Table 2: Catalyst concentrations used in preparing the solution containing While increasing the amount of catalyst used in a reaction, the amount of product produced should vary linearly with the catalyst concentration. With O. Doubling the concentration to 0. The product yield was 8.
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By further increasing the catalyst concentration to 2. The small variation in product yield when changing the catalyst concentration indicates that the H 2 gas availability in the solution could be the limiting step in the reaction FIG.
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The lifetime of the hyperpolarized signal followed an exponential trend as the catalyst concentration increased. The signal was observable for more than s when using a catalyst concentration of O. Doubling the concentration, the lifetime reduced by more than a factor of 3. Further increasing the concentration to 2.
Repeated application of the OPSY experiment would destroy any hyperpolarized signal at a rate of at least 2 N , where N is the number of repetitions. Hyperpolarized signals are shown to persist over a number N larger than 10, however, and over 35 times longer than which were measured to be 5. These results indicate that new product is being continuously formed. Calculations further indicate that after repeated shaking or bubbling, the reaction proceeds to completion. H 2 gas is supplied in an excess to the NMR tube 5mL compressed - 2.
After one sample agitation period the typical yield is 5. This yield could also be achieved by consuming H 2 dissolved in the reaction mixture, if diffusion of H 2 to the reaction center can be considered being the rate limiting step. It is possible that SDS promotes dissolution of H 2.
This shows that the surfactant concentration is crucial in solubilizing H 2 gas and reducing the bottleneck in its transport to the reaction centers. One can imagine this happening by means of reducing the surface tension, thereby providing larger surface area, and by creating hydrophobic micro-environments in the form of micelles.
This circumstance is observable in the present study as a result of the lack of dependence of the reaction rate on catalyst concentrations under the reaction conditions, resulting in the reaction rate responding only to H 2 availability. The observed reaction is therefore highly sensitive to the factors affecting hydrogen transport in solution.
The lifetime increases as the SDS concentration increases up to 7. Above this concentration, the signal lifetime decreased. The prolonged existence of the signal could be related to tiny bubble formation. As the concentration of the surfactant increases, smaller bubble sizes can be produced. The presence of bubbles aids in the diffusion of gas into solution, on the one hand, and provides a reservoir from which hydrogen gas is supplied to the reaction continuously.
Based on the Young-Laplace equation, when the bubble size decreases, the internal pressure increases thus promoting gas diffusion into the surrounding solution. In particular, an NMR or MRI form of the system may be controlled by a hardware processing arrangement aka hardware processor or computing device and may be connected to an output display as well as a storage medium aka hardware storage, physical memory, etc which may contain instructions in the form of computer software or other executable hardware system which may be executed by the processing arrangement The processing arrangement may control the MRI instrument and also obtain the resultant information from a sample according to the present invention.
The processing arrangement may also be used to calculate images, which may then be displayed on output display or may be stored in storage medium The origin of these signals can be traced at least in part to the substantially continuous supply of hydrogen to the reaction. The mechanism preferably includes the appearance of "microstorage" of hydrogen gas within the solution rather than being simply due to increased gas solubility. The use of provides a convenient way for identifying this process, as it would be extremely difficult to measure the reaction progress by using thermally polarized hydrogen.
Using suitable modifications, the technique can be used for at least the following applications:. Fluorine, Deuterium, Oxygen, or other species such as para-H 2 0, which have been polarized via different polarization enhancement methods including the distinction between ortho and para species, optical pumping, or by magnetization transfer from radicals. The application in humans could involve surfactant; but also other microvesicle platforms, such as liposomes.
Thus, stable vesicles can be created that carry p-H to a target site where the hydrogenation reaction may occur in situ to produce hyperpolarized molecules that would act as tracers for MRI imaging, or that could be further metabolized to reveal biochemical processes by NMR spectroscopy. The liposome could also deliver that pre-hydrogenation precursor and catalyst, or these could arrive at a targeted site by other means. All compounds were used without further purification.
The solution was stirred under Argon for 30 minutes at room temperature. Various concentrations of the reagent and surfactant were utilized as described in Table 1. In a septum screw capped NMR tube, 0. One transient was collected for each spectrum. For the p-U. The gradient strengths for the first and second gradients were 6. A single transient was collected for each spectrum. For the conversion from ortho- to parahydrogen, a copper tube containing activated charcoal catalyst was submerged in liquid nitrogen for approximately 15 min.
The initial H 2 gas within the apparatus is purged before introducing -H 2 to the sample at a low magnetic field, approximately 3 m away from the NMR magnet, and at ambient temperature and pressure.
