Para-hydrogen labeled agents and their use in magnetic resonance imaging

• US 20040024307A1
• Filed: 03/24/2003
• Published: 02/05/2004
• Est. Priority Date: 11/12/1997
• Status: Abandoned Application

• Current Assignee: GE Healthcare As (GE Healthcare Technologies, Inc.)
• Original Assignee: Amersham Health (General Electric Company)
• Inventors: Axelsson, Oskar, Mansson, Sven, Petersson, Stefan, Golman, Klaes, Olofsson, Charlotte, Johanneson, Haukur
• Application Number:
  US10/395,002
• Publication Number:
  US 20040024307A1
• Time in Patent Office: Days
• US Class Current: 600/420
• CPC Class Codes: A61K 49/06 Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
• CPC Class Codes: A61K 49/08 characterised by the carrier
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1815 compo-inhalant, e.g. breath tests
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
• CPC Class Codes: G01R 33/62 using double resonance G01R33/24 takes precedence

Abstract

The invention provides a method of magnetic resonance investigation of a sample, said method comprising: (i) reacting para-hydrogen enriched hydrogen with a hydrogenatable MR imaging agent precursor containing a non-hydrogen non-zero nuclear spin nucleus to produce a hydrogenated MR imaging agent; (ii) administering said hydrogenated MR imaging agent to said sample; (iii) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus in said hydrogenated MR imaging agent; (v) detecting magnetic resonance signals of said non-zero nuclear spin nucleus from said sample; and (vi) optionally, generating an image or biological functional data or dynamic flow data from said detected signals.

Claims

1. A method of magnetic resonance investigation of a sample, said method comprising:

(i) reacting para-hydrogen enriched hydrogen with a hydrogenatable MR imaging agent precursor containing a non-hydrogen non zero nuclear spin nucleus to produce a hydrogenated MR imaging agent;

(ii) administering said hydrogenated MR imaging agent to said sample;

(iii) exposing said sample to radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus in said hydrogenated MR imaging agent;

(v) detecting magnetic resonance signals of said non-zero nuclear spin nucleus from said sample; and

(vi) optionally, generating an image or biological functional data or dynamic flow data from said detected signals.

2. A method as claimed in claim 1 wherein said enriched hydrogen has a more than 45% proportion of para-hydrogen.

3. A method as claimed in claim 1 wherein said enriched hydrogen has a more than 90°

proprtion of para-hydrogen.

4. A method as claimed in any of the preceding claims wherein said MR imaging agent precursor contains nuclei selected from F, Li, C, N, Si and P nuclei.

5. A method as claimed in claim 4 wherein said non-zero nuclear spin nucleus is selected from ¹³C, ¹⁵N and ²⁹Si.

6. A method as claimed in claim 5 wherein said non-zero nuclear spin nucleus is ¹³C.

7. A method as claimed in any one of claims 1 to 6 wherein said non-zero nuclear spin nucleus is present at a level greater than its natural isotopic abundance.

8. A method as claimed in any one of claims 1 to 7 wherein said precursor contains a hydrogenatable unsaturated carbon-carbon bond.

9. A method as claimed in claim 8 wherein said non-zero nuclear spin nucleus is present in said precursor one or two bonds distant from said unsaturated bond.

10. A method as claimed in claim 9 wherein said nucleus one or two bonds distant from said unsaturated bond is only directly bonded to atoms which in their predominant isotopic state have zero nuclear spin.

11. A method as claimed in any one of claims 1 to 10 wherein in said MR imaging agent the coupling constant (J) between said non-zero spin nucleus and a proton deriving from para-hydrogen is between 10 and 100 Hz.

12. A method as claimed in claim 11 wherein the nmr signal from said non-zero nuclear spin nucleus in said MR imaging agent has a line width of less than 10 Hz.

13. A method as claimed in claim 12 wherein said MR imaging agent has a molecular weight of less than 500D.

14. A method as claimed in any one of claims 1 to 13 wherein said MR imaging agent is water-soluble.

15. A method as claimed in any one of claims 1 to 14 wherein the chemical shift and/or the coupling constant of said non-zero nuclear spin nucleus in said MR imaging agent is sensitive to the physicochemical environment of said agent.

16. A method as claimed in claim 15 wherein said non-zero nuclear spin nucleus in said MR imaging agent is sensitive to pH and wherein said signals are manipulated to produce an image or data indicative of pH.

17. A method as claimed in any one of claims 1 to 16 wherein step (i) is effected in a magnetic field smaller than the earth'"'"'s ambient field.

18. A method as claimed in claim 17 wherein step (i) is effected in a magnetic field of less than 10 μ

T.

19. A method as claimed in any one of claims 1 to 18 wherein in steps (iii) and (iv) said sample is exposed to a 90°

pulse of radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus followed by 180°

pulses of said radiation, where the time interval between said 180°

pulses is 2τ and

the time interval between said 90°

pulse and the subsequent 180°

C. pulse is τ

plus Δ

τ

where Δ

τ

is 1/(2J) where J is the coupling constant of said non-zero nuclear spin nucleus in said MR imaging agent.

20. A method as claimed in any one of claims 1 to 18 wherein in steps (iii) and (iv) said sample is exposed to a 90°

pulse of radiation of a frequency selected to excite nuclear spin transitions of said non-zero nuclear spin nucleus followed at time intervals of 21 by 180°

pulses of said radiation of the same phase and where for the first n said 180°

pulses said sample is simultaneously exposed to 180°

pulses of radiation of a frequency selected to excite proton nuclear spin transitions, the relation between n and τ

being τ

=1/(4nJ) where J is the coupling constant of said non-zero nuclear spin nucleus in said MR imaging agent.

