Process for the preparation of hyperpolarized carboxylate compounds

Patent metadata

Field	Value
Publication number	US-10695448-B2
Application number	US-201916443183-A
Country	US
Kind code	B2
Filing date	Jun 17, 2019
Priority date	Oct 28, 2013
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

The present invention relates to a process for the preparation of aqueous solutions of [1- 13 C]-hyperpolarized carboxylate containing molecules of diagnostic interest that comprises parahydrogenating with molecular parahydrogen unsaturated alkenyl or alkynyl esters of the concerned 13 C-carboxylate molecules.

First claim

The invention claimed is:

1. A para-hydrogenated ester of formula (III)
R—C*(O)—O—R″  (III)

in which:
C* denotes a naturally 13 C enriched or, optionally, 13 C labeled carboxylate carbon atom;
R is a C 1 -C 5 linear or branched alkyl chain which is optionally interrupted by, or substituted with, one or more groups selected from the group consisting of carbonyl (—CO—), hydroxyl (—OH), amino (—NHR 1 ), halogen atom, halo-alkyl group, carbocyclic aliphatic moiety optionally substituted by one or more hydroxyl groups, and aromatic moiety optionally substituted by one or more hydroxyl groups:

R 1 is H or an amino protecting group; and
R″ is a parahydrogenated allyl residue,
or a physiologically acceptable salt thereof.

2. A method for diagnostic MR imaging of a body organ, region, fluid or tissue, or for MR assessment of a biological parameter or metabolic profile of diagnostic interest in an individual patient that comprises:
i) obtaining an unsaturated alkenyl or alkynyl ester of a carboxylate containing molecule of formula (II)
R—C*(O)—O—R′  (II)

in which:
C* denotes the naturally 13 C enriched or, optionally, 13 C labeled carboxylate carbon atom undergoing 13 C hyperpolarization;
R′ is an allyl of formula —CH 2 —CH═CH 2 or a propargyl residue of formula —CH 2 —C≡CH;
R is a C 1 -C 5 linear or branched alkyl chain, which is optionally interrupted by, or substituted with, one or more groups selected from the group consisting of carbonyl (—CO—), hydroxyl (—OH), amino (—NHR 1 ), halogen atom, halo-alkyl group, carbocyclic aliphatic moiety optionally substituted by one or more hydroxyl groups, and aromatic moiety optionally substituted by one or more hydroxyl groups; and
R 1 is H or an amino protecting group,
or a physiologically acceptable salt thereof, and

reacting said unsaturated ester with a molecular para-hydrogen in an aqueous solvent, optionally including an amount from 10% to 30% of an organic solvent selected from short-chain alcohol or acetone, and in the presence of a water soluble hydrogenation catalyst, to produce a para-hydrogenated ester with an [1- 13 C]-carboxylate carbon atom and added polarized hydrogen;
ii) inducing a polarization transfer from the added polarized hydrogen to the [1- 13 C]-carboxylate carbon atom of the para-hydrogenated ester to produce an [1- 13 C]-hyperpolarized ester; and
iii) hydrolyzing the [1- 13 C]-hyperpolarized ester by adding to the aqueous solution of the [1- 13 C]-hyperpolarized ester obtained at step ii) a base promoting its hydrolysis, to give the aqueous solution of the [1- 13 C]-hyperpolarized carboxylate containing molecule of interest, and collecting an aqueous solution of the [1- 13 C]-hyperpolarized carboxylate containing molecule, or of the corresponding [1- 13 C]-hyperpolarized carboxylic acid;
(iv) removing the hydrogenation catalyst and the optional organic solvent from the obtained aqueous solution, to give the aqueous solution of the [1- 13 C]-hyperpolarized carboxylate containing molecule of interest ready for use in an in vivo application;
v) administering the aqueous solution to the individual patient, or contacting the aqueous solution with an ex vivo sample of the body organ, region, fluid or tissue of the individual patient;
vi) exposing the administered individual patient, or the contacted ex vivo sample to a radiation frequency allowing to excite the hyperpolarized [1- 13 C]-carboxylate carbon atom of the [1- 13 C]-hyperpolarized carboxylate containing molecule;
vii) recording a signal intensity generated by the excited [1- 13 C]-carboxylate carbon atom of the [1- 13 C]-hyperpolarized carboxylate containing molecule and/or of a metabolite or catabolite thereof; and
viii) obtaining an image of the individual patient body organ, region, or tissue, or a suitable estimate of the biological parameter or metabolic profile of interest from the signal intensity.