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The typical time required for the sample to go down the bore of the probe was measured as 1 1 s. Once a signal lock was established, the experiment was initiated. Sequential spectra were acquired in a 2-dimensional manner with a 7 second delay between each experiment unless otherwise stated. The sample was placed back at the top of the magnet bore and brought back down to the probe. A new experiment was executed as soon as the signal lock was achieved. The total time from the start of adding to the solution to the establishment of the lock was approximately 40 s.
Thiostrepton FIG 12 is a natural occurring antibiotic from Streptomyces azureus and was only completely biosynthesized recently. It has been widely studied due to unique features, biosynthesis and newly discovered anticancer properties. The quantity 0. The solution was stirred under argon for 30 minutes at room temperature. The OPSY sequence was employed to suppress thermal signals. Spectra from the single pulse experiment were processed by phasing the thermal peaks and the OPSY spectra were unphased. The sample was bubbled for 30 seconds at low magnetic field then inserted into the probe using the automated air lift of the Bruker system.
Once a lock was established the experiment was executed. Total time from the start of the bubbling to the start of the experiment was approximately 50 seconds. There is evidence of the Deala 2 and Deala 3 being the primary amino acid residues being hydrogenated based on the single pulse NMR spectra shown in FIG The signals for Deala l 5. Traces of newly developed alanine groups are seen at ca. Producing hyperpolarized peaks for the products show a typical antiphase pattern, however the intensity is not as strong and the interference of the thermal peaks make it difficult to clearly distinguish the different sites FIG 14A.
In addition to the expected alanine peaks described above, hyperpolarized signals at 4. These peaks may correspond to species that are mono- hydrogenated. At the time of acquisition, it is possible that in addition to complete hydrogenation, only either Deala 2 or Deala 3 or a mixture of both is hydrogenated at one time exhibiting a chemical shift difference from the situation where both are saturated. New peaks emerge at 5. If only Deala 2 or Deala 3 is hydrogenated then CH 2 peak of the other Deala residue would shift since it is now in a different chemical environment.
When completely hydrogenated all peaks corresponding to Deala 2 and Deala 3 disappear indicating all of these sites are saturated. The initial spectrum displays a single peak at After stirring the solution under H 2 atmosphere until complete hydrogenation, a peak at Distinguishing between the two different diastereomers conformations of the alanine using hyperpolarized signals may prove to be useful in determining chemical properties.
It is not intended to be exhaustive or to limit the present invention to the precise form disclosed, and modifications and variations are possible in light of the above teachings or may be acquired from practice of the present invention. The embodiments were chosen and described in order to explain the principles of the present invention and its practical application to enable one skilled in the art to utilize the present invention in various embodiments, and with various modifications, as are suited to the particular use contemplated.
Ref document number : Country of ref document : EP. Kind code of ref document : A2. Ref country code : DE. A method and system for providing an article of manufacture with increased longevity of hyperpolarized 1H signals and other species for NMR spectroscopy and MRI. The material can be in a solution with a surfactant and catalysts added to enhance the persistence of parahydrogen or other species in the form of enhanced solubility, microbubbles or micelles and resultant hydrogenation or other species of the material. What is claimed is: 1. The method as defined in Claim 1 further including the step of adding a surfactant to the material, thereby providing increased persistence of the parahydrogen for the molecular species.
The method as defined in Claim 1 further including the step of including an additive selected from the group of a catalyst, material, and a solvent. The method as defined in Claim 4 further including the step of adjusting parameters selected from the group of adjusting material and surfactant concentration, adjusting solvent concentration and adjusting catalyst concentration. The method as defined in Claim 1 wherein the step of distributing is selected from the group of injection, bubbling and adding appropriate parahydrogen containing material.
The article of manufacture as defined in Claim 8 wherein the increased persistence comprises microbubbles, micelles, or enhanced solubility. The article of manufacture as defined in Claim 9 wherein selected additives are further provided for control of the hydrogenated form of the starting material. The article of manufacture as defined in Claim 8 wherein the material includes adjustable chemical features selected from the group consisting of concentration of the surfactant, polarity of a solvent included in the material and concentration of a catalyst added to the material.
The article of manufacture as defined in Claim 8 wherein the form of increased persistence has an adjustable size for enhancement of the longevity of the NMR and MRI hyperpolarized signal. The article as defined in Claim 8 wherein the hydrogenated form of the starting material includes micelles.
