared and injected into healthy Sprague Dawley and Wistar rats. Effective hyperpolarization-catalyst removal was performed with silica filters without major losses in hyperpolarization. Metabolic conversion of pyruvate to lactate, alanine, and bicarbonate was detected in vivo. Pyruvate-hydrate was also observed as minor byproduct. Measurements were performed on the liver and kidney at 4.7 T via time-resolved spectroscopy and chemical-shift-resolved MRI. In addition, whole-body metabolic measurements were obtained using a cryogen-free 1.5 T MRI system, illustrating the utility of combining lower-cost MRI systems with simple, low-cost hyperpolarization chemistry to develop safe, and scalable molecular imaging.}, journal={JOURNAL OF MAGNETIC RESONANCE OPEN}, author={Macculloch, Keilian and Browning, Austin and Bedoya, David O. Guarin and Mcbride, Stephen J. and Abdulmojeed, Mustapha B. and Dedesma, Carlos and Goodson, Boyd M. and Rosen, Matthew S. and Chekmenev, Eduard Y. and Yen, Yi-Fen and et al.}, year={2023}, month={Dec} }
 @article{macculloch_browning_tomhon_lehmkuhl_chekmenev_theis_2023, title={Parahydrogen in Reversible Exchange Induces Long-Lived 15N Hyperpolarization of Anticancer Drugs Anastrozole and Letrozole}, volume={5}, ISSN={["1520-6882"]}, url={https://doi.org/10.1021/acs.analchem.2c04817}, DOI={10.1021/acs.analchem.2c04817}, abstractNote={Hyperpolarization modalities overcome the sensitivity limitations of NMR and unlock new applications. Signal amplification by reversible exchange (SABRE) is a particularly cheap, quick, and robust hyperpolarization modality. Here, we employ SABRE for simultaneous chemical exchange of parahydrogen and nitrile-containing anticancer drugs (letrozole or anastrozole) to enhance 15N polarization. Distinct substrates require unique optimal parameter sets, including temperature, magnetic field, or a shaped magnetic field profile. The fine tuning of these parameters for individual substrates is demonstrated here to maximize 15N polarization. After optimization, including the usage of pulsed μT fields, the 15N nuclei on common anticancer drugs, letrozole and anastrozole, can be polarized within 1-2 min. The hyperpolarization can exceed 10%, corresponding to 15N signal enhancement of over 280,000-fold at a clinically relevant magnetic field of 1 T. This sensitivity gain enables polarization studies at naturally abundant 15N enrichment level (0.4%). Moreover, the nitrile 15N sites enable long-lasting polarization storage with [15N]T1 over 9 min, enabling signal detection from a single hyperpolarization cycle for over 30 min.}, number={20}, journal={ANALYTICAL CHEMISTRY}, author={MacCulloch, Keilian and Browning, Austin and TomHon, Patrick and Lehmkuhl, Soeren and Chekmenev, Eduard Y. and Theis, Thomas}, year={2023}, month={May} }
 @article{browning_macculloch_tomhon_mandzhieva_chekmenev_goodson_lehmkuhl_theis_2023, title={Spin dynamics of [1,2-C-13(2)]pyruvate hyperpolarization by parahydrogen in reversible exchange at micro Tesla fields}, volume={25}, ISSN={["1463-9084"]}, url={https://doi.org/10.1039/D3CP00843F}, DOI={10.1039/d3cp00843f}, abstractNote={The spin dynamics during SABRE of [1,2-13C2]pyruvate are detailed. An analytical model and numerical simulations are used to understand the selective formation of hyperpolarized magnetization or singlet order on the 13C2-spin pair.}, number={24}, journal={PHYSICAL CHEMISTRY CHEMICAL PHYSICS}, author={Browning, Austin and Macculloch, Keilian and TomHon, Patrick and Mandzhieva, Iuliia and Chekmenev, Eduard Y. and Goodson, Boyd M. and Lehmkuhl, Soeren and Theis, Thomas}, year={2023}, month={Jun}, pages={16446–16458} }
