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IDEI PCE 168/2017

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The information to be found on the project page is the following:

  1. Project full title; Reservoirs and magnetisation transfer for hyperpolarised nuclear spins.
  2. The acronym; It’s not necessary
  3. Project summary;

The information conveyed by magnetic resonance relies on the amount of the magnetisation used and on the way this collective magnetic state is preserved during the experiment. Recently, significant progress was made in summoning larger amounts of polarised nuclear spins using sparse unpaired electrons, via the procedure known as Dynamic Nuclear Polarisation (DNP). This procedure is a revolution for NMR, a spectroscopy that was previously notorious for its lack of sensitivity, as it can enhance the signal-to-noise by factors up to 10’000-fold. Though powerful, the new applications of this very recent technique remain challenging to implement, especially due to issues related to the lifetimes of hyperpolarised magnetisation. Conveying enhanced magnetisation to the desired molecular location, the intended interaction site within a cell, or the intended imaging site within the body is critically dependent on its characteristic lifetime. Improvements in magnetisation lifetimes can be designed even in a standard NMR context, optimizing molecular probes and excitation techniques before implementation in a DNP context. The NMR methods proposed in this project are intended to decisively contribute, at this point, to the transformation of enhanced magnetic resonance into a more versatile technique. New ways of preserving magnetisation are put forward. Optimal spin eigenstates to preserve magnetisation in molecules with several coupled magnetic nuclei will be theoretically evaluated and experimentally tested. Long-lived magnetisation can travel long distances almost unaltered – that is, preserving its original amplitude, and, therefore, detection sensitivity. This can lead to applications ranging from studies of the mechanism and dynamics of biomolecular interactions, and up to magnetic-resonance angiography of endogenous molecular probes in humans.

  1. General objectives and expected results to be achieved;

Characterization of molecules, polarization offset transfer, using J couplings; creating a strategy adapted to support magnetization in the chosen molecules; control of polarization transfer in proposed molecules; publication and dissemination of the results.

  1. The coordinating institution, possibly with the institution logo and contact details; It’s not necessary
  2. Consortium component; It’s not necessary
  3. Contracting Authority (project financier); UEFISCDI
  4. Project duration;12.07.2017 – 31.12.2019
  5. The activities and responsibilities of each participant (the implementation plan);

The projected team consists of four members with diverse competences and at various stages of advancement in their professional career. One of the team members, recruited as a post-doctoral researcher will bring expertise in DNP substrates and state-of-the-art theory and experiments. This researcher will use their know-how to also perform DNP-enhanced experiments on local molecules in EU laboratories. A key researcher is Anamaria Hanganu, well-anchored scientist in the NMR environment at the University of Bucharest. The person will be in charge of the spectroscopic characterization of molecules and keeping the project close to the environment: identifying molecular probes for the production of which the expertise of local synthesis chemists can have a major impact and valorizing the outputs of the project for other groups: using enhanced lifetimes for slow diffusion and slow exchange experiments. Master students will be trained within and contribute to the project. NB: a PhD student may join the project, after the first year, once administrative procedures linked to doctoral guidance for the PI are finalized. The student will have a scholarship from distinct funds.

  1. The results obtained at each stage of the project (public report, result indicators, etc.);

Stage 1

In this project stage the following were achieved:

  1. A strategy has been developed to support magnetization in molecules containing an aromatic ring adjacent to nitrogen nuclei.
  2. Models have been established for polarization transfer study for purchased substances: pyruvate, lactate, Ala-Gly, glutamine, glutamic acid, aspartic acid, asparagine. For the same type of experiment, a number of compounds were also purchased: glycine 1-13C, glucose 6-13C and asparagine 4-13

Broad description of the experiments performed and results presentation:

Long-lived states (LLS) of nuclear spin order were used for the first time to probe interactions between molecules and diamagnetic metal ions. LLS are currently employed in two contexts: (i) hyperpolarized NMR experiments using dissolution Dynamic Nuclear Polarization (d-DNP) or parahydrogen for sensitivity enhancement: in these experiments, LLS are used to maintain hyperpolarized magnetization and can subsequently detect changes in the chemical environment of the polarized molecular probe; (ii) NMR experiments that start from thermal-equilibrium magnetization to encode LLS. In this context, the LLS information can be complementary to data obtained from standard longitudinal relaxation rates.

