# US 11,027,028 B2 · Manganese complexes with substituted bisphosphonates useful as imaging and therapeutic agents

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- Number: US 11,027,028 B2
- Document ID: US11027028B2
- Status: Granted
- Kind: B2
- Application number: 16/095,076
- Filed: 2016-10-26
- Published: 2019-04-18
- Granted: 2021-06-08
- Earliest claimed: 2015-04-24
- Assignees: Duke University
- Applicants: Duke University
- Inventors: Christopher David Lascola
- Web page: https://patentgrep.com/patent/US11027028B2

## CPC

- A61K 49/103: {the complex-forming compound being acyclic, e.g. DTPA}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/663: Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 47/548: {Phosphates or phosphonates, e.g. bone-seeking (phospholipids A61K47/544)}
- A61K 49/085: {conjugated systems}
- A61K 49/101: {the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals}
- A61P 35/00: Antineoplastic agents
- A61K 49/06: Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein is a compound useful as a magnetic resonance imaging (MRI) contrast agent and a therapeutic agent, said compound having a structure represented by: Y—X—Z wherein, X is Mn(II), and Y and Z are each independently a bisphosphonate coupled to one or more therapeutic agents. Methods of use of the compound for MRI imaging and treatment for cancer or a microbial infection are also provided.

## Claims

### Claim 1

A compound useful as a magnetic resonance imaging (MRI) contrast agent and a therapeutic agent, said compound having a structure represented by:
Y—X—Z
wherein,
X is Mn(II), and Y and Z are each independently a bisphosphonate of the formula:
wherein:
R1 is —OH,
R2, R3, R4, R5 and R6 are each independently H, alkyl, or -LR′, wherein at least one of R2, R3, R4, R5 and R6 is -LR′,
wherein each L is present or absent and when present is a linking group, and
wherein each R′ is independently a therapeutic agent,
or a pharmaceutically acceptable hydrate thereof,
wherein said compound has a stoichiometry of 1:2 (Mn(II): bisphosphonate),
wherein said compound is a salt comprising at least one alkali metal and at least one alkaline earth metal, and
wherein the contrast agent has a molecular weight of less than 2,000 daltons.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2 is -LR′, and R3, R4, R5 and R6 are each independently H or alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein L comprises a poly(alkylene oxide).

### Claim 4 (depends on 1)

The compound of claim 1, wherein said therapeutic agent is a cytotoxin.

### Claim 5 (depends on 4)

The compound of claim 4, wherein said cytotoxin is an anti-cancer agent or an antimicrobial.

### Claim 6 (depends on 4)

The compound of claim 4, wherein said cytotoxin is selected from the group consisting of: lapatinib, aminoquinolines, and HSP-90 inhibitors.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the contrast agent has a molecular weight of less than 800 daltons.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is octahedral.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is a monohydrate or a dihydrate.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the alkali metal comprises sodium or potassium.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the alkaline earth metal is selected from calcium and magnesium.

### Claim 12 (depends on 1)

The compound of claim 1, comprising:
at least one water molecule coordinated with said Mn(II).

### Claim 13 (depends on 1)

The compound of claim 1, wherein said compound has an r2 relaxivity of 5 to 18 mM−1 sec−1 measured at 7 Tesla, 22 degrees Celsius, in 2 mM Tris buffered ddH2O, pH 7.0.

### Claim 14 (depends on 1)

The compound of claim 1, wherein said alkaline earth metal comprises calcium.

### Claim 15 (depends on 14)

The compound of claim 14, wherein said alkali metal comprises sodium.

### Claim 16 (depends on 1)

A composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.

### Claim 17 (depends on 16)

The composition of claim 16, wherein said pharmaceutically acceptable carrier is water or phosphate buffered saline.

### Claim 18 (depends on 16)

The composition of claim 16, wherein said composition has a pH of from 6.0 to 8.0.

### Claim 19 (depends on 1)

A method of performing a magnetic resonance imaging (MRI) scan on a subject comprising:
performing the MRI scan; and
administering the compound of claim 1 to said subject prior to and/or during said performing the MRI scan.

### Claim 20 (depends on 1)

A method of administering a therapeutic agent to a subject in need thereof, comprising administering the compound claim 1 to said subject in a treatment effective amount.

### Claim 21 (depends on 20)

The method of claim 20, further comprising detecting the compound in said subject with MRI.

### Claim 22 (depends on 21)

The method of claim 21, wherein said administering is adjusted based upon said detecting.

### Claim 23 (depends on 20)

The method of claim 20, wherein said subject is in need of treatment for cancer.

### Claim 24 (depends on 20)

The method of claim 20, wherein said subject is in need of treatment for a microbial infection.

### Claim 25 (depends on 24)

The method of claim 24, wherein said microbial infection is a recalcitrant or chronic bacterial infection.