# US 2015/0147273 A1 · Radiolabeled analog(s) of compound 0118 and use thereof in connection with pet and/or spect imaging to determine whether a pharmaceutical containing compound 0118 is a candidate cancer treatment for a patient

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- Number: US 2015/0147273 A1
- Document ID: US20150147273A1
- Status: Published application
- Kind: A1
- Application number: 14/404,657
- Filed: 2013-06-10
- Published: 2015-05-28
- Earliest claimed: 2012-06-11
- Assignees: Koninklijke Philips N.V.
- Applicants: Koninklijke Philips N.V.
- Inventors: Tilman Lappchen; Holger Gruell; Marc Stefan Robillard; Johan Lub
- Web page: https://patentgrep.com/patent/US20150147273A1

## CPC

- A61K 51/0453: {having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole}
- A61B 6/037: {Emission tomography}
- A61K 31/4192: 1,2,3-Triazoles
- A61K 49/0008: {Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure}
- A61K 51/0406: {Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines}
- A61P 35/00: Antineoplastic agents
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07B 59/002: {Heterocyclic compounds}
- C07C 235/20: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- 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)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- 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)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A method for determining whether compound 0118 is a candidate treatment for a patient includes processing, via a processor, image data of tissue of interest of a patient including a cancer to determine whether a radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data and generating a signal indicating that compound 0118 is a candidate treatment for the patient in response to the determining that the radiolabeled analog of compound 0118 is present in a predetermined amount in the tissue of interest represented in the image data, wherein the presence of the radiolabeled analog of compound 0118 in the tissue of interest indicates presence of a sub-type of cancer having a galectin-1 molecular target, which is a sub-type of treatable by compound 0118.

## Claims

### Claim 1

A method for determining whether compound 0118 is a candidate treatment for a patient, comprising:
processing, via a processor, image data of tissue of interest of a patient including a cancer to determine whether a radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data; and
generating a signal indicating that compound 0118 is a candidate treatment for the patient in response to the determining that the radiolabeled analog of compound 0118 is present in a predetermined amount in the tissue of interest represented in the image data,
wherein the presence of the radiolabeled analog of compound 0118 in the tissue of interest indicates presence of a sub-type of cancer having a galectin-1 molecular target, which is a sub-type treatable by compound 0118.

### Claim 2 (depends on 1)

The method of claim 1, further comprising:
visually presenting the image data and a notification indicating that compound 0118 is a candidate treatment for the patient.

### Claim 3 (depends on 1)

The method of claim 1, wherein the signal indicates that compound 0118 is not a candidate treatment in response to determining that the radiolabeled analog of compound 0118 is not present in the predetermined amount in the tissue of interest represented in the image data.

### Claim 4 (depends on 1)

The method of claim 1, further comprising:
determining the patient has cancer based on image data from an initial scan of the patient which was performed prior to all of the acts of claim 1.

### Claim 5 (depends on 4)

The method of claim 4, wherein the initial scan includes one or more of a [18F]Fluorodeoxyglucose, [18F]fluoride, [18F]deoxyfluorothymidine, [18F]fluoromisonidazole, [11C]choline, or [11C]methionine based PET scan.

### Claim 6 (depends on 1)

The method of claim 1, further comprising:
processing image data of a subsequent scan performed after at least one treatment with compound 0118 to determine whether the radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data; and
generating and presenting a recommendation signal recommending ceasing treatment with compound 0118 in response to the image data of the subsequent scan indicating the radiolabeled analog of compound 0118 is not present in the predetermined amount in the tissue of interest represented in the image data.

### Claim 7 (depends on 6)

The method of claim 6, further comprising:
determining an absence of the cancer from the tissue of interest based on image data from a second subsequent scan of the tissue of interest; and
generating and presenting a notification indicating the cancer is no longer present in the tissue of interest.

### Claim 8 (depends on 6)

The method of claim 6, further comprising:
determining a presence of the cancer from the tissue of interest based on a second subsequent scan of the tissue of interest; and
generating and presenting a notification indicating compound 0118 is no longer effective to treat the cancer.

### Claim 9 (depends on 1)

The method of claim 1, further comprising:
processing image data of a subsequent scan of the patient after at least one treatment with compound 0118 to determine whether the radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data; and
generating and presenting a recommendation signal recommending continuing treatment with compound 0118 in response to the image data of the subsequent scan indicating the radiolabeled analog of compound 0118 is present in the predetermined amount in the tissue of interest represented in the image data.

### Claim 10 (depends on 9)

The method of claim 9, further comprising:
comparing the image data of the scan and the image data of the subsequent scan;
determining a change in geometry of the cancer based on the comparison; and
presenting a notification indicating the change in geometry.

