Process for the preparation of aqueous solutions of hyperpolarized molecules

Patent metadata

Field	Value
Publication number	US-8961933-B2
Application number	US-200913122209-A
Country	US
Kind code	B2
Filing date	Sep 30, 2009
Priority date	Oct 3, 2008
Publication date	Feb 24, 2015
Grant date	Feb 24, 2015

Abstract

The invention relates to a one-step process for the preparation of aqueous solutions of hyperpolarized molecules in which, in a single step, the said hyperpolarized molecules are separated from the crude solution by means of a fast phase-transfer extraction and isolated in an impurity-free aqueous solution, ready for use in the MRI diagnostic imaging of organs, region or tissues of the human or animal body.

First claim

The invention claimed is:

1. A one-step process for the preparation of an aqueous solution of hyperpolarized molecules that comprises para-hydrogenating a suitable unsaturated substrate in an organic solvent immiscible with water and in the presence of a catalyst soluble in the organic solvent but insoluble in water and isolating the hyperpolarized molecule through a phase transfer extraction, by diluting the crude reaction medium with an aqueous solution and collecting the aqueous phase containing the hyperpolarized molecule ready for use in vivo MRI applications.

2. A process according to claim 1 wherein the unsaturated substrate is insoluble or scarcely water soluble and the corresponding hyperpolarized molecule is water soluble.

3. A process according to claim 2 wherein the unsaturated substrate comprises a suitable alkynyl or alkenyl group and the corresponding para-hydrogenated molecule comprises the corresponding alkenyl or saturated alkyl group, respectively.

4. A process according to claim 3 wherein the unsaturated substrate further comprises a hydrolysable group.

5. A process according to claim 1 wherein the organic solvent immiscible with water is selected from an organochlorinated solvent, an aromatic or etheral solvent, or an aliphatic hydrocarbon, ethyl acetate or a long chain alcohol.

6. A process according to claim 1 wherein the unsaturated substrate is labelled with a non-proton nucleus having nuclear spin ½.

7. A process according to claim 6 wherein the unsaturated substrate is 13 C or 15 N enriched.

8. A process according to claim 1 wherein the catalyst is [Bis(diphenylphosphinobutane)(1,5-cyclooctadiene)]Rh(I).

9. A process according to claim 1 wherein:
a) a suitable unsaturated substrate is solubilised in an organic solvent immiscible with water and hydrogenated with para-hydrogen, in the presence of a catalyst soluble in the organic solvent but insoluble in water, to give the corresponding para-hydrogenated compound, and
b) the para-hydrogenated compound is isolated from the organic reaction medium by diluting it with water, or with an aqueous solution, and then collecting the aqueous phase containing the hyperpolarized product; or alternatively,
c) the para-hydrogenated compound obtained in step a) is quickly and selectively converted into a water soluble derivative thereof that is isolated from the organic reaction medium by diluting it with water, or with an aqueous solution, and then collecting the aqueous phase containing the hyperpolarized derivative compound.

10. A process according to claim 9 wherein the para-hydrogenated molecule obtained in step a) is rapidly and selectively converted into a water soluble derivative thereof by diluting the organic reaction medium with water or an aqueous solution.

11. A process according to claim 9 in which, additionally, a suitable field cycling is applied to the parahydrogenated molecule obtained in the step a) of the process so as to give the corresponding molecule with a net polarization on a suitable heteronucleus.

12. A process according to claim 11 in which the heteronucleus is a 13 C or a 15 N enriched nucleus.

13. A MR contrast agent consisting of the aqueous phase collected from the process of any one of claim 1 , 9 or 11 .

14. A method for the diagnostic visualization of a human or animal body organ, region, fluid or tissue by use of Magnetic Resonance Imaging comprising:
i) parahydrogenating a MR imaging agent precursor in an organic solvent immiscible with water and in the presence of a catalyst soluble into the organic solvent but insoluble in water by use of the PHIP technique, optionally applying a suitable field cycling to give the corresponding MR agent with a net hyperpolarization on a non-proton nucleus, diluting the organic reaction medium with water or an aqueous solution and collecting, by means of a phase transfer extraction, the aqueous phase containing the hyperpolarized MR agent ready for use in in vivo MRI applications;
ii) administering the said aqueous phase to a human or animal body;
iii) exposing the said human or animal body to a radiation frequency allowing to excite the hyperpolarized nucleus in the said MR agent; and
iv) recording the signal generated by the excited nucleus and generating an image of the body region or the biological data of interest from the said signal.

Assignees

• Reineri Francesca
• Viale Alessandra
• Giovenzana Giovanni Battista
• Santelia Daniela
• Dastru′ Walter
• Gobetto Roberto
• Aime Silvio
• Uggeri Fulvio
• Bracco Imaging Spa

Inventors

• Reineri Francesca
• Viale Alessandra
• Giovenzana Giovanni Battista
• Santelia Daniela
• Dastru′ Walter
• Gobetto Roberto
• Aime Silvio
• Uggeri Fulvio

Classifications

• A61K49/10 Primary

  Organic compounds · CPC title