21. A method as claimed in any one of claims 1 to 19 wherein step (i) is effected using a rhodium-based hydrogenation catalyst.

22. Use of para-hydrogen enriched hydrogen in the manufacture of an MR imaging agent for non-proton MR imaging of a sample.

24. Use as claimed in either one of claims 22 and 23 wherein said imaging is ¹³C NMR imaging of a sample.

23. Use of para-hydrogen enriched hydrogen in MR imaging of a sample.

25. A precursor compound:

(i) containing a hydrogenatable unsaturated bond;

(ii) containing a non-hydrogen non zero nuclear spin nucleus at greater than natural isotopic abundance;

(iii) having a molecular weight below 1000OD; and

(iv) which following hydrogenation has an nmr spectrum for said non-hydrogen non zero nuclear spin nucleus which is a multiplet having a coupling constant relative to one of the hydrogens introduced by hydrogenation of 1 to 300 Hz and having a linewidth of less than 100 Hz,

and wherein when said precursor compound is a ¹³C enriched compound then said nucleus is a quaternary carbon nucleus.

26. A compound as claimed in claim 25 containing the following molecular sub-units:

(i) at least one C═

C or C≡

C bonds;

(ii) a C, N or Si atom separated by one or two bonds from a C═

C or C≡

C bond, bound only to atoms the naturally most abundant isotope form of which has a nuclear spin I=0, and not coupled by a series of covalent bonds to any atoms the naturally most abundant isotopic form of which has I>

½

; and

(iii) at least one water-solubilizing moiety, ie. a functional group which imparts water solubility to the molecule.

27. A reporter compound:

(i) containing at least two protons;

(ii) containing a non-hydrogen non zero nuclear spin nucleus at greater than natural isotopic abundance;

(iii) having a molecular weight below 1000D; and

(iv) having an nmr spectrum for said non-hydrogen non zero nuclear spin nucleus which is a multiplet having a coupling constant relative to one of said at least two protons 1 to 300 Hz and having a linewidth of less than 100 Hz,

and wherein when said reporter compound is a ¹³C enriched compound then said nucleus is a quaternary carbon nucleus.

28. A compound as claimed in claim 27 containing the following molecular sub-units:

(i) at least one CH—

CH or CH═

CH moiety;

(ii) a C, N or Si atom separated by one or two bonds from a CH—

CH or CH═

CH moiety, bound only to atoms the naturally most abundant isotopic form of which has I=0, and not coupled by a series of covalent bounds to any atoms the naturally most abundant isotopic form of which has I>

½

; and

(iii) at least one water-solubilizing moiety, ie. a functional group which imparts water solubility to the molecule.

29. A physiologically tolerable MR imaging agent composition comprising an MR imaging agent together with one or more physiologically tolerable carriers or excipients, said imaging agent containing non-hydrogen nuclei having a nuclear spin of ½

, characterised in that said nuclei are polarized such that their nmr signal intensity is equivalent to a signal intensity achievable in a magnetic field of at least 0.1T.

30. A composition as claimed in claim 29 wherein said nuclei are polarized such that their nmr signal intensity is equivalent to a signal intensity achievable in a magnetic field of at least 100T.

31. A composition as claimed in either one of claims 29 and 30 wherein said nucleus is present in an amount in excess of its natural isotopic abundance.

32. A composition as claimed in claim 31 wherein said nucleus is present in a selected position in the molecular structure of said agent at an abundance of at least 50%.

33. A composition as claimed in any one of claims 29 to 32 wherein T₁ for said nuclei at earth'"'"'s magnetic field and at ambient temperature is at least 1 second.

34. An apparatus for hydrogenation comprising:

a reaction chamber having therein a reaction zone, said reaction chamber having a gas inlet and a gas outlet;

a temperature controller arranged to control the temperature in said reaction zone; and

magnetic shielding arranged about said reaction zone and sufficient to cause the magnetic field in said reaction zone to be less than 10 μ

T.

35. Apparatus as claimed in claim 34 wherein said reaction zone contains a particulate bed and said reaction chamber is provided with a liquid outlet below said bed and a liquid inlet above said bed.

36. Apparatus as claimed in claim 35 comprising:

(i) a reservoir of para-hydrogen enriched hydrogen;

(ii) a reaction chamber having a reaction zone containing a particulate bed and having a first gas inlet below said bed, a first gas outlet above said bed, a solution inlet above said bed and a solution outlet below said bed;

(iii)

a gas conduit from said reservoir to said first gas inlet in the reaction chamber;

(iv) a temperature controller disposed around said reaction chamber at at least said reaction zone; and

(v) a magnetic shield disposed around said reaction chamber at at least said reaction zone.

37. The use of para-hydrogen enriched hydrogen in the manufacture of an MR imaging agent for use in a method of diagnosis involving generation of an MR image by non-proton MR imaging.

38. The use of a hydrogenatable compound containing a non hydrogen non zero nuclear spin nucleus in the manufacture of an MR imaging agent for use in a method of diagnosis involving generation of an MR image by non-proton MR imaging, said manufacture involving hydrogenation of said compound with para-hydrogen enriched hydrogen.