SABRE-SHEATH Hyperpolarization of [1,5-C]Z-OMPD for Noninvasive pH Sensing.

Hyperpolarized (HP) C-labeled probes are emerging as promising agents to noninvasively image pH in vivo. HP [1,5-C]Z-OMPD (Z-4-methyl-2-oxopent-3-enedioic acid) in particular has recently been used to simultaneously report on kidney perfusion, filtration, and pH homeostasis, in addition to the ability to detect local tumor acidification. In previous studies, dissolution dynamic nuclear polarization was used to hyperpolarize Z-OMPD.

Carbon-13 Hyperpolarization of α-Ketocarboxylates with Parahydrogen in Reversible Exchange.

Signal Amplification by Reversible Exchange (SABRE) is a relatively simple and fast hyperpolarization technique that has been used to hyperpolarize the α-ketocarboxylate pyruvate, a central metabolite and the leading hyperpolarized MRI contrast agent. In this work, we show that SABRE can readily be extended to hyperpolarize C nuclei at natural abundance on many other α-ketocarboxylates. Hyperpolarization is observed and optimized on pyruvate (P=17 %) and 2-oxobutyrate (P=25 %) with alkyl chains in the R-group, oxaloacetate (P=11 %) and alpha-ketoglutarate (P=13 %) with carboxylate moieties in the R group, and phenylpyruvate (P=2 %) and phenylglyoxylate (P=2 %) with phenyl rings in the R-group.

Toward Next-Generation Molecular Imaging with a Clinical Low-Field (0.064 T) Point-of-Care MRI Scanner.

Low-field (LF) MRI promises soft-tissue imaging without the expensive, immobile magnets of clinical scanners but generally suffers from limited detection sensitivity and contrast. The sensitivity boost provided by hyperpolarization can thus be highly synergistic with LF MRI. Initial efforts to integrate a continuous-bubbling SABRE (signal amplification by reversible exchange) hyperpolarization setup with a portable, point-of-care 64 mT clinical MRI scanner are reported.

Toward Ultra-High-Quality-Factor Wireless Masing Magnetic Resonance Sensing.

It has recently been shown that a bolus of hyperpolarized nuclear spins can yield stimulated emission signals similar in nature to maser signals, potentially enabling new ways of sensing hyperpolarized contrast media, including most notably [1-C]pyruvate that is under evaluation in over 50 clinical trials for metabolic imaging of cancer. The stimulated NMR signal emissions lasting for minutes do not require radio-frequency excitation, offering unprecedented advantages compared to conventional MR sensing. However, creating nuclear spin maser emission is challenging in practice due to stringent fundamental requirements, making practical in vivo applications hardly possible using conventional passive MR detectors.

Single Nucleotide Polymorphism in Cell Adhesion Molecule L1 Affects Learning and Memory in a Mouse Model of Traumatic Brain Injury.

The L1 cell adhesion molecule (L1) has demonstrated a range of beneficial effects in animal models of spinal cord injury, neurodegenerative disease, and ischemia; however, the role of L1 in TBI has not been fully examined. Mutations in the gene affecting the extracellular domain of this type 1 transmembrane glycoprotein have been identified in patients with L1 syndrome. These patients suffer from hydrocephalus, MASA (mental retardation, adducted thumbs, shuffling gait, aphasia) symptoms, and corpus callosum agenesis.

C MRI of hyperpolarized pyruvate at 120 µT.

Nuclear spin hyperpolarization increases the sensitivity of magnetic resonance dramatically, enabling many new applications, including real-time metabolic imaging. Parahydrogen-based signal amplification by reversible exchange (SABRE) was employed to hyperpolarize [1-C]pyruvate and demonstrate C imaging in situ at 120 µT, about twice Earth's magnetic field, with two different signal amplification by reversible exchange variants: SABRE in shield enables alignment transfer to heteronuclei (SABRE-SHEATH), where hyperpolarization is transferred from parahydrogen to [1-C]pyruvate at a magnetic field below 1 µT, and low-irradiation generates high tesla (LIGHT-SABRE), where hyperpolarization was prepared at 120 µT, avoiding magnetic field cycling. The 3-dimensional images of a phantom were obtained using a superconducting quantum interference device (SQUID) based magnetic field detector with submillimeter resolution.

Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation of the Hyperpolarized Ketone and Hemiketal Forms of Allyl [1-C]Pyruvate.

C hyperpolarized pyruvate is an emerging MRI contrast agent for sensing molecular events in cancer and other diseases with aberrant metabolic pathways. This metabolic contrast agent can be produced via several hyperpolarization techniques. Despite remarkable success in research settings, widespread clinical adoption faces substantial roadblocks because the current sensing technology utilized to sense this contrast agent requires the excitation of C nuclear spins that also need to be synchronized with MRI field gradient pulses.

Facile hyperpolarization chemistry for molecular imaging and metabolic tracking of [1-C]pyruvate in vivo.

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-C]pyruvate.

Delivering Robust Proton-Only Sensing of Hyperpolarized [1,2-C]-Pyruvate Using Broad-Spectral-Range Nuclear Magnetic Resonance Pulse Sequences.

Hyperpolarized [1-C]pyruvate is the leading hyperpolarized injectable contrast agent and is currently under evaluation in clinical trials for molecular imaging of metabolic diseases, including cardiovascular disease and cancer. One aspect limiting broad scalability of the technique is that hyperpolarized C MRI requires specialized C hardware and software that are not generally available on clinical MRI scanners, which employ proton-only detection. Here, we present an approach that uses pulse sequences to transfer C hyperpolarization to methyl protons for detection of the C-C pyruvate singlet, employing proton-only excitation and detection only.

Small Organic Compounds Mimicking the Effector Domain of Myristoylated Alanine-Rich C-Kinase Substrate Stimulate Female-Specific Neurite Outgrowth.

