Composition comprising acetic anhydride and a gadolinium complex, and method for the use in hyperpolarisation in MRI analysis

Patent metadata

Field	Value
Publication number	US-9693828-B2
Application number	US-201214362447-A
Country	US
Kind code	B2
Filing date	Dec 3, 2012
Priority date	Dec 5, 2011
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

The present invention generally relates to a composition comprising acetic anhydride, a DNP agent and a gadolinium complex and its use for the preparation of hyperpolarised imaging agent for MR diagnostic analysis.

First claim

The invention claimed is:

1. A composition comprising:
acetic anhydride,
a DNP agent, and
a gadolinium complex of formula (A):

wherein:
R′, R″ and R′″ are independently selected from: optionally substituted phenyl, (C 1 -C 6 )alkylene-phenyl and C 6 -C 10 heterocyclic ring.

2. A composition according to claim 1 wherein the gadolinium complex is [[α1,α4,α7-tris [(phenylmethoxy)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetato(4-)]gadolinate(1-)]hydrogen, of formula (I):

3. A composition according to claim 1 wherein the DNP agent is a compound of formula (B):

wherein:
R the same or different, represents a straight chain or branched C1-C6-alkyl group optionally deuterated and substituted by one or more hydroxyl group, methoxy group, or a group of formula —(CH 2 ) n —O—R2, wherein n is 1, 2 or 3;
R2 is a straight or branched C1-C6-alkyl group, optionally substituted by one or more hydroxyl groups or methoxy groups; and
X is independently selected from: H, an alkaline metal, an optionally substituted straight or branched C1-C6 alkyl group, optionally interrupted by Sulphur or Oxygen atoms, and an optionally substituted aliphatic or aromatic C3-C8 cyclic group or hetero group.

4. A composition according to claim 2 wherein the DNP agent is a compound of formula (B):

wherein:
R the same or different, represents a straight chain or branched C1-C6-alkyl group optionally deuterated and substituted by one or more hydroxyl group, methoxy group, or a group of formula —(CH 2 ) n —O—R2, wherein n is 1, 2 or 3;
R2 is a straight or branched C1-C6-alkyl group, optionally substituted by one or more hydroxyl groups or methoxy groups; and
X is independently selected from: H, an alkaline metal, an optionally substituted straight or branched C1-C6 alkyl group, optionally interrupted by Sulphur or Oxygen atoms, and an optionally substituted aliphatic or aromatic C3-C8 cyclic group or hetero group.

5. A composition according to claim 3 wherein in formula (B) R is CH3or CD3.

6. A composition according to claim 4 wherein in formula (B) R is CH3or CD3.

7. A process for the preparation of liquid hyperpolarised acetic acid, said process comprising; the steps of:
a) subjecting the composition as defined in claim 1 to dynamic nuclear polarisation (DNP) to obtain hyperpolarised acetic anhydride; and
b) contacting the hyperpolarised acetic anhydride of step a) with an aqueous carrier to transform said hyperpolarised acetic anhydride into hyperpolarised acetic acid; and optionally
c) removing the gadolinium complex of formula (A) and the DNP agent.

8. A process for the preparation of liquid hyperpolarised acetic acid, said process comprising, the steps of:
a) subjecting the composition as defined in claim 2 to dynamic nuclear polarisation (DNP) to obtain hyperpolarised acetic anhydride; and
b) contacting the hyperpolarised acetic anhydride of step a) with an aqueous carrier to transform said hyperpolarised acetic anhydride into hyperpolarised acetic acid; and optionally
c) removing the gadolinium complex of formula (A) and the DNP agent.

9. A process for the preparation of liquid hyperpolarised acetic acid, said process comprising the steps of:
a) subjecting the composition as defined in claim 3 to dynamic nuclear polarisation (DNP) to obtain hyperpolarised acetic anhydride; and
b) contacting the hyperpolarised acetic anhydride of step a) with an aqueous carrier to transform said hyperpolarised acetic anhydride into hvperpolarised acetic acid; and optionally
c) removing the gadolinium complex of formula (A) and the DNP agent.

