Process for the preparation of hyperpolarized derivatives for use in MRI analysis

Patent metadata

Field	Value
Publication number	US-9511154-B2
Application number	US-201214350478-A
Country	US
Kind code	B2
Filing date	Oct 11, 2012
Priority date	Oct 12, 2011
Publication date	Dec 6, 2016
Grant date	Dec 6, 2016

Abstract

The present invention relates to a process for the preparation of aqueous solutions of hyperpolarized carboxylic organic acids ready for use in in-vivo MR diagnostic imaging, and the use of the corresponding anhydrides or esters as glass-forming agents.

First claim

The invention claimed is:

1. A process for preparing a hyperpolarized carboxylic organic acid for use in a method of magnetic resonance investigation, which comprises the steps of:
a) preparing a mixture of said carboxylic organic acid and an anhydride or ester precursor thereof that upon contact with an aqueous carrier provides at least said acid;
b) subjecting the mixture of step a) to dynamic nuclear polarisation (DNP) methods to obtain a hyperpolarized mixture; and
c) contacting the hyperpolarized mixture of step b) with an aqueous carrier to transform the precursor into the hyperpolarized carboxylic organic acid.

2. The process of claim 1 , wherein the mixture comprises a carboxylic organic acid of formula (A):
R—COOH  (A);

and
at least an ester derivative of formula (II)
R—COOR′  (II),

wherein R is selected from: C1-C20 linear or branched alkyl group, saturated or unsaturated, and R′ is a C1-C6 linear or branched alkylic group, optionally substituted.

3. The process according to claim 2 wherein, R′ is ethyl.

4. The process of claim 2 wherein: the acid is succinic acid, and the ester is mono or di-ethyl succinate, or the acid is 2-oxoglutaric acid and the ester is 2-oxoglutarate mono or di-ethyl ester, or the acid is malic acid and the ester is mono or di-ethylmalate, or the acid is pyroglutamic acid and the ester is pyroglutamate ethyl ester, or the acid is 2-oxothiazolidine-4-carboxylic acid and the ester is 2-oxothiazolidine-4-carboxylate ethyl ester.

5. The process of claim 1 , wherein the mixture comprises a carboxylic acid of formula (A):
R—COOH  (A);

and
at least a symmetric anhydride of formula (I):

wherein R and R′ are the same, selected from: C1-C20 linear or branched alkyl group, saturated or unsaturated, optionally substituted.

6. The process according to claim 5 , wherein the acid/anhydride mixture is selected from the group consisting of: acetic acid/acetic anhydride, propionic acid/propionic anhydride and butyric acid/butyric anhydride.

7. The process according to claim 1 , wherein the mixture comprises a carboxylic acid of formula (A):
R—COOH  (A); and

at least a mixed anhydride of formula (I):

wherein R and R′ are differently and independently selected from: C1-C20 linear or branched alkyl group, saturated or unsaturated, optionally substituted.

8. The process according to claim 1 , wherein the precursor and the carboxylic organic acid are present in the mixture in a 1:1 molar ratio.

9. The process according to claim 1 , wherein said transformation of the precursor according to step c) is effected by hydrolysis of the precursor.

10. The process according to claim 9 , wherein the precursor is an ester, and the hydrolysis is performed in the presence of an enzyme.

Assignees

• Bracco Imaging Spa

Inventors

• Aime Silvio
• Colombo Serra Sonia
• Giovenzana Giovanni Battista
• Jensen Pernille Rose
• Karlsson Magnus
• Lerche Mathilde H
• Tedoldi Fabio

Classifications

• G01R33/5601

  involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent · CPC title

• A61K49/10 Primary

  Organic compounds · CPC title

• C07B59/001

  Acyclic or carbocyclic compounds · CPC title