# US 8,784,778 B2 · MRI contrast agents endowed with concentration independent responsiveness

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,784,778 B2
- Document ID: US8784778B2
- Status: Granted
- Kind: B2
- Application number: 11/919,529
- Filed: 2006-04-28
- Published: 2009-01-22
- Granted: 2014-07-22
- Earliest claimed: 2005-04-29
- Assignees: Bracco Imaging S.P.A.
- Applicants: Silvio Aime; Enzo Terreno
- Inventors: Silvio Aime; Enzo Terreno
- Web page: https://patentgrep.com/patent/US8784778B2

## CPC

- A61K 49/085: {conjugated systems}
- A61K 49/10: Organic compounds
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to a method for the in vivo, ex vivo, or in vitro determination of physical or chemical parameters of diagnostic interest by use of a slow tumbling paramagnetic agent that is responsive to changes of said physical or chemical parameter through changes in the R2p/R1p ratio allowing the determination of the said parameter in a manner that is independent on the actual agent concentration.

## Claims

### Claim 1

A method for the in vivo determination, by use of the MRI technique, of the value of a physical or chemical parameter of diagnostic interest selected from the group consisting of temperature, pH, partial pressure of oxygen or carbon dioxide, specific ion or metabolite concentration and specific enzymatic activity in a human or animal body organ, fluid or tissue, said method comprising:
administering to said human or animal a diagnostically effective amount of a slow tumbling paramagnetic agent that is a nano-sized system comprising a liposome entrapping HPDO3A complexed with a paramagnetic metal in an inner aqueous phase at a minimum concentration of 5 mM, and having a mean diameter ≧5 nm;
recording a MRI image;
calculating the R2p/R1p ratio, which acts as a reporter of a change in the parameter of interest; and
determining the value of the parameter of interest through the obtained R2p/R1p ratio.

### Claim 2 (depends on 1)

The method of claim 1, wherein the metal of the paramagnetic complex is a Lanthanide or a Transition metal ion.

### Claim 3 (depends on 2)

The method of claim 2 wherein the metal ion is selected from Fe(2+), Fe(3+), Cu(2+), Cr(3+), Eu(3+), Dy(3+), La(3+), Yb(3+) or Mn(2+) and Gd(3+).

### Claim 4 (depends on 3)

The method of claim 3 wherein the metal ion is Gd(3+).

### Claim 5

A method for the in vivo determination, by use of the MRI technique, of the value of a physical or chemical parameter of diagnostic interest selected from the group consisting of temperature, pH, partial pressure of oxygen or carbon dioxide, specific ion or metabolite concentration and specific enzymatic activity in a human or animal body organ, fluid or tissue, said method comprising:
administering to said human or animal a diagnostically effective amount of a slow tumbling paramagnetic agent that is a macromolecular paramagnetic metal complex endowed with at least one labile water molecule coordinated to the metal center, having a τR value from 1 to 10 ns and a τM value from 0.01 to 1 μs, and including a polyamino acid;
recording a MRI image;
calculating the R2p/R1p ratio, which acts as a reporter of a change in the parameter of interest; and
determining the value of the parameter of interest through the obtained R2p/R1p ratio.

### Claim 6 (depends on 5)

The method of claim 5, wherein the macromolecular paramagnetic metal complex is the Gd-DOTP/polyarginine adduct, or the Gd-II macromolecular adduct.

### Claim 7 (depends on 5)

The method of claim 5, wherein the metal of the paramagnetic complex or agent is a Lanthanide or a Transition metal ion.

### Claim 8 (depends on 7)

The method of claim 7, wherein the metal ion is selected from Fe(2+), Fe(3+), Cu(2+), Cr(3+), Eu(3+), Dy(3+), La(3+), Yb(3+) or Mn(2+) and Gd(3+).

### Claim 9 (depends on 8)

The method of claim 8, wherein the metal ion is Gd(3+).