10. A process for the preparation of liquid hyperpolarised acetic acid, said process comprising the steps of:
a) subjecting the composition as defined in claim 4 to dynamic nuclear polarisation (DNP) to obtain hyperpolarised acetic anhydride; and
b) contacting the hyperpolarised acetic anhydride of step a) with an aqueous carrier to transform said hyperpolarised acetic anhydride into hyperpolarised acetic acid; and optionally
c) removing the gadolinium complex of formula (A) and the DNP agent.

11. A process for the preparation of liquid hyperpolarised acetic acid, said process comprising the steps of:
a) subjecting the composition as defined in claim 5 to dynamic nuclear polarisation (DNP) to obtain hyperpolarised acetic anhydride; and
b) contacting the hyperpolarised acetic anhydride of step a) with an aqueous carrier to transform said hyperpolarised acetic anhydride into hyperpolarised acetic acid; and optionally
c) removing the gadolinium complex of formula (A) and the DNP agent.

12. A process for the preparation of liquid hyperpolarised acetic acid, said process comprising the steps of:
a) subjecting the composition as defined in claim 6 to dynamic nuclear polarisation (DNP) to obtain hyperpolarised acetic anhydride; and
b) contacting the hyperpolarised acetic anhydride of step a) with an aqueous carrier to transform said hyperpolarised acetic anhydride into hyperpolarised acetic acid; and optionally
c) removing the gadolinium complex of formula (A) and the DNP agent.

13. The method of claim 7 further comprising the steps of:
a)administering the hyperpolarised acetic acid to a subject;
b)submitting the subject, which has been positioned in a MRI system, to a radiation frequency selected to excite nuclear spin transitions in a non-zero nuclear spin nuclei of said hyperpolarised acetic acid; and
c)recording a MR signal from said excited nuclei.

14. The method of claim 8 further comprising the steps of:
a) administering the hyperpolarised acetic acid to a subject;
b) submitting the subject, which has been positioned in a MRI system, to a radiation frequency selected to excite nuclear spin transitions in a non-zero nuclear spin nuclei of said hyperpolarised acetic acid; and
c) recording a MR signal from said excited nuclei.

15. The method of claim 9 further comprising the steps of:
a) administering the hyperpolarised acetic acid to a subject;
b) submitting the subject, which has been positioned in a MRI system, to a radiation frequency selected to excite nuclear spin transitions in a non-zero nuclear spin nuclei of said hyperpolarised acetic acid; and
c) recording a MR signal form a said excited nuclei.

16. The method of claim 10 further comprising the steps of:
a) administering the hyperpolarised acetic acid to a subject;
b) submitting the subject, which has been positioned in a MRI system, to a radiation frequency selected to excite nuclear spin transitions in a non-zero nuclear spin nuclei of said hyperpolarised acetic acid; and
c) recording a MR signal from said excited nuclei.

17. The method of claim 11 further comprising the steps of:
a) administering the hyerpolarised acetic acid to a subject;
b) submitting the subject, which has been positioned in a MRI system, to a radiation frequency selected to excite nuclear spin transitions in a non-zero nuclear spin nuclei of said hyperpolarised acetic acid; and
c) recording a MR signal from said excited nuclei.

18. The method of claim 12 further comprising the steps of:
a) administeri

Assignees

• Bracco Imaging Spa

Inventors

• Aime Silvio
• Colombo Serra Sonia
• Jensen Pernille Rose
• Karlsson Magnus
• Lerche Mathilde H
• Tedoldi Fabio
• Visigalli Massimo

Classifications

• G01R33/286

  involving passive visualization of interventional instruments, i.e. making the instrument visible as part of the normal MR process · CPC title

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K49/108

  the metal complex being Gd-DOTA · CPC title

• A61B2090/374

  NMR or MRI · CPC title

• A61B34/20 Primary

  Surgical navigation systems; Devices for tracking or guiding surgical instruments, e.g. for frameless stereotaxis · CPC title