Oxadiazole derivatives are electron transporting and luminescent molecules that have recognized potential for the fabrication of organic light-emitting diodes (OLEDs). Such interactions were initially described in oxadiazole derivatives bearing substituents that feature donor groups able to coordinate metal ions. It was recently observed that the two nitrogen atoms of the oxadiazole ring itself feature interactions with silver that can lead to the formation of coordination polymers even without the aid of any other donor group. It is therefore worth investigating the interactions between the two adjacent nitrogens of the heterocycle and metal ions.

NMR experiments were recorded in a field B0 = 11.75 T using a Bruker Avance spectrometer operating at the 1H Larmor frequency m0 = 500.13 MHz. The temperature was T = 25 0C. NMR spectra were acquired using TopSpin and spectral intensities extracted using Topspin, Mestrec, and Matlab functions. The relaxation curves were fitted using the dedicated Matlab function and errors were calculated from a Monte-Carlo analysis performed using 100 points for each fit.

Natural-abundance nitrogen-15 spectra were recorded to probe the effect of the nonsymmetrical substituents on the 15N shifts. Direct 15N detection was first tested on a standard formamide sample. Proton reference spectra and LLS experiments were recorded

with 64 transients and a recovery delay of 20 s, proton T1 experiments were recorded using 16 transients and a recovery delay of 25 s, and nitrogen detection was performed with 8192 transients and a 15 s recovery delay.

NMR 1H and 15N spectra recorded for the studied oxadiazole molecule is shown in Figure 1:

Figure 1. Oxodiazole: 2-(4-metoxifenil)-5-(p-tolil)-1,3,4-oxadiazol.

Figure 1. Oxodiazole: 2-(4-metoxifenil)-5-(p-tolil)-1,3,4-oxadiazol.

Structural characterization of oxodiazole was performed by recording the 1D and 2D-NMR spectra (Figures 2A-2G).

1H-NMR (500.13 MHz, MeOD-d4, δ ppm, J Hz): 8.02 (d, 2H, H-S, H-S’, 8.5 Hz), 7.96 (d, 2H, H-R, H-R’, 8.0 Hz), 7.37 (d, 2H, H-K, H-K’, 8.0 Hz), 7.09 (d, 2H, H-I, H-I’, 8.5 Hz), 3.87 (s, 3H, A3), 2.41 (s, 3H, H-B3).

13C-NMR (125.77 MHz, MeOD-d4, δ ppm): 165.7 (CQ4), 165.6 (CQ3), 164.0 (CQ1), 143.8 (CQ6), 130.8 (C-K, C-K’), 129.67 (C-S, C-S’), 127.6 (C-R, C-R’), 121.7 (CQ5), 116.7 (CQ2), 115.6 (C-I, C-I’), 55.9 (C-A3), 21.7 (C-B3).

Figure 2A. 1D 1H NMR spectra of oxodiazole (blank)

Figure 2A. 1D 1H NMR spectra of oxodiazole (blank)

Figure 2B. 1D 13C NMR spectra of oxodiazole (blank)

Figure 2B. 1D 13C NMR spectra of oxodiazole (blank)

Figure 2C. 1D Apt-NMR spectra of oxodiazole (blank)

Figure 2C. 1D Apt-NMR spectra of oxodiazole (blank)

Figure 2E. 2D HMQC-NMR spectra of oxodiazole (blank)

Figure 2E. 2D HMQC-NMR spectra of oxodiazole (blank)

Figure 2F. 2D HMB-NMR spectra of oxodiazole (blank)

Figure 2F. 2D HMB-NMR spectra of oxodiazole (blank)

Figure 2G. 2D HMBC- NMR spectra of oxodiazole (blank)

Figure 2G. 2D HMBC- NMR spectra of oxodiazole (blank)

 

A strategy was developed to study the interactions between organic compound (oxodiazole) and metal ions (silver Ag (I)) using LLS method. A stock solution of CF3SO3Ag was prepared. Portions of this solution were added to the NMR tube over the oxodiazole solution (Figure 3).

