Polarisation transfer via a second metal complex

Abstract

There is described a method for preparation of an imaging medium via transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of: (i) preparing a system containing: parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, said complex including a reversibly bound small molecule transference substrate; applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate; (ii) introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised.

Claims

1. A method for the preparation of an imaging medium via transfer from a hyperpolarised singlet state that is not parahydrogen, said method comprising the steps of: (i) preparing a system containing: parahydrogen; a magnetisation transfer complex, with a molecular symmetry that allows the creation of a singlet state between spin pairs within it, the magnetization transfer complex including a reversibly bound small molecule transference substrate; applying a magnetic field such that hyperpolarisation is transferred into the magnetization transfer complex, including the reversibly bound small molecule transference substrate; (ii) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised; and (iii) providing an imaging medium by: (a) separating the hyperpolarised recipient complex; (b) separating the hyperpolarised recipient substrate; or (c) separating the bound small molecule transference substrate.

2. A method according to claim 1 wherein the hyperpolarisation is achieved by SABRE.

3. A method according to claim 1 wherein the small molecule transference substrate is characterised by a long lifetime in a low magnetic field.

4. A method according to claim 1 wherein the small molecule transference substrate has a singlet state lifetime that will be 20 seconds or more.

5. A method according to claim 2 wherein the method includes the use of a SABRE hyperpolarisation transfer catalyst.

6. A method according to claim 5 wherein a SABRE hyperpolarisation transfer catalyst is placed in an aqueous phase.

7. A method according to claim 1 wherein parahydrogen (p-H.sub.2) gas is added to the system whilst agitating the system.

8. A method according to claim 7 wherein ultrasound is used to agitate the system.

9. A method according to claim 1 wherein the recipient complex contains appropriate .sup.2H, Cl or O labels to maximise the relaxation times of the nuclei spins that are to be hyperpolarised.

10. A method according to claim 1 wherein the small molecule transference substrate contains appropriate .sup.13C or .sup.15N labelling to maximise the proportion of the substrate that can be created in a hyperpolarised NMR visible form in conjunction with appropriate .sup.2H, O or Cl labelling to extend their magnetic state lifetimes.

11. A method according to claim 1 wherein the selected small molecule transference substrate contains spin pairs of appropriate .sup.1H, .sup.13C, .sup.31P, .sup.15N, .sup.29Si or .sup.19F labels to enable the formation of long-lived states between corresponding spin pairs within a molecular scaffold that contains appropriate .sup.2H or Cl labelling to extend their lifetime.

12. A method according to claim 1 wherein the small molecule transference substrate contains spin pairs that are homo-nuclear.

13. A method according to claim 1 wherein the small molecule transference substrate contains spin pairs that are selected from .sup.1H/.sup.1H and .sup.13C/.sup.13C.

14. A method according to claim 1 wherein the small molecule transference substrate contains spin pairs that are hetero-nuclear.

15. A method according to claim 6 wherein the hyperpolarisation transfer catalyst is provided with at least one suitable ligation site enabling it to interact with one or more small molecule transference substrates.

16. A method according to claim 15 wherein the hyperpolarisation transfer catalyst comprises an iridium based catalyst.

17. A method according to claim 6 wherein the hyperpolarization transfer catalyst includes iridium with at least one N-heterocyclic carbene (NHC) ligand.

18. A method according to claim 17 wherein the N-heterocyclic carbene (NHC) ligand is selected from: ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##

19. A method according to claim 1 wherein the small molecule transference substrate is selected from one or more of pyridine (py), pyridazine (pdz), methyl-pyridazine (methyl-pdz), d.sub.2-nicotinate (nic) and Cl.sub.2-d.sub.2-.sup.15N.sub.2-pyridazine.

20. A method according to claim 1 wherein a biphasic element is introduced in order to enable the hyperpolarisation transfer process to be completed in a single vessel.