The article of manufacture as defined in Claim 1 1 wherein the solvent comprises methanol and water. The article of manufacture as defined in Claim 8 wherein the surfactant is selected from the group consisting of a cationic surfactant and a neutral surfactant. The system of claim 16, wherein the hyperpolanzation material is selected from the group consisting of 2 H, 13 C, l N, 31 P, 6 Li, and l9 F. The system of claim 16, wherein the hyperpolanzation material is dispersed within the sample container as micelles or microbubbles.
The system of claim 16, wherein the sample container is pressurized to greater than ambient pressure. USP true USB2 en. For example, tracking of fast folding-upon-binding processes of proteins, of in-cell metabolic conversion, 50 enzyme kinetics 51 , pH jumps 52 or biomineralization processes. The general principle in all these applications is to hyperpolarize one interaction partner and to mix it with another interaction partner upon dissolution and transfer to the detection spectrometer followed by real-time NMR detection by either low-dimensional or higher-dimensional ultrafast-detected techniques cf.
Among many excellent examples, one very interesting demonstration by Hilty and co-workers 54 is based on monitoring signal intensities of live anionic chain ends in the polymerization of polystyrene. The d-DNP approach allowed to deduce details about reaction mechanisms and kinetic parameters with high precision. Another example by Abergel and co-workers is based on enzymatic conversion of hyperpolarized metabolites that are mixed upon dissolution with a protein cocktail that mimics parts of the physiological metabolic network.
By analyzing the decay of the educt GLU signal and the signal build-up of the product glucosephosphate G6P with elaborate kinetic models, unprecedented insights e. Crusher gradients are shown in grey. The selected coherence transfer pathway is shown in red. Reproduced with permission from reference In the following, we will give an account of the current state-of-the-art and possible future avenues as well as consequences for possible applications of d-DNP.
The fast decaying and, more importantly, non-renewable nature of DNP-enhanced polarization, once in solution, makes it challenging, and in many cases, impossible, to collect multidimensional NMR spectra with classic time-incremented experiments. An important exception is the HMQC experiment, which is compatible with multi-scan acquisition when implemented with small-tip angle excitation pulses.
This requires the use of convection-compensated diffusion encoding schemes. One limitation of the approach is that many single-scan 2D methods are not compatible with the acquisition of multiple consecutive spectra, while most applications of d-DNP concern time-evolving samples. While the sensitivity penalty associated with the gradient-based acquisition of UF2DNMR may also be a concern, it is counter-balanced in d-DNP by the single vs multi scan nature of the experiment.
Several strategies have also been reported to obtain effectively multidimensional information from a small number of scans, in a way that is compatible with new renewable hyperpolarized signals. For example, Hilty and co-workers have used off resonance 13 C decoupling to scale the apparent 13 C- 1 H coupling in 1 H 1D spectra and provide access to the chemical shift of the coupled carbon for each proton.
A main shortcoming of the d-DNP state-of-the-art is its low sample throughput. Hyperpolarization buildup times are often on the order of hours such that only few experiments are possible per day. To overcome this bottleneck, an instrumentation workaround has recently been developed that allows one to hyperpolarize several samples at the same time, but to dissolve them sequentially such that high experimental repetition rates and multi-shot experiments become possible. It is most likely that these advances will be further improved in the near future by better radiofrequency coil designs.
Another route to improve the throughput would be the use of more efficient PAs that would polarize 1 H-nuclei faster and higher, possibly even at higher temperatures. However recently, it has been demonstrated that a transfer of some solid samples is likewise feasible if the transfer is very rapid, i. After DNP left the solid sample is pushed by pressurized helium through a tube surrounded by a solenoid that maintains a non-zero magnetic field during the transfer within ca. The transfer of solids is a promising method to study the effect of temperature jumps on spin dynamics , as has been shown in a recent example where the para-to-ortho conversion of proton nuclear spins was studied in hyperpolarized water molecules enclosed in C60 fullerene cages H 2 O C Such conversions have been subject to many speculations due to the omnipresence of ortho- and para-water, 75 but have so far been cumbersome to access due to fast proton exchange in water.
Yet, Meier and co-wokers showed that hyperpolarized H 2 O C60 facilitated the access to these states and to study their properties, albeit somewhat artificial conditions. Similar principles can be applied to a plethora of other substrates to study the effect of rapid temperature changes on nuclear polarizations and dynamics. Especially in highly symmetric systems interesting results can be anticipated. Another potential provided by the transfer-then-dissolution approach lies in the study of dissolved gases. The traditional dissolution-then-transfer strategy often suffers from imminent degassing of the solution.
