Magnetic resonance imaging agents for detection and delivery of therapeutic agents and detection of physiological substances

• US 20030004236A1
• Filed: 04/22/2002
• Published: 01/02/2003
• Est. Priority Date: 04/20/2001
• Status: Abandoned Application

• Current Assignee: California Institute of Technology
• Original Assignee: California Institute of Technology
• Inventors: Meade, Thomas J.
• Application Number:
  US10/128,131
• Publication Number:
  US 20030004236A1
• Time in Patent Office: Days
• US Class Current: 524/98
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/122 dimers of complexes or complex-forming compounds
• CPC Class Codes: A61K 49/128 comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
• CPC Class Codes: A61K 49/146 the peptide being a polyamino acid, e.g. poly-lysine

Abstract

The invention relates to magnetic resonance imaging moieties, having increased in vivo residence time and amplified MRI signal, comprising a polymer and a plurality of activatable magnetic resonance imaging contrasting agents each attached to the polymer by a cleavable linkage; methods of detecting physiological signals or substances; and methods of drug delivery and drug detection for treatment of diseases.

Claims

1. An imaging moiety comprising a polymer and a plurality of MRI contrast agents each linked to said polymer by a cleavable linkage, wherein at least one of said MRI contrast agents comprises:

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 which 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 in said remaining coordination sites is increased.

2. The imaging moiety according to claim 1, wherein at least one of said MRI contrast agents has the formula:

3. The imaging moiety according to claim 1, wherein at least one of said MRI contrast agents has the formula:

7. The imaging moiety according to any one of claims 1, 2, 3, 4, 5, or 6, wherein said cleavable linkage is an esterase linkage.

8. The imaging moiety according to any one of claims 1, 2, 3, 4, 5, 6, or 7, wherein said MRI agent or said polymer further comprises a targeting moiety.

9. The imaging moiety according to any one of claims 1, 2, 3, 4, 5, 6, 7, or 8, wherein said blocking moiety is a therapeutic blocking moiety.

10. The imaging moiety according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein said blocking moiety is a TAAGM.

4. An imaging moiety comprising a polymer and a plurality of MRI contrast agents each linked to said polymer by a cleavable linker, and wherein at least one of said MRI contrast agents comprises:

a) at least a first paramagnetic metal ion bound to a first complex, said first complex comprising;

i) a first chelator; and

ii) a blocking moiety covalently attached to said first chelator which binds in at least a first coordination site of said first 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 of said first metal ion is increased; and

b) at least a second paramagnetic metal ion bound to a second complex, said second complex comprising;

i) a second chelator; and

ii) a blocking moiety covalently attached to said second chelator which binds in at least a first coordination site of said second 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 of said second metal ion is increased.

5. An imaging moiety comprising a polymer and a plurality of MRI contrast agents each linked to said polymer by a cleavable linker, wherein at least one of said MRI contrast agents comprises at least a first MRI duplex moiety, said MRI duplex moiety comprising:

a) a first chelator comprising a first paramagnetic metal ion;

b) a second chelator comprising a second paramagnetic metal ion;

c) a blocking moiety covalently attached to at least one of said first or said second chelators, said blocking moiety providing at least a first coordination atom of each of said first and said second metal ions and which is capable of interacting with a target substance such that the exchange of water in at least a first coordination site in at least one of said metal ions is increased.

6. An imaging moiety comprising a polymer and a plurality of MRI contrast agents each linked to said polymer by a cleavable linker, and wherein at least one of said MRI contrast agents comprises 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.