Figure 3. 1D 1H NMR spectra of: A – control sample of oxadiazol (blank); B–0.25:1[CF3SO3Ag]:[ oxadiazol]; C–0.5:1 [CF3SO3Ag]:[ oxadiazol]; D–0.75:1 [CF3SO3Ag]:[ oxadiazol].

Figure 3. 1D 1H NMR spectra of: A – control sample of oxadiazol (blank); B–0.25:1[CF3SO3Ag]:[ oxadiazol]; C–0.5:1 [CF3SO3Ag]:[ oxadiazol]; D–0.75:1 [CF3SO3Ag]:[ oxadiazol].

LLS with relaxation time constants (‘lifetimes’) up to TLLS = 1/RLLS ~ 10 s were detected on aromatic protons in oxadiazole and were used to probe molecular interactions with Ag(I) ions. The pulse sequence used for LLS excitation and detection is shown in Fig. 4, alongside a standard inversion-recovery experiment designed to measure the spin-lattice relaxation rate constant.

Figure 4: (A) NMR experiment used to probe LLS. (B) LLS relaxation profile obtained for free oxadiazole dissolved in methanol at B0 = 11.75 T, spins (K, R). (C) NMR inversion -recovery experiment. (D) Inversion-recovery curve detected on spin R in the free oxadiazole derivative.

Figure 4: (A) NMR experiment used to probe LLS. (B) LLS relaxation profile obtained for free oxadiazole dissolved in methanol at B0 = 11.75 T, spins (K, R). (C) NMR inversion -recovery experiment. (D) Inversion-recovery curve detected on spin R in the free oxadiazole derivative.

Table 1 lists the longitudinal relaxation constants of oxadiazole derivatives.

Table 1. Values of R1 and RLLS for free compound 1 and mixtures of compound 1 with increasing concentrations of Ag(I) salt (from 0.25 molar equivalents to 0.75 molar equivalents).

R1 (s-1)RLLS (s-1)Detected on signals of spin R, spin I (in bold) and, respectively, detected on signals of spin K, spin S (in italics)
Eq. de Ag(I)00.250.50.7500.250.50.75
Spin R0.22±0.010.27±0.010.30±0.010.31±0.010.096±0.0050.139±0.0050.152±0.0040.166±0.005
Spin K0.29±0.010.36±0.010.40±0.010.41±0.01(0.094±0.005)(0.138±0.005)(0.153±0.005)(0.162±0.006)
Spin I0.33±0.010.40±0.010.43±0.020.45±0.010.122±0.0040.172±0.0080.179±0.0080.204±0.012
Spin S0.22±0.010.27±0.010.30±0.010.32±0.01(0.110±0.010)(0.150±0.020)(0.171±0.008)(0.180±0.016)

The longitudinal relaxation time constants T1=1/R1, on the order of five seconds, are significantly shorter than the detected LLS lifetimes. Sample degassing extends all relaxation rate constants by a factor of 2. The R1 rates measured for oxadiazole in presence of silver ions increase by cu 0.05-0.07 s-1 (ca. 20%) upon addition of 0.25 molar equivalents of silver salt and remain almost the same at higher Ag(I) concentrations. As far as LLS are concerned, the addition of silver(I) to the oxadiazole solution leads to a increase by 70% in LLS relaxation rates, RLLS, of the (I, S) pair and by 65% for the (S,K) pair. Therefore, variations in RLLS = 1 / TLLS upon silver addition offer significantly improved contrast compared to variations in R1 = 1 / T1, making LLS a sensitive probe for mapping the interaction (Fig. 5 and Fig.6).

Figure 5. LLS relaxation rate constants of the aromatic protons of free oxadiazole (blue), on a 1:0.25 molar mixture of oxadiazole and silver salt (green), on a 1:0.50 molar mixture of oxadiazole and silver salt (yellow) and on a 1:0.75 molar mixture of oxadiazole and silver salt (red) at B0 = 11.75 T.