 @article{schmidt_maissin_adelabu_nantogma_ettedgui_tomhon_goodson_theis_chekmenev_2022, title={Catalyst-Free Aqueous Hyperpolarized [1-13C]Pyruvate Obtained by Re-Dissolution Signal Amplification by Reversible Exchange}, volume={11}, ISSN={["2379-3694"]}, url={https://doi.org/10.1021/acssensors.2c01715}, DOI={10.1021/acssensors.2c01715}, abstractNote={Despite great successes in oncology, patient outcomes are often still discouraging, and hence the diagnostic imaging paradigm is increasingly shifting toward functional imaging of the pathology to better understand individual disease biology and to personalize therapies. The dissolution Dynamic Nuclear Polarization (d-DNP) hyperpolarization method has enabled unprecedented real-time MRI sensing of metabolism and tissue pH using hyperpolarized [1-13C]pyruvate as a biosensor with great potential for diagnosis and monitoring of cancer patients. However, current d-DNP is expensive and suffers from long hyperpolarization times, posing a substantial translational roadblock. Here, we report the development of Re-Dissolution Signal Amplification By Reversible Exchange (Re-D SABRE), which relies on fast and low-cost hyperpolarization of [1-13C]pyruvate by chemical exchange with parahydrogen at microtesla magnetic fields. [1-13C]pyruvate is precipitated from catalyst-containing methanol using ethyl acetate and rapidly reconstituted in aqueous media. 13C polarization of 9 ± 1% is demonstrated after redissolution in water with residual iridium mass fraction of 8.5 ± 1.5 ppm; further improvement is anticipated via process automation. Re-D SABRE makes hyperpolarized [1-13C]pyruvate biosensor available at a fraction of the cost (<$10,000) and production time (≈1 min) of currently used techniques and makes aqueous hyperpolarized [1-13C]pyruvate "ready" for in vivo applications.}, number={11}, journal={ACS SENSORS}, author={Schmidt, Andreas B. and Maissin, Henri and Adelabu, Isaiah and Nantogma, Shiraz and Ettedgui, Jessica and TomHon, Patrick and Goodson, Boyd M. and Theis, Thomas and Chekmenev, Eduard Y.}, year={2022}, month={Nov} }
 @article{nantogma_eriksson_adelabu_mandzhieva_browning_tomhon_warren_theis_goodson_chekmenev_2022, title={Interplay of Near-Zero-Field Dephasing, Rephasing, and Relaxation Dynamics and [1-C-13]Pyruvate Polarization Transfer Efficiency in Pulsed SABRE-SHEATH}, volume={11}, ISSN={["1520-5215"]}, url={https://doi.org/10.1021/acs.jpca.2c07150}, DOI={10.1021/acs.jpca.2c07150}, abstractNote={Hyperpolarized [1-13C]pyruvate is a revolutionary molecular probe enabling ultrafast metabolic MRI scans in 1 min. This technology is now under evaluation in over 30 clinical trials, which employ dissolution Dynamic Nuclear Polarization (d-DNP) to prepare a batch of the contrast agent; however, d-DNP technology is slow and expensive. The emerging SABRE-SHEATH hyperpolarization technique enables fast (under 1 min) and robust production of hyperpolarized [1-13C]pyruvate via simultaneous chemical exchange of parahydrogen and pyruvate on IrIMes hexacoordinate complexes. Here, we study the application of microtesla pulses to investigate their effect on C-13 polarization efficiency, compared to that of conventional SABRE-SHEATH employing a static field (∼0.4 μT), to provide the matching conditions of polarization transfer from parahydrogen-derived hydrides to the 13C-1 nucleus. Our results demonstrate that using square-microtesla pulses with optimized parameters can produce 13C-1 polarization levels of up to 14.8% (when detected, averaging over all resonances), corresponding to signal enhancement by over 122,000-fold at the clinically relevant field of 1.4 T. We anticipate that our results can be directly translated to other structurally similar biomolecules such as [1-13C]α-ketoglutarate and [1-13C]α-ketoisocaproate. Moreover, other more advanced pulse shapes can potentially further boost heteronuclear polarization attainable via pulsed SABRE-SHEATH.}, number={48}, journal={JOURNAL OF PHYSICAL CHEMISTRY A}, author={Nantogma, Shiraz and Eriksson, Shannon L. and Adelabu, Isaiah and Mandzhieva, Iuliia and Browning, Austin and TomHon, Patrick and Warren, Warren S. and Theis, Thomas and Goodson, Boyd M. and Chekmenev, Eduard Y.}, year={2022}, month={Nov} }