Typically, pressurized helium is used to rapidly push the dissolved sample in the liquid state through a capillary towards the detection NMR spectrometer. This process has undergone intense optimization in recent years. This problem could be overcome by first transferring a hyperpolarized frozen gas pellet to the detection NMR spectrometer and then dissolving it in a suitable liquid in-situ within the spectrometer.
Such, NMR of important substances such as methane, ethylene or 15 N 2 , might become possible. The concept of solid-state transfer of the DNP sample is also currently opening new avenues for remote transport of hyperpolarized samples, which will ultimately make the presence of a DNP machine at the point of the NMR experiment unnecessary. Three proof of concept papers that were recently published indeed demonstrated that transport of hyperpolarized substances could be possible over tens of hours timescales.
This was done either by brute force polarization with PA-free sample formulation 80 , by 1 H- 13 C CP-DNP on sub-micron heterogenous sample formulations 81 , or by thermal annihilation of photo-induced radicals using UV excitation The key in these approaches always is the absence of paramagnetic relaxation during the transport step. It is likely that in the next couple of years, these methods will develop further and enable remote hyperpolarized applications such as real-time metabolic imaging, metabolomics, drug discovery, etc.
The prospect of hyperpolarization in dedicated DNP centers may raise the question of a scaling-up of DNP sample quantities and throughput to much higher extents than today, which may lead to a radical transformation of the DNP instrumentation towards high volume cryostats, high power microwave sources, lower cryogenic fluid consumption, etc. This article tried to outline selected possible applications of d-DNP that might be of interest for a broader community covering physical, chemical and biological research.
Many potentials emerged up to now due to the progress d-DNP has undergone since its invention in , and its future developments seem promising in view of the current state-of-the-art. However, d-DNP remains a complicated method, which is often cumbersome to use, and expert operators are often necessary as many factors need to be considered ranging from low-temperature nuclear physics, over hydrodynamics to rapid NMR detection. A possible avenue for a more widespread application of d-DNP could be hyperpolarization user facilities, where external users can apply and be supported by local expert staff.
If such direction were to be pursued, developments that NMR spectroscopy has undergone in the last 40 years, from an expert method to almost completely automated facilities could be envisaged for future developments of d-DNP. Alternatively, the prospects of transportable hyperpolarization might also definitely eliminate the need for an on-site d-DNP access and simply transform hyperpolarization into a consumable such as PET tracers. Support from the Corsaire metabolomics core facility is also acknowledged.
Introduction Dissolution dynamic nuclear polarization d-DNP is a technique that aims at overcoming experimental limitations of solution state nuclear magnetic resonance NMR spectroscopy imposed by its intrinsically low sensitivity. The d-DNP methodology - merits and pitfalls d-DNP goes back to an invention by Ardenkjaer-Larsen, Golman and co-workers in , 1 who combined DNP of frozen liquids at low-temperatures see 15 and references therein for a detailed discussion of DNP mechanisms with a subsequent dissolution and rapid transition to ambient temperatures to increase signal intensities in liquid state NMR spectroscopy.
Open in a separate window. Figure 1. Figure 2. Applications of d-DNP for chemists, biologists and physicists With a general outline of the d-DNP method at hand, we will highlight in following selected state-of-the-art examples and extrapolate these with respect to potential avenues to future d-DNP applications. High-resolution d-DNP vs. Figure 3. Applications of hyperpolarized NMR to protein interactions As the nature of hyperpolarized protein NMR is somewhat differing from established applications, novel possibilities to investigate protein interactions become conceivable.
Figure 4. Potential of d-DNP for metabolomics Metabolomics is a growing application field that could benefit in the near future from the sensitivity boost offered by d-DNP. Figure 5. Interaction monitoring — Applications to General Chemistry and Biochemistry The potential of real-time monitoring has given rise to some remarkable studies in the recent past.
Figure 6. Perspective on instrumentation and methods developments Like NMR spectroscopy in general, d-DNP devices and techniques are undergoing continuous developments. Sample throughput A main shortcoming of the d-DNP state-of-the-art is its low sample throughput. Solid transfer, liquid transfer — Applications to spin physics Typically for d-DNP, samples are dissolved within the DNP apparatus and subsequently transferred in the liquid state to the detection NMR spectrometer.
Figure 7. Transportable hyperpolarized substrates The concept of solid-state transfer of the DNP sample is also currently opening new avenues for remote transport of hyperpolarized samples, which will ultimately make the presence of a DNP machine at the point of the NMR experiment unnecessary. Outlook This article tried to outline selected possible applications of d-DNP that might be of interest for a broader community covering physical, chemical and biological research.
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