Using Parahydrogen to Hyperpolarize Amines, Amides, Carboxylic Acids, Alcohols, Phosphates and Carbonates

Hyperpolarization turns weak NMR and MRI responses into strong signals so normally impractical measurements are possible. We use parahydrogen here to rapidly hyperpolarize appropriate 1H, 13C, 15N and 31P responses of analytes such as NH3 and important amines such as phenylethylamine, amides such as acetamide, urea and methacrylamide, alcohols spanning methanol through octanol and glucose, the sodium salts of carboxylic acids such as acetic acid and pyruvic acid, sodium phosphate, disodium adenosine 5’triphosphate and sodium hydrogen carbonate. The associated signal gains are used to demonstrate it is possible to collect informative single-shot NMR spectra of these analytes in seconds at the micromole level in a 9.4 T observation field. To achieve these wide ranging signal gains, we first employ the Signal Amplification By Reversible Exchange (SABRE) process to hyperpolarize an amine or ammonia and then employ their exchangeable NH protons to relay polarization into the analyte without changing its identity. We found the 1H signal gains reach as high as 650-fold per proton, while for 13C, the corresponding signal gains achieved in a 1H-13C refocused INEPT experiment exceed 570-fold and those in a direct detected 13C measurement 400-fold. Thirty one examples are described to demonstrate the applicability of this technique

Iridium Cyclooctene Complex Forms a Hyperpolarization Transfer Catalyst Before Converting to a Binuclear C-H Bond Activation Product Responsible for Hydrogen Isotope Exchange

[IrCl(COE)2]2 ( 1 ) reacts with pyridine and H2 to form crystallo-graphically characterized IrCl(H)2(COE)(py)2 ( 2 ). 2 undergoes pyridine loss to form 16-electron IrCl(H)2(COE)(py) (3) with equivalent hydride ligands. When this reaction is studied with parahydrogen, 1 efficiently achieves the hyperpolarization of free pyridine (and nicotinamide, nicotine, 5-aminopyrimidine and 3,5-lutudine) via signal amplification by reversible exchange (SABRE) and hence reflects a simple and readily available precatayst for this process. 2 reacts further over 48 hrs at 298 K to form crystallographically characterized (Cl)(H)(py)(μ-Cl)(μ-H)(κ-μ-NC5H4)Ir(H)(py)2 (4). This dimer is shown to be active in the hydrogen isotope exchange process that is used in radiophar-maceutical preparations. Furthermore, while [Ir(H)2(COE)(py)3]PF6 ( 6 ) forms on addition of AgPF6 to 2 , its stability precludes its efficient involvement in SABRE

Achieving Biocompatible SABRE : An in vitro Cytotoxicity Study

Production of a biocompatible hyperpolarized bolus for signal amplification by reversible exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to preclinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Herein, we exemplify the cytotoxicity of the SABRE approach using invitro cell assays. We conclude that the main cause of the observed toxicity is due to the SABRE catalyst. We therefore illustrate two catalyst removal methods: one involving deactivation and ion-exchange chromatography, and the second using biphasic catalysis. These routes produce a bolus suitable for future invivo study

Optimisation of Pyruvate Hyperpolarisation using SABRE by Tuning the Active Magnetisation Transfer Catalyst

Hyperpolarisation techniques such as Signal Amplification By Reversible Exchange (SABRE) can deliver NMR signals several orders of magnitude larger than those derived under Boltzmann conditions. SABRE is able to catalytically transfer latent magnetisation from para-hydrogen to a substrate in reversible exchange via temporary associations with an iridium complex. It has recently been applied to the hyperpolarisation of pyruvate, a substrate often used in many in vivo MRI studies. In this work, we seek to optimise the pyruvate-13C2 signal gains delivered through SABRE by fine tuning the properties of the active polarisation transfer catalyst. We present a detailed study of the effects of varying the carbene and sulfoxide ligands on the formation and behaviour of the active [Ir(H)2(η2-pyruvate)(sulfoxide)(NHC)] catalyst to produce a rational for achieving high pyruvate signal gains in a cheap and refreshable manner. This optimisation approach allows us to achieve signal enhancements of 2140 and 2125-fold for the 1-13C and 2-13C sites respectively of sodium pyruvate-1,2-[13C2]