 @article{brown_mandzhieva_tomhon_theis_castellano_2022, title={Triplet Photosensitized para-Hydrogen Induced Polarization}, volume={11}, ISSN={["2374-7951"]}, url={https://doi.org/10.1021/acscentsci.2c01003}, DOI={10.1021/acscentsci.2c01003}, abstractNote={Despite its enormous utility in structural characterization, nuclear magnetic resonance (NMR) spectroscopy is inherently limited by low spin polarization. One method to address the low polarization is para-hydrogen (p-H2) induced polarization (PHIP) which uses the singlet spin isomer of H2 to generate disparate nuclear spin populations to amplify the associated NMR signals. PHIP often relies on thermal catalysis or, more infrequently, UV-activated catalytic hydrogenation. Light-activated hydrogenation enables direct and timed control over the hyperpolarization of target substrates, critical for identifying short-lived intermediates. Here, we use an established Ir(III) triplet photosensitizer (PS) to visible light sensitize the triplet ligand-field states in the d6-transition metal dihydride Ru(CO)(PPh3)3(H)2 (1). Excitation inside a 9.4 T NMR spectrometer with the PS and a 420 nm blue LED, under 3 atm of p-H2, successfully photosensitized hyperpolarization in 1 and in a range of unsaturated substrates at and below room temperature, up to 1630-fold. In otherwise identical experimental conditions without light activation, no polarization was realized in 1 or the substrates evaluated. We believe triplet-sensitized PHIP (Trip-PHIP) represents a facile experimental means for probing triplet sensitized light activation in transition metal catalysts possessing low-lying triplet ligand-field states, providing mechanistic insight of potentially tremendous value in chemical catalysis.}, number={11}, journal={ACS CENTRAL SCIENCE}, author={Brown, Emily E. and Mandzhieva, Iuliia and TomHon, Patrick M. and Theis, Thomas and Castellano, Felix N.}, year={2022}, month={Nov} }
 @article{tomhon_han_lehmkuhl_appelt_chekmenev_abolhasani_theis_2021, title={A Versatile Compact Parahydrogen Membrane Reactor}, volume={10}, ISSN={["1439-7641"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85118185085&partnerID=MN8TOARS}, DOI={10.1002/cphc.202100667}, abstractNote={Abstract}, number={24}, journal={CHEMPHYSCHEM}, author={TomHon, Patrick M. and Han, Suyong and Lehmkuhl, Soren and Appelt, Stephan and Chekmenev, Eduard Y. and Abolhasani, Milad and Theis, Thomas}, year={2021}, month={Oct} }
 @article{lin_tomhon_lehmkuhl_laasner_theis_blum_2021, title={Density Functional Theory Study of Reaction Equilibria in Signal Amplification by Reversible Exchange}, volume={9}, ISSN={["1439-7641"]}, url={https://doi.org/10.1002/cphc.202100204}, DOI={10.1002/cphc.202100204}, abstractNote={Abstract}, number={19}, journal={CHEMPHYSCHEM}, publisher={Wiley}, author={Lin, Kailai and TomHon, Patrick and Lehmkuhl, Soren and Laasner, Raul and Theis, Thomas and Blum, Volker}, year={2021}, month={Sep} }
 @article{lin_tomhon_lehmkuhl_laasner_theis_blum_2021, title={Density Functional Theory Study of Reaction Equilibria in Signal Amplification by Reversible Exchange}, volume={22}, ISSN={["1439-7641"]}, url={https://doi.org/10.1002/cphc.202100678}, DOI={10.1002/cphc.202100678}, abstractNote={Abstract}, number={19}, journal={CHEMPHYSCHEM}, author={Lin, Kailai and TomHon, Patrick and Lehmkuhl, Soren and Laasner, Raul and Theis, Thomas and Blum, Volker}, year={2021}, month={Oct}, pages={1937–1938} }
 @article{lin_tomhon_lehmkuhl_laasner_theis_blum_2021, title={Front Cover: Density Functional Theory Study of Reaction Equilibria in Signal Amplification by Reversible Exchange (ChemPhysChem 19/2021)}, url={https://doi.org/10.1002/cphc.202100677}, DOI={10.1002/cphc.202100677}, abstractNote={The Front Cover shows the reaction network of Signal Amplification by Reversible Exchange (SABRE), elucidated by density functional theory (DFT). More information can be found in the Article by T. Theis, V. Blum, and co-workers.}, journal={ChemPhysChem}, author={Lin, Kailai and TomHon, Patrick and Lehmkuhl, Sören and Laasner, Raul and Theis, Thomas and Blum, Volker}, year={2021}, month={Oct} }
