# US 7,608,249 B2 · Enhanced substrate imaging by reversible binding to a paramagnetic complex

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- Number: US 7,608,249 B2
- Document ID: US7608249B2
- Status: Granted
- Kind: B2
- Application number: 10/492,231
- Filed: 2002-10-09
- Published: 2004-12-23
- Granted: 2009-10-27
- Earliest claimed: 2001-10-11
- Assignees: Bracco Imaging S.P.A.
- Inventors: Enzo Terreno; Silvio Aime; Mauro Botta
- Web page: https://patentgrep.com/patent/US7608249B2

## CPC

- A61K 49/085: {conjugated systems}
- A61K 49/103: {the complex-forming compound being acyclic, e.g. DTPA}
- C07D 257/02: not condensed with other rings
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention relates to a method for the Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Imaging of a substrate molecule different from water wherein the NMR signal is enhanced by a reversible binding of the substrate molecule to a paramagnetic chelate complex, as well as to the use of a paramagnetic chelate complex in said method and the pharmaceutical composition for use therein.

## Claims

### Claim 1

A method of obtaining images comprising:
administering a paramagnetic chelate complex comprising a lanthanide metal ion with atomic number ranging from 58 to 70, or a transition metal ion with atomic number from 21 to 29 and from 42 and 44 and a chelating ligand selected from, 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazaciclododecane-1,4,7-tris-[(aminocarbonyl)methyl], and 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazaciclododecane-1,4,7-triacetic acid, or a physiologically acceptable salt thereof, which non covalently binds with a binding strength of at least 10M-1 to a substrate molecule, thereby shortening the relaxation times of the magnetic nuclei of the substrate molecule by forming a non-covalent reversible binding between the substrate and the paramagnetic chelate complex and
registering the image of the substrate molecule in a human or animal body organ or tissue by use of the Magnetic Resonance Imaging techniques,
wherein said image is obtained in vivo and
wherein said substrate molecule is an endogenous substrate selected from lactate, citrate, carbonate, phosphate, pyruvate, natural amino-acids, oxalate, tartrate, succinate, choline, creatine, acetate, and malonate in a human or animal body organ or tissue.

### Claim 2 (depends on 1)

The method of claim 1 for the Magnetic Resonance Imaging of lactate, wherein said paramagnetic chelate complex is 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazaciclododecane-1,4,7-tris-[(aminocarbonyl)methyl], and 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazaciclododecane-1,4,7-triacetic acid or a physiologically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of claim 1 for the Magnetic Resonance Imaging of citrate, wherein said paramagnetic chelate complex is the gadolinium complex of 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-tris-[(aminocarbonyl)methyl]chelating ligand or a physiologically acceptable salt thereof).

### Claim 4 (depends on 1)

The method of claim 1 for the Magnetic Resonance Imaging of tartrate, wherein said paramagnetic chelate complex is the gadolinium complex of 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid or a physiologically acceptable salt thereof.

### Claim 5 (depends on 2)

The method of claim 2 for the detection of brain tumors.

### Claim 6 (depends on 3)

The method of claim 3 for the detection of prostatic carcinoma.

### Claim 7 (depends on 1)

The method of claim 1 wherein the paramagnetic ion is selected from the group consisting of: gadolinium (III), iron (II), iron (III), manganese (II), manganese (III), chromium (III), cobalt (III), copper (II), nickel (II), dysprosium (III), erbium (III), terbium (III), holmium (III), thulium (III), ytterbium (III), europium (II) and europium (III).

### Claim 8 (depends on 7)

The method of claim 7 wherein the paramagnetic ion is Gadolinium (III), manganese (II) or manganese (III).

### Claim 9

A compound which is selected from: 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-tris-[(aminocarbonyl)methyl], the gadolinium complex thereof optionally in form of the ternary complex with citrate, 10-[(3-methoxyphenyl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid and the gadolinium complex thereof.

### Claim 10 (depends on 9)

A pharmaceutical composition comprising, together with a physiologically tolerable carrier, a compound of claim 9 or a physiologically acceptable salt thereof.