INTERVENÇÃO DA TERAPIA OCUPACIONAL EM CRIANÇA COM ATROFIA MUSCULAR ESPINHAL NO CONTEXTO HOSPITALAR: UM RELATO DE CASO

Introduction: Palliative care in pediatrics is important when available early, preserving life, patient and family autonomy, treating children who go through a situation of advanced, progressive or chronic disease. The performance of occupational therapy in palliative care contributes to the search for maintaining the meaning of life, enabling pleasurable experiences through play, autonomy, building daily life. Objective: To report the experiences of the resident and occupational therapist regarding the care of a 9-year-old child diagnosed with spinal muscular atrophy (SMA) type 1, in a clinical hospital in the state of Minas Gerais, Brazil. Method: This is a case report, elaborated through occupational therapeutic care in the hospital context with a female child. Results and discussion: During the intervention process it was sought to create a therapeutic bond with the child and their caregivers, the introduction of images for the composition of the communication board and occupational therapeutic care through the sensory stimulation protocol. Through alternative augmentative communication (AAC) and playing in bed, the child interacted through looks, emission of sounds and discrete movements in the upper limbs (MMSS) and lower limbs (LLLL). Final considerations: It was evident the importance of the role of the occupational therapist in improving the quality of life of the child, favoring their autonomy, especially through the use of practices focused on palliative. care, alternative augmentative communication and sensory stimulation.Introducción: Los cuidados paliativos en pediatría son importantes cuando se dispone de ellos temprano, preservando la autonomía de la vida, del paciente y de la familia, tratando a los niños que atraviesan una situación de enfermedad avanzada, progresiva o crónica. La realización de la terapia ocupacional en cuidados paliativos contribuye a la búsqueda de mantener el sentido de la vida, posibilitando experiencias placenteras a través del juego, la autonomía, la construcción de la vida cotidiana. Objetivo: Relatar las experiencias del residente y terapeuta ocupacional sobre el cuidado de un niño de 9 años diagnosticado de atrofia muscular espinal (AME) tipo 1, en un hospital clínico del estado de Minas Gerais, Brasil. Método: Se trata de un relato de caso, elaborado a través de la atención terapéutica ocupacional en el contexto hospitalario con un niño de la niña. Resultados y discusión: Durante el proceso de intervención se buscó crear un vínculo terapéutico con el niño y sus cuidadores, se realizó la introducción de imágenes para la composición del tablero de comunicación y la atención terapéutica ocupacional a través del protocolo de estimulación sensorial. A través de la comunicación aumentativa alternativa (CAA) y el juego en la cama, el niño interactuó a través de miradas, emisión de sonidos y movimientos discretos en las extremidades superiores (MMSS) y miembros inferiores (LLLL). Introdução: Os cuidados paliativos em pediatria são importantes quando disponibilizados precocemente, preservando a vida, a autonomia do paciente e familiares, tratando crianças que passam por uma situação de doença avançada, progressiva ou crônica. A atuação da terapia ocupacional em cuidados paliativos, contribui na busca de manutenção do sentido da vida, possibilitando vivências prazerosas através do brincar, da autonomia, construindo o cotidiano. Objetivo: Relatar as experiências vivenciadas pela residente e terapeuta ocupacional acerca do cuidado com uma criança de 9 anos com o diagnóstico de atrofia muscular espinhal (AME) tipo 1, em um hospital de clínicas do estado de Minas Gerais, Brasil. Método: Trata-se de um relato de caso, elaborado mediante atendimentos terapêuticos ocupacionais no contexto hospitalar com uma criança do sexo feminino. Resultados e discussão: Durante o processo de intervenção buscou-se a criação de vínculo terapêutico com a criança e seus cuidadores, foi realizada a introdução de imagens para composição de prancha de comunicação e atendimentos terapêuticos ocupacionais através do protocolo de estimulação sensorial. Através da comunicação alternativa aumentativa (CAA) e brincar no leito, a criança interagia por meio de olhares, emissão de sons e discretas movimentações em membros superiores (MMSS) e inferiores (MMII). Considerações finais: Ficou evidente a importância do papel do terapeuta ocupacional na melhora da qualidade de vida da criança, favorecendo sua autonomia, especialmente através da utilização de práticas voltadas para os cuidados paliativos, para a comunicação alternativa aumentativa e a estimulação sensorial.Introdução: Os cuidados paliativos em pediatria são importantes quando disponibilizados precocemente, preservando a vida, a autonomia do paciente e familiares, tratando crianças que passam por uma situação de doença avançada, progressiva ou crônica. A atuação da terapia ocupacional em cuidados paliativos, contribui na busca de manutenção do sentido da vida, possibilitando vivências prazerosas através do brincar, da autonomia, construindo o cotidiano. Objetivo: Relatar as experiências vivenciadas pela residente e terapeuta ocupacional acerca do cuidado com uma criança de 9 anos com o diagnóstico de atrofia muscular espinhal (AME) tipo 1, em um hospital de clínicas do estado de Minas Gerais, Brasil. Método: Trata-se de um relato de caso, elaborado mediante atendimentos terapêuticos ocupacionais no contexto hospitalar com uma criança do sexo feminino. Resultados e discussão: Durante o processo de intervenção buscou-se a criação de vínculo terapêutico com a criança e seus cuidadores, foi realizada a introdução de imagens para composição de prancha de comunicação e atendimentos terapêuticos ocupacionais através do protocolo de estimulação sensorial. Através da comunicação alternativa aumentativa (CAA) e brincar no leito, a criança interagia por meio de olhares, emissão de sons e discretas movimentações em membros superiores (MMSS) e inferiores (MMII). Considerações finais: Ficou evidente a importância do papel do terapeuta ocupacional na melhora da qualidade de vida da criança, favorecendo sua autonomia, especialmente através da utilização de práticas voltadas para os cuidados paliativos, para a comunicação alternativa aumentativa e a estimulação sensorial