21. A method according to claim 1 wherein the recipient substrate is selected from the group consisting of nicotinamide, nicotine, pyrazine, 5-methyl pyrimidine, acetate, pyruvate, ethoxide, hydroxide, oxalate or gluconate, sugars, glucose, fructose, urea, amides, amino acids, glutamate, glycine, cysteine, aspartate, GABA (y-aminobutyric acid), nucleotides, vitamins, ascorbic acid, serotonin, penicillin derivatives and sulfonamides.

22. A method of producing a hyperpolarised target substrate imaging medium, said method comprising the steps of: (i) preparing a system containing a magnetisation transfer complex, said complex including a reversibly bound small molecule transference substrate; (ii) adding H.sub.2 or parahydrogen (p-H.sub.2) gas to the system; (iii) applying a magnetic field such that hyperpolarisation is transferred into the transfer complex, including the reversibly bound small molecule transference substrate; (iv) separately or simultaneously introducing a recipient complex capable of binding the small molecule transference substrate, said recipient complex including a recipient substrate, such that the recipient complex and recipient substrate, including the bound transference substrate, is hyperpolarised; and (v) separating the hyperpolarised recipient complex; the hyperpolarised recipient substrate; or the separating the transference substrate to provide a hyperpolarised target substrate imaging medium.

Description

(1) The invention will now be illustrated by way of example only and with reference to the accompanying drawings, in which:

(2) FIG. 1 is a .sup.1H NMR spectrum (a.) and .sup.1H {.sup.31P} NMR spectrum (b.) of [Pt(OTf).sub.2(dppp)] in d.sub.4-methanol, with pyridine;

(3) FIG. 2 is a .sup.31P {.sup.1H} NMR spectrum of [Pt(OTf).sub.2(dppp)] in d.sub.4-methanol, with pyridine;

(4) FIG. 3 is a .sup.31P {.sup.1H} NMR spectrum of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and pyridine;

(5) FIG. 4 is a .sup.1H NMR spectrum of the signals observed in the hydride region of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and pyridine;

(6) FIG. 5 is a comparison of the .sup.1H NMR spectrum collected under Boltzmann conditions (above, with signal multiplied by 8), and the .sup.1H NMR spectrum collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and pyridine;

(7) FIG. 6 is a .sup.31P {.sup.1H} NMR spectrum of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and pyridazine;

(8) FIG. 7 is a comparison of the .sup.1H NMR spectrum collected under Boltzmann conditions (above, with signal multiplied by 4), and the .sup.1H NMR spectrum collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and pyridazine;

(9) FIG. 8 is a .sup.31P {.sup.1H} NMR spectrum of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and d.sub.2-nicotinate;

(10) FIG. 9 is a comparison of the .sup.1H NMR spectrum collected under Boltzmann conditions (above, with signal multiplied by 64), and the .sup.1H NMR spectrum collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and d.sub.2-nicotinate;

(11) FIG. 10 is a comparison of the 4-scan .sup.31P NMR spectra collected under Boltzmann conditions (above, with signal multiplied by 2 in both cases), and the 4-scan .sup.31P NMR spectra collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and d.sub.2-nicotinate (the top set of NMR spectra were collected using a 90° pulse, whereas the bottom set were collected using a 45° pulse);

(12) FIG. 11 is a comparison of the .sup.1H NMR spectra collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and d.sub.2-nicotinate at different polarisation transfer fields;

(13) FIG. 12 is a comparison of the .sup.1H NMR spectrum collected under Boltzmann conditions (above, with signal multiplied by 64), and the .sup.1H NMR spectrum collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pd(OTf).sub.2(dppp)] and d.sub.2-nicotinate;

(14) FIG. 13 is a comparison of the 45° pulse 4-scan .sup.31P NMR spectra collected under Boltzmann conditions (above), and the 45° pulse 4-scan .sup.31P NMR spectra collected under SABRE conditions of a d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pd(OTf).sub.2(dppp)] and d.sub.2-nicotinate; and

