# US 2009/0022668 A1 · Mri contrast agents endowed with concentration independent responsiveness

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- Number: US 2009/0022668 A1
- Document ID: US20090022668A1
- Status: Published application
- Kind: A1
- Application number: 11/919,529
- Filed: 2006-04-28
- Published: 2009-01-22
- Earliest claimed: 2005-04-29
- Assignees: Bracco Imaging Folli S.p.A.
- Inventors: Silvio Aime; Enzo Terreno
- Web page: https://patentgrep.com/patent/US20090022668A1

## 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 a physical or chemical parameter of diagnostic interest 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 responsive to microenvironmental changes of said parameter through changes in the R2p/R1p ratio;
recording a MRI; and
calculating the R2p/R1p ratio responsive for said parameter.

### Claim 2 (depends on 1)

The method of claim 1 wherein the slow tumbling paramagnetic agent is a macromolecular paramagnetic metal complex endowed with at least one labile water molecule coordinated to the metal center and having a τR value ≧1 ns and a τM value from 0.01 to 1 μs.

### Claim 3 (depends on 2)

The method of claim 2 wherein τR of the macromolecular paramagnetic complex is from 1 to 10 ns.

### Claim 4 (depends on 1)

The method of claim 1 wherein the slow tumbling paramagnetic agent is a nano-sized system entrapping a paramagnetic metal complex.

### Claim 5 (depends on 4)

The method of claim 4 wherein the nano-sized system has a mean diameter ≧5 nm, and the concentration of the entrapped complex is ≧5 mM.

### Claim 6 (depends on 1)

The method of claim 1, wherein the measured R2p/R1p ratio acts as a reporter of a change in the parameter of interest.

### Claim 7 (depends on 2, 4)

The method of any one of claims 2 or 4, 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+).

### Claim 10 (depends on 2, 3)

The method of any one of claims 2 or 3 wherein the macromolecular paramagnetic metal complex is the (Gd-1)4/Avidin adduct, or the Gd-DOTP/polyarginine adduct, or the Gd-II macromolecular adduct.

### Claim 11 (depends on 4, 5)

The method of any one of claims 4 or 5 wherein the paramagnetic nano-sized system is a liposome entrapping Gd-HPDO3A.

### Claim 12 (depends on 1, 2, 4)

The method of any one of claims 1, 2 or 4, wherein the physical or chemical parameter of diagnostic interest is selected from temperature, pH, partial pressure of oxygen or carbon dioxide, specific ion or metabolite concentration, specific enzymatic activity.

### Claim 13

A diagnostic composition comprising at least one slow tumbling paramagnetic agent endowed with a τR value from 1 to 10 ns and a τM value from 0.01 to 1 μs and for which the rotational mobility τR and/or the mean residence lifetime τM of the mobile protons dipolarly coupled to their metal center and/or the longitudinal electronic relaxation time τ1S are dependent on the physical or chemical parameter of diagnostic interest, for use in determining the said parameter in a human or animal body organ or tissue, by use of MR Imaging.

### Claim 14 (depends on 13)

A diagnostic composition according to claim 13 wherein the slow tumbling paramagnetic agent is a nano-sized system with a mean diameter ≧5 nm entrapping a paramagentic metal complex at a concentration ≧5 mM for which the size of the system and/or the magnetic susceptibility effects are dependent on a parameter of diagnostic interest.

### Claim 15

A slow tumbling paramagnetic agent responsive to changes of a given physical or chemical parameter of diagnostic interest through changes in R2p/R1p ratio for use in the determination of the said parameter in a human or animal body organ, fluid or tissue, by use of the MRI, in a manner which is independent on the absolute concentration of said administered agent.

### Claim 16 (depends on 15)

A slow tumbling paramagnetic agent according to claim 15 comprising a macromolecular paramagnetic metal complex endowed with both dipolarly coupled protons and τR value ≧1 ns, and wherein the rotational mobility τR and/or the mean residence lifetime τM of the mobile protons dipolarly coupled to their metal center and/or their longitudinal electronic relaxation time τ1S are dependent on a physical or chemical parameter of diagnostic interest.

### Claim 17 (depends on 15)

A slow tumbling paramagnetic agent according to claim 15 comprising a nano-sized system entrapping a paramagnetic metal complex for which the transverse relaxation rate is affected by magnetic susceptibility effects and for which the size and/or the extent of the magnetic susceptibility are dependent on a physical or chemical parameter or a physiological or metabolic process of diagnostic interest.

### Claim 18 (depends on 16)

A slow tumbling paramagnetic agent according to claim 16, wherein the metal ion is gadolinium, having a τR value from 1 to 10 ns and a τM from 0.01 to 1 μs.

### Claim 19

A compound selected from the following:
the (Gd-1)4/Avidin adduct wherein Gd-1 has the following structure
the macromolecular adduct Gd-II.

### Claim 20 (depends on 19)

The compound of claim 19 for use as a contrast agent.