Direct and Indirect Hyperpolarisation of Amines using Parahydrogen

Nuclear Magnetic Resonance (NMR) and Magnetic Resonance Imaging (MRI) are two widely used techniques for the study of molecules and materials. Hyperpolarisation methods, such as Signal Amplification By Reversible Exchange (SABRE), turn typically weak magnetic resonance responses into strong signals. In this article we detail how it is possible to hyperpolarise the 1H, 13C and 15N nuclei of a range of amines. This involved showing how primary amines form stable but labile complexes of the type [Ir(H)2(IMes)(amine)3]Cl that allow parahydrogen to relay its latent polarisation into the amine. By optimising the temperature and parahydrogen pressure a 1000-fold per proton NH signal gain for deuterated benzylamine is achieved at 9.4 T. Additionally, we show that sterically hindered and electron poor amines that bind poorly to iridium can be hyperpolarised by either employing a co-ligand for complex stabilisation, or harnessing the fact that it is possible to exchange hyperpolarised protons between amines in a mixture, through the recently reported SABRE-RELAY method. These chemical refinements have significant potential to extend the classes of agent that can be hyperpolarised by readily accessible parahydrogen

Achieving High Levels of NMR-Hyperpolarization in Aqueous Media With Minimal Catalyst Contamination via SABRE

Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1H NMR signals in a range of substrates in aqueous media. In order to achieve this outcome phase-transfer-catalysis is exploited which leads to less than less than 1.5 x 10-6 mol dm-3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called CAtalyst Separated Hyperpolarization via Signal Amplification By Reversible Exchange or CASH-SABRE. We illustrate this method for the substrates pyrazine, 5-methylpyrimidine, 4,6-d2-methyl nicotinate, 4,6-d2-nicotinamide and pyridazine achieving 1H signals gains of approximately 790-, 340-, 3000-, 260- and 380-fold per proton at 9.4 T at the time point where phase separation is complete

Achieving Biocompatible SABRE: An invitro Cytotoxicity Study

Production of a biocompatible hyperpolarized bolus for signal amplification by reversible exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to preclinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Herein, we exemplify the cytotoxicity of the SABRE approach using in vitro cell assays. We conclude that the main cause of the observed toxicity is due to the SABRE catalyst. We therefore illustrate two catalyst removal methods: one involving deactivation and ion‐exchange chromatography, and the second using biphasic catalysis. These routes produce a bolus suitable for future in vivo study

Quantification of hyperpolarisation efficiency in SABRE and SABRE-Relay enhanced NMR spectroscopy

para-Hydrogen (p-H 2) induced polarisation (PHIP) is an increasingly popular method for sensitivity enhancement in NMR spectroscopy. Its growing popularity is due in part to the introduction of the signal amplification by reversible exchange (SABRE) method that generates renewable hyperpolarisation in target analytes in seconds. A key benefit of PHIP and SABRE is that p-H 2 can be relatively easily and cheaply produced, with costs increasing with the desired level of p-H 2 purity. In this work, the efficiency of the SABRE polarisation transfer is explored by measuring the level of analyte hyperpolarisation as a function of the level of p-H 2 enrichment. A linear relationship was found between p-H 2 enrichment and analyte 1H hyperpolarisation for a range of molecules, polarisation transfer catalysts, NMR detection fields and for both the SABRE and SABRE-Relay transfer mechanisms over the range 29-99% p-H 2 purity. The gradient of these linear relationships were related to a simple theoretical model to define an overall efficiency parameter, E, that quantifies the net fraction of the available p-H 2 polarisation that is transferred to the target analyte. We find that the efficiency of SABRE is independent of the NMR detection field and exceeds E = 20% for methyl-4,6-d 2-nicotinate when using a previously optimised catalyst system. For the SABRE-Relay transfer mechanism, efficiencies of up to E = 1% were found for 1H polarisation of 1-propanol, when ammonia was used as the polarisation carrier

Iridium α-carboxyimine complexes hyperpolarized with parahydrogen exist in nuclear singlet states before conversion into iridium carbonates

The formation and hyperpolarization of an [Ir(H)2(amine)(IMes)(η2-imine)]Cl complex that can be created in a hyperpolarized nuclear singlet state is reported. These complexes are formed when an equilibrium mixture of pyruvate, amine (benzylamine or phenylethylamine), and the corresponding imine condensation product, react with preformed [Ir(H)2(amine)3(IMes)]Cl. These iridium -carboxyimine complexes exist as two regioisomers differentiated by the position of amine. When examined with para-hydrogen the hydride resonances of the isomer with amine trans to hydride become strongly hyperpolarized. The initial hydride singlet states readily transfer to the corresponding 13C2 state in the labelled imine and exhibit magnetic state lifetimes of up to 11 seconds. Their 13C signals have been detected with up to 420 fold signal gains at 9.4 T. On a longer timescale, and in the absence of H2, further reaction leads to the formation of neutral carbonate containing [Ir(amine)(η2-CO3)(IMes)(η2-imine)]. Complexes are characterized by, IR, MS, NMR and X-ray diffraction