(15) FIG. 14 illustrates (a) Hyperpolarized .sup.31P{.sup.1H} NMR spectra of d2-nicotinate mixed with 2 variants of catalyst and dissolved in d.sub.4-methanol solution. The spectra were acquired over 4 transients under optimized (60 G mixing field) SABRE conditions and using a double-quantum filter. Thermally acquired NMR spectra of the same solution in equilibrium when acquired over (b) 4 transients and (c) 100 transients. A net enhancement of ˜25-fold are observed for .sup.31P nuclei attached to [Pd(py).sub.2(dppp)] catalyst.

EXAMPLE 1

Metal Complex 1

(16) The first complex investigated for these purposes is shown in Scheme 1. It is a platinum complex chelated by a bidentate 1,3-bis(diphenylphosphino)propane (dppp) ligand and two triflate ligands. The bis-chelating dppp acts to stabilise the platinum, whilst the triflate ligands are labile and easily displaced by N-heterocycles. Once they have been displaced, they act as anions and stabilise any positive platinum complexes that result.

(17) ##STR00009##

(18) [Pt(OTf).sub.2(dppp)] was synthesised according to the pathway shown in Scheme 2. Platinum dichloride was refluxed in neat benzonitrile to form [Pt(Cl).sub.2(PhCN).sub.2]. The benzonitrile was then displaced with dppp to form [Pt(Cl).sub.2(dppp)]. The chlorides were abstracted using silver triflate to form silver chloride, with the triflate ligands now binding to platinum, forming [Pt(OTf).sub.2(dppp)].

(19) ##STR00010##

EXAMPLE 2

Metal Complex 1 with Pyridine

(20) Displacement of the triflate ligands of [Pt(OTf).sub.2(dppp)] in d.sub.4-methanol with 10 equivalents of pyridine (py) was investigated. NMR spectra were collected to identify any signals corresponding to bound pyridine. The .sup.1H and .sup.1H {.sup.31P} NMR spectra are given in FIGS. 1 and 2.

(21) In the .sup.1H NMR spectrum the large signals at δ 8.57, 7.91 and 7.50 correspond to unbound pyridine in solution. The smaller signals at δ 8.80, 7.71, and 7.24, correspond to the ortho, para, and meta protons of pyridine bound to platinum and those at δ 7.72, 7.50 (hidden beneath unbound pyridine peak), and 7.43 correspond to the ortho, para, and meta protons of the phenyl rings in dppp.

(22) The .sup.31P {.sup.1H} NMR spectrum contains just one singlet at δ −14.68 with a J.sub.PPt splitting of 3000 Hz. The singlet nature of the .sup.31P NMR signal confirms that the platinum complex has C.sub.2v symmetry, which can only be the case when both triflate ligands are replaced with pyridine, forming [Pt(py).sub.2(dppp)][OTf].sub.2, shown in Scheme 3.

(23) ##STR00011##

(24) This evidence supports the potential for [Pt(OTf).sub.2(dppp)] to bind to polarised N-heterocycles which may transfer polarisation to the ligands at platinum.

EXAMPLE 3

Metal Complex 1 with pyridine and [IrCl(COD)(IMes)]

(25) ##STR00012##

(26) Exchange of hyperpolarised pyridine ligands of [Ir(H).sub.2(IMes)(py).sub.3]Cl with [Pt(py).sub.2(dppp)] in d.sub.4-methanol with 10 equivalents of pyridine (py) was investigated. NMR spectra were first collected to identify any different platinum complexes that formed in the presence of [IrCl(COD)(IMes)] signals. There were no obvious differences in the .sup.31P {.sup.1H} NMR spectrum collected with [IrCl(COD)(IMes)] present, therefore the same [Pt(py).sub.2(dppp)] complex was present in solution.

