# US 2018/0022768 A1 · Radioactive phospholipid metal chelates for cancer imaging and therapy

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- Number: US 2018/0022768 A1
- Document ID: US20180022768A1
- Status: Published application
- Kind: A1
- Application number: 15/343,604
- Filed: 2016-11-04
- Published: 2018-01-25
- Earliest claimed: 2016-07-25
- Assignees: Wisconsin Alumni Research Foundation
- Applicants: Wisconsin Alumni Research Foundation
- Inventors: Jamey Weichert; Anatoly Pinchuk; Reinier Hernandez
- Web page: https://patentgrep.com/patent/US20180022768A1

## CPC

- C07F 9/6524: having four or more nitrogen atoms as the only ring hetero atoms
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/0489: {Phosphates or phosphonates, e.g. bone-seeking phosphonates; (phospholipids: A61K51/0408; nucleotides or nucleic acids: A61K51/0491)}
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 35/00: Antineoplastic agents
- C07B 59/004: {Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium}
- G01N 33/575: for cancer
- G01N 33/60: involving radioactive labelled substances
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Alkylphosphocholine analogs incorporating a chelating moiety that chelates a radioactive metal isotope are disclosed herein. The alkylphophocholine analogs, which can be used to treat or detect solid tumors, have the formula: R1 includes a chelating agent that is chelated to a metal atom, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, or an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is —H, —OH, —COOH, —COOX, —OCOX, or —OX, wherein X is an alkyl or an arylalkyl; R2 is —N+H3, —N+H2Z, —N+HZ2, or —N+Z3, wherein each Z is independently an alkyl or an aroalkyl; and b is 1 or 2.

## Claims

### Claim 1

A compound having the formula:
or a salt thereof, wherein:
R1 comprises a chelating agent that is chelated to a metal atom, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, or an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days;
a is 0 or 1;
n is an integer from 12 to 30;
m is 0 or 1;
Y is selected from the group consisting of —H, —OH, —COOH, —COOX, —OCOX, and —OX, wherein X is an alkyl or an arylalkyl;
R2 is selected from the group consisting of —N+H3, —N+H2Z, —N+HZ2, and —N+Z3, wherein each Z is independently an alkyl or an aroalkyl; and
b is 1 or 2.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the metal isotope is selected from the group consisting of Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Ga-67, In-111, and Tc-99m.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days.

### Claim 5 (depends on 4)

The compound of claim 4, wherein the metal isotope is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, and Th-227.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the chelating agent is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and its derivatives; 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) and its derivatives; 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives; 1,4,7-triazacyclononane, 1-glutaric acid-4,7-diacetic acid (NODAGA) and its derivatives; 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and its derivatives; 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) and its derivatives; diethylene triamine pentaacetic acid (DTPA), its diester, and its derivatives; 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A″-DTPA) and its derivatives; deforoxamine (DFO) and its derivatives; 1,2-[[6-carboxypyridin-2-yl]methylamino]ethane (H2dedpa) and its derivatives; and DADA and its derivatives.

### Claim at position 7

-18. (canceled)

### Claim 19 (depends on 1)

The compound of claim 1, wherein the chelating agent chelated to the metal atom is selected from the group consisting of:

### Claim 20 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:
wherein the selected compound is chelated to the metal atom.

### Claim 21 (depends on 1)

A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 22 (depends on 1)

A method for treating a cancer in a subject, comprising administering to a subject having cancer an effective amount of a compound of claim 1, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days;
whereby the cancer is successfully treated in the subject.

### Claim at position 12

-26. (canceled)

### Claim 27 (depends on 22)

The method of claim 22, wherein the cancer that is treated is an adult solid tumor or a pediatric solid tumor.

### Claim 28 (depends on 27)

The method of claim 27, wherein the cancer is selected from the group consisting of melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell cancer, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, Ewings sarcoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, Wilms' tumor, and pediatric brain tumors.

### Claim 29 (depends on 1)

A method for inhibiting the proliferation or growth of malignant cells, comprising contacting one or more malignant cells with an effective amount of a compound of claim 1, wherein the metal atom is an alpha, beta or Auger emitting metal isotope with a half life of greater than 6 hours and less than 30 days;
whereby growth or proliferation of the malignant cells is inhibited.

### Claim at position 16

-33. (canceled)

### Claim 34 (depends on 1)

A method for detecting or imaging one or more cancer cells in a biological sample, comprising:
(a) contacting the biological sample with a compound of claim 1, wherein the metal atom is a positron or single photon emitting metal isotope with a half life of greater than or equal to 4 hours, whereby the compound is differentially taken up by malignant solid tumor cells within the biological sample; and
(b) identifying individual cells or regions within the biological sample that are emitting signals characteristic of the metal isotope, whereby one or more cancer cells are detected or imaged.

### Claim 35

(canceled)

### Claim 36 (depends on 34)

The method of claim 34, wherein the step of identifying individual cells or regions within the biological sample that are emitting signals characteristic of the metal isotope is performed by positron emission tomography (PET) imaging, single-photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

### Claim at position 20

-39. (canceled)

### Claim 40 (depends on 34)

The method of claim 34, wherein the cancer cells are adult solid tumor cells or pediatric solid tumor cells.

### Claim 41 (depends on 40)

The method of claim 40, wherein the cancer cells are selected from the group consisting of melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell cancer cells, intestinal cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewings sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, Wilms' tumor cells, and pediatric brain tumor cells.

### Claim 42 (depends on 34)

A method of diagnosing cancer in a subject, comprising performing the method of claim 34, wherein the biogical sample is obtained from, part of, or all of a subject, and whereby if cancer cells are detected or imaged, the subject is diagnosed with cancer.

### Claim at position 24

-44. (canceled)

### Claim 45 (depends on 34)

A method of monitoring the efficacy of a cancer therapy in a human subject, comprising performing the method of claim 34 at two or more different times on the biological sample, wherein the biogical sample is obtained from, part of, or all of a subject, and whereby the change in strength of the signals characteristic of the metal isotope between the two or more different times is correlated with the efficacy of the cancer therapy.

### Claim 46

(canceled)

### Claim 47 (depends on 34)

A method of treating cancer in a subject, comprising performing the method of claim 34, wherein the biogical sample is part of or all of a subject, and directing an external radiotherapy beam to the identified individual cells or regions within the subject.