Myristoylated alanine-rich C-kinase substrate (MARCKS) is a critical member of a signaling cascade that influences disease-relevant neural functions such as neural growth and plasticity. The effector domain (ED) of MARCKS interacts with the extracellular glycan polysialic acid (PSA) through the cell membrane to stimulate neurite outgrowth in cell culture. We have shown that a synthetic ED peptide improves functional recovery after spinal cord injury in female but not male mice.

Sex Differences in Immune Cell Infiltration and Hematuria in SCI-Induced Hemorrhagic Cystitis.

Rats manifest a condition called hemorrhagic cystitis after spinal cord injury (SCI). The mechanism of this condition is unknown, but it is more severe in male rats than in female rats. We assessed the role of sex regarding hemorrhagic cystitis and pathological chronic changes in the bladder.

Spin dynamics of [1,2-C]pyruvate hyperpolarization by parahydrogen in reversible exchange at micro Tesla fields.

Hyperpolarization of C-pyruvate Signal Amplificaton By Reversibble Exchange (SABRE) is an important recent discovery because of both the relative simplicity of hyperpolarization and the central biological relevance of pyruvate as a biomolecular probe for or studies. Here, we analyze the [1,2-C]pyruvate-SABRE spin system and its field dependence theoretically and experimentally. We provide first-principles analysis of the governing 4-spin dihydride-C Hamiltonian and numerical spin dynamics simulations of the 7-spin dihydride-C-CH system.

C Radiofrequency Amplification by Stimulated Emission of Radiation Threshold Sensing of Chemical Reactions.

Conventional nuclear magnetic resonance (NMR) enables detection of chemicals and their transformations by exciting nuclear spin ensembles with a radio-frequency pulse followed by detection of the precessing spins at their characteristic frequencies. The detected frequencies report on chemical reactions in real time and the signal amplitudes scale with concentrations of products and reactants. Here, we employ Radiofrequency Amplification by Stimulated Emission of Radiation (RASER), a quantum phenomenon producing coherent emission of C signals, to detect chemical transformations.

Parahydrogen in Reversible Exchange Induces Long-Lived N Hyperpolarization of Anticancer Drugs Anastrozole and Letrozole.

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 N polarization.

LIGHT-SABRE Hyperpolarizes 1-C-Pyruvate Continuously without Magnetic Field Cycling.

Nuclear spin hyperpolarization enables real-time observation of metabolism and intermolecular interactions . 1-C-pyruvate is the leading hyperpolarized tracer currently under evaluation in several clinical trials as a promising molecular imaging agent. Still, the quest for a simple, fast, and efficient hyperpolarization technique is ongoing.

Efficient SABRE-SHEATH Hyperpolarization of Potent Branched-Chain-Amino-Acid Metabolic Probe [1-C]ketoisocaproate.

Efficient C hyperpolarization of ketoisocaproate is demonstrated in natural isotopic abundance and [1-C]enriched forms via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). Parahydrogen, as the source of nuclear spin order, and ketoisocaproate undergo simultaneous chemical exchange with an Ir-IMes-based hexacoordinate complex in CDOD. SABRE-SHEATH enables spontaneous polarization transfer from parahydrogen-derived hydrides to the C nucleus of transiently bound ketoisocaproate.

SABRE Hyperpolarization with up to 200 bar Parahydrogen in Standard and Quickly Removable Solvents.

hydrogen (-H)-based techniques are known to drastically enhance NMR signals but are usually limited by -H supply. This work reports -H-based SABRE hyperpolarization at -H pressures of hundreds of bar, far beyond the typical ten bar currently reported in the literature. A recently designed high-pressure setup was utilized to compress -H gas up to 200 bar.

Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions.

The L1 cell adhesion molecule plays an essential role in neural development and repair. It is not only a 'lock and key' recognition molecule, but an important signal transducer that stimulates regenerative-beneficial cellular functions such as neurite outgrowth, neuronal cell migration, survival, myelination, and synapse formation. Triggering L1 functions after neurotrauma improves functional recovery.

Interplay of Near-Zero-Field Dephasing, Rephasing, and Relaxation Dynamics and [1-C]Pyruvate Polarization Transfer Efficiency in Pulsed SABRE-SHEATH.

Hyperpolarized [1-C]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-C]pyruvate via simultaneous chemical exchange of parahydrogen and pyruvate on IrIMes hexacoordinate complexes.

Triplet Photosensitized -Hydrogen Induced Polarization.

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 -hydrogen (-H) induced polarization (PHIP) which uses the singlet spin isomer of H 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.

Parahydrogen-Induced Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation.

The feasibility of Carbon-13 Radiofrequency (RF) Amplification by Stimulated Emission of Radiation (C-13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1- C]acetate. Hyperpolarized ethyl [1- C]acetate was prepared via pairwise addition of parahydrogen to vinyl [1- C]acetate and polarization transfer from nascent parahydrogen-derived protons to the carbon-13 nucleus via magnetic field cycling yielding C-13 nuclear spin polarization of approximately 6 %. RASER signals were detected from samples with concentration ranging from 0.

CHL1-Deficient and Wild-Type Male Mice do Not Differ in Locomotor Recovery from Spinal Cord Injury.

CHL1 is a close homolog of L1, a cell adhesion molecule that plays major roles in neural and tumor cell functions. We had found that young adult female mice deficient in CHL1 recovered better than their wild-type female littermates after thoracic Spinal Cord Injury (SCI). This observation was surprising, because CHL1 increases neurite outgrowth in vitro.

Catalyst-Free Aqueous Hyperpolarized [1-C]Pyruvate Obtained by Re-Dissolution Signal Amplification by Reversible Exchange.

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-C]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.