(27) On ‘activation’ of the iridium complex with para-H.sub.2, the .sup.31P {.sup.1H} NMR spectrum changed due to the formation of a new platinum complex. In addition to the original singlet observed at δ −14.68, two doublets were also observed at δ −5.09 and −14.49, each with J.sub.PP=28.1 Hz. These likely correspond to the platinum complex given in Scheme 5, where now only one pyridine molecule is bound to platinum. The characteristic signals for the active iridium complex, shown in Scheme 4, were also observed and the corresponding hydride is shown in FIG. 4 (δ −22.64). A second hydride is also present at δ −22.58, which is likely to correspond to the hydride ligand in the same complex, but where one hydride ligand is now replaced with deuterium.

(28) ##STR00013##

(29) Replacing the hydrogen gas in the sample with para-H.sub.2 (3 bar) led to the enhancement of all the signals in the aromatic region, thus the platinum complexes in solution must be hyperpolarised. An example spectrum is shown in FIG. 5.

(30) Unfortunately, no polarisation transfer into the .sup.31P nuclei was observed.

EXAMPLE 4

Metal Complex 1 with Pyridazine and [IrCl(COD)(IMes)]

(31) Exchange of hyperpolarised pyridazine ligands of [Ir(H).sub.2(IMes)(pdz).sub.3]Cl with [Pt(py).sub.2(dppp)] in d.sub.4-methanol with 10 equivalents of pyridazine (pdz) was also investigated due to an increasing interest in the formation of singlet states on similar pyridazine ligands. NMR spectra were first collected to identify any different platinum complexes that formed in the presence of [IrCl(COD)(IMes)] and pyridazine. Although the .sup.1H NMR spectra are more complicated, due to breaking of the C.sub.2, symmetry of pyridazine on ligation of one nitrogen atom, the .sup.31P {.sup.1H} NMR spectrum (FIG. 6) confirm that a single platinum complex has formed, that contains two chemically inequivalent phosphorus nuclei. This is likely to be the complex given in Scheme 6, which is the pyridazine analogue of the pyridine complex mentioned previously.

(32) ##STR00014##

(33) Addition of para-H.sub.2 resulted in the formation of [Ir(H).sub.2(IMes)(pdz).sub.3]Cl, which was identified by its characteristic .sup.1H NMR hydride signal at δ−21.35. As with pyridine, polarisation transferred into all the aromatic signals corresponding to bound and free pyridazine (FIG. 7), which suggests that the bound pyridazine protons of [Pt(OTf)(pdz)(dppp)][OTf] are enhanced using this method.

(34) Unfortunately, polarisation transfer to the .sup.31P nuclei of [Pt(OTf)(pdz)(dppp)][OTf] was not observed by .sup.31P {.sup.1H} NMR.

EXAMPLE 5

Metal Complex 1 with d.SUB.2.-nicotinate and [IrCl(COD)(IMes)]

(35) Transfer of polarisation from d.sub.2-nicotinate (Scheme7) onto the platinum complex was investigated. Deuterated nicotinate is already known to polarise effectively when using [IrCl(COD)(IMes)] and the polarised protons have long T.sub.1 values, which makes this N-heterocycle a promising candidate for polarisation transfer to the platinum complex.

(36) ##STR00015##

(37) [IrCl(COD)(IMes)] and [Pt(py).sub.2(dppp)] were dissolved in d.sub.4-methanol with 10 equivalents of d.sub.2-nicotinate. NMR spectra were collected prior to the addition of para-H.sub.2. As with the analogous pyridazine solution, only one platinum complex is present with two chemically inequivalent phosphorus nuclei (see FIG. 8). This likely corresponds to [Pt(OTf)(dppp)(nic)]OTf, shown in Scheme, where nic is d.sub.2-nicotinate.

