# US 5,707,605 A · Magnetic resonance imaging agents for the detection of physiological agents

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- Number: US 5,707,605 A
- Document ID: US5707605A
- Status: Granted
- Kind: A
- Application number: 08/486,968
- Filed: 1995-06-07
- Granted: 1998-01-13
- Earliest claimed: 1995-06-02
- Assignees: Research Corporation Technologies, Inc.
- Inventors: Thomas Meade; Scott Fraser; Russell Jacobs
- Web page: https://patentgrep.com/patent/US5707605A

## CPC

- A61K 49/10: Organic compounds
- A61K 49/085: {conjugated systems}
- A61K 49/103: {the complex-forming compound being acyclic, e.g. DTPA}
- A61K 49/106: {the complex-forming compound being cyclic, e.g. DOTA}
- 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 invention relates to magnetic resonance imaging agents comprising a paramagnetic metal ion bound to a complex wherein said complex comprises a chelator and a blocking moiety convalently attached to said chelator which binds in at least a first coordination site of said metal ion and which is capable of interacting with a target substance such that the exchange of water in at least said first coordination site is increased.

## Claims

### Claim 1

A MRI agent comprising a paramagnetic metal ion bound to a complex, said complex comprising:
a) a chelator; and
b) a blocking moiety covalently attached to said chelator which binds in at least a first coordination site of said metal ion and which is capable of interacting with a target substance such that the exchange of water in at least said first coordination site is increased.

### Claim 2 (depends on 1)

A MRI agent according to claim 1 wherein said chelator is DOTA.

### Claim 3 (depends on 1)

A MRI agent according to claim 1 wherein said chelator is DPTA.

### Claim 4 (depends on 1)

A MRI agent according to claim 1 wherein said paramagnetic metal ion is selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Cr(III) or Dy(III).

### Claim 5 (depends on 1)

A MRI agent according to claim 1 wherein said paramagnetic metal ion is Gd(III).

### Claim 6

A MRI agent comprising
a) a paramagnetic metal ion capable of binding n coordination atoms, wherein said metal ion is bound to a chelator such that said metal ion has coordination atoms at (n-1) or (n-2) coordination sites of said metal ion; and
b) a blocking moiety covalently attached to said chelator that hinders the rapid exchange of water in the remaining coordination site or sites,
wherein said blocking moiety is capable of interacting with a target substance, such that the exchange of water at the remaining coordination site or sites is increased.

### Claim 7 (depends on 6)

A MRI agent according to claim 6 comprising
a) a Gd(III) ion with coordination atoms at 8 coordination sites of said Gd(III) ion; and
b) a blocking moiety which hinders the rapid exchange of water in a 9th coordination site,
wherein said blocking moiety is capable of interacting with a target substance, such that the exchange of water at the 9th coordination site is increased.

### Claim 8 (depends on 6)

A MRI agent according to claim 6 comprising a Gd(III) ion bound to a chelator with 8 coordination atoms.

### Claim 9

A MRI agent having the formula comprising: ##STR21## wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Cr(III) and Dy(III);
A, B, C and D are either single bonds or double bonds;
W, X, Y and Z are --OH, --COO--, --CH.sub.2 OH or --CH.sub.2 COO--;
R.sub.1 -R.sub.12 are hydrogen, alkyl, substituted alkyl, phosphorus moiety, or a blocking moiety;
wherein at least one of R.sub.1 -R.sub.12 is a blocking moiety.

### Claim 10 (depends on 9)

An MRI agent according to claim 9 having the formula comprising: ##STR22## wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Cr(III) and Dy(III);
A, B, C and D are either single bonds or double bonds;
W, X, Y and Z are --OH, --COO--, --CH.sub.2 OH or --CH.sub.2 COO--; and
R.sub.1 -R.sub.12 are hydrogen, alkyl, substituted alkyl, or phosphorus moiety.

### Claim 11

A MRI agent having the formula comprising: ##STR23## wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Cr(III) and Dy(III);
A, B, C, and D are either single or double bonds;
S, T, U and V are --OH, --COO--, --CH2OH, --CH2COO--, or a blocking moiety;
R.sub.1 -R.sub.12 are hydrogen, alkyl, substituted alkyl, or phosphorus moiety;
wherein at least one of S, T, U or V is a blocking moiety.

### Claim 12 (depends on 11)

An MRI agent according to claim 11 having the formula comprising: ##STR24## wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Cr(III) and Dy(III);
A, B, C and D are either single bonds or double bonds;
W, X, Y and Z are --OH, --COO--, --CH.sub.2 OH or --CH.sub.2 COO--; and
R.sub.1 -R.sub.12 are hydrogen, alkyl, substituted alkyl, phosphorus moiety or a blocking moiety; and
R.sub.22, R.sub.23 and R.sub.24 comprise a blocking moiety, with R.sub.23 being a coordination site barrier.

### Claim 13 (depends on 11)

An MRI agent according to claim 11 having the formula comprising: ##STR25## wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Dy(III), and Cr(III);
A, B, C and D are either single bonds or double bonds;
W, X, and Y are --OH, --COO--, --CH.sub.2 OH or --CH.sub.2 COO--; and
R.sub.1 -R.sub.12 are hydrogen, alkyl, substituted alkyl, or phosphorus moiety.

### Claim 14

A MRI agent having the formula comprising: ##STR26## wherein M is a paramagnetic metal ion selected from the group consisting of Gd(III), Fe(III), Mn(II), Yt(III), Cr(III) or Dy(III);
H, I, J, K and L are --OH, --COO--, --CH2OH, --CH2COO--, or a blocking moiety;
R.sub.13 -R.sub.21 are hydrogen, alkyl, substituted alkyl, phosphorus moiety or a blocking moiety;
wherein at least one of R.sub.13 -R.sub.21, H, I, J, K or L is a blocking moiety.

### Claim 15 (depends on 9, 11, 12, 14)

A MRI agent according to claim 9, 11, 12 or 14 wherein said blocking moiety comprises an enzyme substrate.

### Claim 16 (depends on 1)

A method of magnetic resonance imaging of a cell, tissue or patient comprising administering an MRI agent according to claim 1 to a cell, tissue or patient and rendering a magnetic resonance image of said cell, tissue or patient.