 @article{macculloch_tomhon_browning_akeroyd_lehmkuhl_chekmenev_theis_2021, title={Hyperpolarization of common antifungal agents with SABRE}, volume={6}, ISSN={["1097-458X"]}, url={https://doi.org/10.1002/mrc.5187}, DOI={10.1002/mrc.5187}, abstractNote={Abstract}, number={12}, journal={MAGNETIC RESONANCE IN CHEMISTRY}, publisher={Wiley}, author={MacCulloch, Keilian and Tomhon, Patrick and Browning, Austin and Akeroyd, Evan and Lehmkuhl, Soren and Chekmenev, Eduard Y. and Theis, Thomas}, year={2021}, month={Jun} }
 @article{han_ramezani_tomhon_abdel-latif_epps_theis_abolhasani_2021, title={Intensified continuous extraction of switchable hydrophilicity solvents triggered by carbon dioxide}, volume={23}, ISSN={["1463-9270"]}, url={https://doi.org/10.1039/D1GC00811K}, DOI={10.1039/d1gc00811k}, abstractNote={An intensified continuous flow strategy is developed and utilized for scalable extraction of switchable hydrophilicity solvents triggered by carbon dioxide.}, number={8}, journal={GREEN CHEMISTRY}, publisher={Royal Society of Chemistry (RSC)}, author={Han, Suyong and Ramezani, Mahdi and TomHon, Patrick and Abdel-Latif, Kameel and Epps, Robert W. and Theis, Thomas and Abolhasani, Milad}, year={2021}, month={Apr}, pages={2900–2906} }
 @article{arunkumar_bucher_turner_tomhon_glenn_lehmkuhl_lukin_park_rosen_theis_et al._2021, title={Micron-Scale NV-NMR Spectroscopy with Signal Amplification by Reversible Exchange}, volume={2}, ISSN={2691-3399}, url={http://dx.doi.org/10.1103/prxquantum.2.010305}, DOI={10.1103/PRXQuantum.2.010305}, abstractNote={High-resolution sensing of weak signals is implemented by means of an integrated diamond---nuclear-magnetic-resonance technique}, number={1}, journal={PRX Quantum}, publisher={American Physical Society (APS)}, author={Arunkumar, Nithya and Bucher, Dominik B. and Turner, Matthew J. and TomHon, Patrick and Glenn, David and Lehmkuhl, Sören and Lukin, Mikhail D. and Park, Hongkun and Rosen, Matthew S. and Theis, Thomas and et al.}, year={2021}, month={Jan}, pages={010305} }
 @article{adelabu_tomhon_kabir_nantogma_abdulmojeed_mandzhieva_ettedgui_swenson_krishna_theis_et al._2021, title={Order-Unity C-13 Nuclear Polarization of [1-C-13]Pyruvate in Seconds and the Interplay of Water and SABRE Enhancement}, volume={11}, ISSN={["1439-7641"]}, url={https://doi.org/10.1002/cphc.202100839}, DOI={10.1002/cphc.202100839}, abstractNote={Abstract}, number={2}, journal={CHEMPHYSCHEM}, publisher={Wiley}, author={Adelabu, Isaiah and TomHon, Patrick and Kabir, Mohammad S. H. and Nantogma, Shiraz and Abdulmojeed, Mustapha and Mandzhieva, Iuliia and Ettedgui, Jessica and Swenson, Rolf E. and Krishna, Murali C. and Theis, Thomas and et al.}, year={2021}, month={Dec} }
 @article{tomhon_abdulmojeed_adelabu_nantogma_kabir_lehmkuhl_chekmenev_theis_2021, title={Temperature Cycling Enables Efficient 13C SABRE-SHEATH Hyperpolarization and Imaging of [1-13C]Pyruvate}, url={https://doi.org/10.26434/chemrxiv-2021-cpz32}, DOI={10.26434/chemrxiv-2021-cpz32}, abstractNote={Current metabolic imaging in humans is dominated by positron emission tomography (PET) methods. An emerging non-ionizing alternative for molecular imaging is hyperpolarized MRI. In particular, imaging of hyperpolarized 13C-pyruvate is a leading candidate because pyruvate is innocuous and has a central role in metabolism. However, simi-lar to PET, hyperpolarized MRI with dynamic nuclear polarization (DNP) is complex, costly and requires complex in-frastructure. In contrast, signal amplification by reversible exchange (SABRE) is a fast, cheap, and scalable hyperpo-larization technique. In particular, SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) transfers polarization from parahydrogen to 13C in pyruvate, however, to date, SABRE-SHEATH of 13C-pyruvate was limited in polarization levels relative to DNP (1.7% with SABRE-SHEATH vs. ~60% with DNP). Here we introduce a temperature cycling method for SABRE-SHEATH that enables >10% polarization on [1-13C]pyruvate, sufficient for successful in vivo experiments. First, at lower temperatures, ~20% polarization is accumulated on SABRE-catalyst bound pyruvate, which is subsequently released into free pyruvate in solution at elevated temperatures. We take ad-vantage of the achieved polarization to demonstrate first 13C pyruvate images with a cryogen-free MRI system operat-ed at 1 T. This illustrates that inexpensive hyperpolarization methods can be combined with low-cost MRI systems to obtain a broadly available, yet highly sensitive metabolic imaging platform.}, journal={ChemRxiv}, author={TomHon, Patrick and Abdulmojeed, Mustapha and Adelabu, Isaiah and Nantogma, Shiraz and Kabir, Mohammad Shah Hafez and Lehmkuhl, Sören and Chekmenev, Eduard Y. and Theis, Thomas}, year={2021}, month={Aug} }