Figure 5. LLS relaxation rate constants of the aromatic protons of free oxadiazole (blue), on a 1:0.25 molar mixture of oxadiazole and silver salt (green), on a 1:0.50 molar mixture of oxadiazole and silver salt (yellow) and on a 1:0.75 molar mixture of oxadiazole and silver salt (red) at B0 = 11.75 T.

Figure 6. T1 relaxation rate constants of the aromatic protons of free oxadiazole (blue), on a 1:0.25 molar mixture of oxadiazole and silver(I) salt (green), on a 1:0.50 molar mixture of oxadiazole and silver(I) salt (yellow) and on a 1:0.75 molar mixture of oxadiazole and silver(I) salt (red) at B0 = 11.75.

Figure 6. T1 relaxation rate constants of the aromatic protons of free oxadiazole (blue), on a 1:0.25 molar mixture of oxadiazole and silver(I) salt (green), on a 1:0.50 molar mixture of oxadiazole and silver(I) salt (yellow) and on a 1:0.75 molar mixture of oxadiazole and silver(I) salt (red) at B0 = 11.75.

The interaction between an oxadiazole derivative and silver(I) ions was sensed using proton LLS. The relaxation rate constants of LLS excited on hydrogen nuclei situated in the immediate vicinity of donor atoms were seen to be more sensitive probes than standard NMR longitudinal relaxation for the interaction.

Hyperpolarization of the detected nuclear spins can offer additional insights on this type of interactions at low sample concentrations.

The experimental results obtained at this stage were disseminated by publishing an article in Journal of Magnetic Resonance (FI = 2.432):

Cristina Stavarache, Anamaria Hanganu, Anca Paun, Codruta Paraschivescu, Mihaela Matache, Paul R. Vasos, “Long-lived states detect interactions between small molecules and diamagnetic metal ions”, Journal of Magnetic Resonance, 2017, 284, 15-19, http://dx.doi.org/10.1016/j.jmr.2017.09.001.

Also, the preliminary results obtained were disseminated through oral presentations within the following scientific manifestations by the members of the research team:

  • Paul Vasos, “Enhanced NMR to follow enzymatic reactions in living cells”, Oral presentation, 20th Romanian International Conference on Chemistry and Chemical Engineering, 6-9 September 2017, Poiana Brasov, Romania.
  • Aude Sadet, CRUK Cambridge Institute, Workshop, 6-9 December 2017, Molecular probes useful for in vivo MRI experiments
  1. Description / presentation of various events within the project (exp: conferences, seminars, partner meetings, etc.);
  • Paul Vasos, “Enhanced NMR to follow enzymatic reactions in living cells”, Oral presentation, 20th Romanian International Conference on Chemistry and Chemical Engineering, 6-9 September 2017, Poiana Brasov, Romania.
  • Aude Sadet, CRUK Cambridge Institute, Workshop, 6-9 December 2017, Molecular probes useful for in vivo MRI experiments
  • Aude Sadet, Glasgow, United Kingdom 25 – 27 June 2018,Artificial Water Channels Faraday Discussion
  1. Links to various other pages of interest to the visitor. Ex: legislative pages in the project field of activity, similar or complementary projects, webpages of the partner institutions in the project, etc;
  2. Contact details of the project director; Vasos Paul

e-mail: paul.vasos@icub.unibuc.ro

Phone: 021.3159249

  1. Final results of the project. It’s not necessary

Project code: PN-III-P4-ID-PCE-2016-0887

  • Cristina Stavarache, Anamaria Hanganu, Anca Paun, Codruta Paraschivescu, Mihaela Matache, Paul R. Vasos, “Long-lived states detect interactions between small molecules and diamagnetic metal ions”, Journal of Magnetic Resonance, 2017, 284, 15-19, http://dx.doi.org/10.1016/j.jmr.2017.09.001.

https://www.ncbi.nlm.nih.gov/pubmed/28938134

  • Viorel Vasile Nastasa, Cristina Stavarache, Anamaria Hanganu, Adina Coroaba, Alina Nicolescu, Calin Deleanu, Aude Sadet, Paul Vasos, “Hyperpolarised NMR to Follow Water Proton Transport through Membrane Channels via Exchange with Biomolecules”, Faraday Discussions, 2018, DOI: 10.1039/C8FD00021B.

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