(38) ##STR00016##

(39) Addition of para-H.sub.2 resulted in the formation of [Ir(H).sub.2(IMes)(nic).sub.3]Cl, which was identified by its characteristic .sup.1H NMR hydride signal at δ −22.7. Polarisation transferred into all the aromatic signals corresponding to bound and free pyridazine (FIG. 9), which suggests that the bound nicotinate protons of [Pt(OTf)(nic)(dppp)] [OTf] are enhanced using this method.

(40) Further proof of polarisation transfer into the platinum complex was established through the collection of enhanced .sup.31P NMR spectra (FIG. 10). Using both 45 and 90° pulses lead to similar enhancements (˜5 fold per phosphorus nucleus), but the 90° pulse gave more polarisation on the phosphorus signals that are coupled to platinum.

(41) This d.sub.4-methanol solution containing [IrCl(COD)(IMes)], [Pt(OTf).sub.2(dppp)] and d.sub.2-nicotinate is stable. After several weeks, there were no signs of degradation by NMR, nor was any precipitate observed to form. This NMR solution mixture was therefore injected into flow apparatus that allows the effect of the polarisation transfer field to be investigated. The aim was to optimise polarisation transfer to phosphorus, however enhanced phosphorus signals were not observed when using the flow apparatus, both at low field (0 and 10G) and at the optimum field used to transfer polarisation to the protons of nicotinate.

(42) The optimum polarisation transfer fields for polarisation transfer to the protons of d.sub.2-nicotinate were found to be 40 and 110 G, where each proton was enhanced by ˜1000-fold. Interestingly, in between these fields, phase changes were observed in the signals that corresponded to free nicotinate. This resulted in the signal cancelling, as can be seen in FIG. 11, thus although 65 G is typically the optimum polarisation transfer field for the protons of free N-heterocycles, it is not optimum here.

EXAMPLE 6

Metal Complex 2 with d.SUB.2.-nicotinate and [IrCl(COD)(IMes)]

(43) The palladium analogue of the platinum complex was synthesised using the same reaction scheme shown in Scheme 2, but where platinum is now replaced with palladium. As palladium is not NMR active, the T.sub.1 values of the phosphorus nuclei in the [Pd(OTf).sub.2(dppp)] complex are predicted to be longer due to less dipole-dipole relaxation.

(44) [IrCl(COD)(IMes)] and [Pd(py).sub.2(dppp)] were dissolved in d.sub.4-methanol with 10 equivalents of d.sub.2-nicotinate. NMR spectra were collected prior to the addition of para-H.sub.2, however the signals in both the .sup.1H and .sup.31P {.sup.1H} NMR spectra were broad, presumably due to fast exchange in solution. On addition of para-H.sub.2, all of the aromatic signals were enhanced (FIG. 12), and the hydride signal at δ−22.7 (characteristic of [Ir(H).sub.2(IMes)(nic).sub.3]Cl) was observed.

(45) As with the platinum analogue, polarisation transfer into the phosphorus nuclei on the palladium complex was observed when using both a 45° (FIG. 13), and a 90° pulse. There was no obvious difference in the signal enhancements observed on changing the pulse length from 90° to 45°, in both cases the .sup.31P enhancement was ˜7-fold. This enhancement proves that polarisation has transferred from para-H.sub.2, to nicotinate, to the phosphorus nuclei in dppp.

(46) Again, over several weeks the sample was stable there was no evidence for degradation in the NMR spectra. A small amount of dark precipitate was observed to form in the NMR tube, however as no free dppp ligand can be detected in the NMR spectra, this could be a small amount of AgCl side-product left over from synthesis. Due to this precipitate, this solution has not been investigated using the flow apparatus.

(47) The maximum enhancement for 1H (standard SABRE process) is at 60 G. Using [IrCl(COD)(IMes)] and [Pd(py).sub.2(dppp)] dissolved in d.sub.4-methanol with 10 equivalents of d.sub.2-nicotinate a 600-800 fold enhancement was observed (FIG. 14), via flow method at this field. The enhancement for the bound peaks is around 100-folds compared to free-thermal peaks.

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