 @article{tomhon_abdulmojeed_adelabu_nantogma_kabir_lehmkuhl_chekmenev_theis_2021, title={Temperature Cycling Enables Efficient C-13 SABRE-SHEATH Hyperpolarization and Imaging of [1-C-13]-Pyruvate}, volume={12}, ISSN={["1520-5126"]}, url={https://doi.org/10.1021/jacs.1c09581}, DOI={10.1021/jacs.1c09581}, abstractNote={Molecular metabolic imaging in humans is dominated by positron emission tomography (PET). An emerging nonionizing alternative is hyperpolarized MRI of 13C-pyruvate, which is innocuous and has a central role in metabolism. However, similar to PET, hyperpolarized MRI with dissolution dynamic nuclear polarization (d-DNP) is complex costly, and requires significant infrastructure. In contrast, Signal Amplification By Reversible Exchange (SABRE) is a fast, cheap, and scalable hyperpolarization technique. SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) can transfer polarization from parahydrogen to 13C in pyruvate; however, polarization levels remained low relative to d-DNP (1.7% with SABRE-SHEATH versus ≈60% with DNP). Here we introduce a temperature cycling method for SABRE-SHEATH that enables >10% polarization on [1-13C]-pyruvate, sufficient for successful in vivo experiments. First, at lower temperatures, ≈20% polarization is accumulated on SABRE catalyst-bound pyruvate, which is released into free pyruvate at elevated temperatures. A kinetic model of differential equations is developed that explains this effect and characterizes critical relaxation and buildup parameters. With the large polarization, we demonstrate the first 13C pyruvate images with a cryogen-free MRI system operated at 1.5 T, illustrating that inexpensive hyperpolarization methods can be combined with low-cost MRI systems to obtain a broadly available, yet highly sensitive metabolic imaging platform.}, number={1}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, publisher={American Chemical Society (ACS)}, author={TomHon, Patrick and Abdulmojeed, Mustapha and Adelabu, Isaiah and Nantogma, Shiraz and Kabir, Mohammad Shah Hafez and Lehmkuhl, Soren and Chekmenev, Eduard Y. and Theis, Thomas}, year={2021}, month={Dec} }
 @article{tomhon_akeroyd_lehmkuhl_chekmenev_theis_2020, title={Automated pneumatic shuttle for magnetic field cycling and parahydrogen hyperpolarized multidimensional NMR}, volume={312}, ISSN={1090-7807}, url={http://dx.doi.org/10.1016/j.jmr.2020.106700}, DOI={10.1016/j.jmr.2020.106700}, abstractNote={We present a simple-to-implement pneumatic sample shuttle for automation of magnetic field cycling and multidimensional NMR. The shuttle system is robust allowing automation of hyperpolarized and non-hyperpolarized measurements, including variable field lifetime measurements, SABRE polarization optimization, and SABRE multidimensional experiments. Relaxation-protected singlet states are evaluated by variable-field T1 and TS measurements. Automated shuttling facilitates characterization of hyperpolarization dynamics, field dependence and polarization buildup rates. Furthermore, reproducible hyperpolarization levels at every shuttling event enables automated 2D hyperpolarized NMR, including the first inverse 15N/1H HSQC. We uncover binding mechanisms of the catalytic species through cross peaks that are not accessible in standard one-dimensional hyperpolarized experiments. The simple design of the shuttling setup interfaced with standard TTL signals allows easy adaptation to any standard NMR magnet.}, journal={Journal of Magnetic Resonance}, publisher={Elsevier BV}, author={TomHon, Patrick and Akeroyd, Evan and Lehmkuhl, Sören and Chekmenev, Eduard Y. and Theis, Thomas}, year={2020}, month={Mar}, pages={106700} }