3. A method for diagnostic MR imaging of a body organ, region, fluid, or tissue, or for MR assessment of a biological parameter or metabolic profile of diagnostic interest in an individual patient comprising:
i) obtaining an unsaturated alkenyl or alkynyl ester of a carboxylate containing molecule of formula (II)
R—C*(O)—O—R′  (II)

in which:
C* denotes the naturally 13 C enriched or, optionally, 13 C labeled carboxylate carbon atom undergoing 13 C hyperpolarization;
R′ is an allyl of formula —CH 2 —CH═CH 2 or a propargyl residue of formula —CH 2 —C≡CH;
R is a C 1 -C 5 linear or branched alkyl chain, which is optionally interrupted by, or substituted with, one or more groups selected from the group consisting of carbonyl (—CO—), hydroxyl (—OH), amino (—NHR 1 ), halogen atom, halo-alkyl group, carbocyclic aliphatic moiety optionally substituted by one or more hydroxyl groups, and aromatic moiety optionally substituted by one or more hydroxyl groups; and
R 1 is H or an amino protecting group,

or a physiologically acceptable salt thereof, and reacting the unsaturated ester with a molecular para-hydrogen in an organic solvent, or a suitable mixture of organic solvents, and in the presence of a hydrogenation catalyst soluble in the organic solvent and insoluble in an aqueous solvent;
ii) inducing a polarization transfer from the added polarized hydrogen to the [1- 13 C]-carboxylate carbon atom of the para-hydrogenated ester to produce an [1- 13 C]-hyperpolarized ester;
iii) diluting the organic solution of the [1- 13 C]-hyperpolarized ester obtained at step ii) with an aqueous solution promoting the hydrolysis of the ester to the corresponding water soluble [1- 13 C]-hyperpolarized carboxylate containing molecule, or the corresponding carboxylic acid, and then collecting, by phase transfer extraction, the aqueous solution of the [1- 13 C]-hyperpolarized compound of interest, which is ready for use in an in vivo application;
iv) administering the collected aqueous solution to the individual patient, or contacting the aqueous solution with an ex vivo sample of the body organ, fluid, or tissue of the individual patient;
v) exposing the administered individual patient, or the contacted ex vivo sample to a radiation frequency allowing to excite the hyperpolarized [1- 13 C]-carboxylate carbon atom of the [1- 13 C]-hyperpolarized carboxylate containing molecule;
vi) recording a signal intensity generated by the excited hyperpolarized [1- 13 C]-carboxylate carbon atom of the [1- 13 C]-hyperpolarized carboxylate containing molecule and/or of any suitable metabolite or catabolite thereof; and
vii) obtaining an image of the individual patient body, organ, region, or tissue, or a suitable estimate of the biological parameter or metabolic profile of interest from the signal intensity.

4. The ester according to claim 1 , wherein R is a hydroxyethyl residue of formula CH 3 CH(OH)—.

Assignees

• Bracco Imaging Spa

Inventors

• Aime Silvio
• Boi Tommaso
• Cerutti Erika
• Reineri Francesca

Classifications

• A61B5/055

  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging · CPC title

• A61K49/10 Primary

  Organic compounds · CPC title

• G01R33/5601

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

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title

• C07C51/09

  from carboxylic acid esters or lactones · CPC title