### Claim 11

A method for monitoring treatment of cancer with compound 0118, comprising:
processing image data of a treatment scan performed after at least one treatment with compound 0118 to determine whether a radiolabeled analog of compound 0118 is present in tissue of interest represented in the image data, wherein the presence of the radiolabeled analog of compound 0118 in the tissue of interest indicates presence of a sub-type of cancer having a galectin-1 molecular target, which is a sub-type of treatable by compound 0118; and
generating and presenting a first recommendation signal recommending continuing treatment with compound 0118 in response to the image data of the treatment scan indicating the radiolabeled analog of compound 0118 is present in a predetermined amount in the tissue of interest represented in the image data.

### Claim 12 (depends on 11)

The method of claim 11, further comprising:
comparing the image data of the treatment scan and the image data of an earlier scan;
determining a change in geometry of the cancer based on the comparison; and
presenting a notification indicating the change in geometry.

### Claim 13 (depends on 11)

The method of claim 11, further comprising:
generating and presenting a second recommendation signal recommending ceasing treatment with compound 0118 in response to the image data of the treatment scan indicating the radiolabeled analog of compound 0118 is not present in the predetermined amount in the tissue of interest represented in the image data.

### Claim 14 (depends on 13)

The method of claim 13, further comprising:
determining an absence of the cancer from the tissue of interest based on a subsequent scan of the tissue of interest therefrom; and
generating and presenting a notification indicating the cancer is no longer present in the tissue of interest.

### Claim 15 (depends on 13)

The method of claim 13, further comprising:
determining a presence of the cancer from the tissue of interest based on a subsequent scan of the tissue of interest; and
generating and presenting a notification indicating compound 0118 is no longer effective to treat the cancer.

### Claim 16 (depends on 11)

The method of claim 11, further comprising:
determining the patient has cancer based on image data from an initial scan performed prior to all of the acts of claim 11.

### Claim 17 (depends on 16)

The method of claim 16, wherein the initial scan includes one or more of a [18F]Fluorodeoxyglucose, [18F]fluoride, [18F]deoxyfluorothymidine, [18F]fluoromisonidazole, [11C]choline, or [11C]methionine based scan.

### Claim 18 (depends on 16)

The method of claim 16, further comprising:
processing image data of a pre treatment scan of the tissue of interest to determine whether the radiolabeled analog of compound 0118 is present in the tissue of interest represented in the image data; and
generating a first signal indicating that compound 0118 is a candidate treatment for the patient in response to the determining that the radiolabeled analog of compound 0118 is present in a predetermined amount in the tissue of interest represented in the image data.

### Claim 19 (depends on 18)

The method of any of claim 18, further comprising:
generating a second signal indicating that compound 0118 is not a candidate treatment for the patient in response to the determining that the radiolabeled analog of compound 0118 is present in the predetermined amount in the tissue of interest represented in the image data.

### Claim 20

A computing system, comprising:
a radiotracer identifier that processes at least one of PET or SPECT image data and identifies a presence or absence of a predetermined amount of radiolabeled analog of compound 0118 in tissue of interest of a patient represented in the image data; and
a recommender that generates and visually presents a first recommendation indicating that compound 0118 is a candidate treatment for the patient in response to the radiotracer identifier identifying the presence of the predetermined amount of radiolabeled analog of compound 0118 in tissue of interest of a patient represented in the image data.

### Claim 21 (depends on 20)

The computing system of claim 20, wherein the recommender generates and visually presents a second recommendation indicating that compound 0118 is not a candidate treatment for the patient in response to the radiotracer identifier identifying the absence of the predetermined amount of radiolabeled analog of compound 0118 in tissue of interest of a patient represented in the image data.

### Claim 22 (depends on 20)

The computing system of claim 20, wherein the radiotracer identifier identifies the presence of the predetermined amount of the radiolabeled analog of compound 0118 prior to a treatment of the patient with compound 0118.

### Claim 23 (depends on 20)

The computing system of claim 20, wherein the radiotracer identifier identifies the presence or absence of the predetermined mount of the radiolabeled analog of compound 0118 during treatment of the patient with compound 0118.

### Claim 24 (depends on 23)

The computing system of claim 23, wherein the recommender recommends continuing treatment with compound 0118 in response to the radiotracer identifier identifying the presence the predetermined amount of the radiolabeled analog of compound 0118 during treatment of the patient with compound 0118.

### Claim 25 (depends on 23)

The computing system of claim 23, wherein the recommender recommends discontinuing treatment with compound 0118 in response to the radiotracer identifier identifying the absence of the predetermined amount of the radiolabeled analog of compound 0118 during treatment of the patient with compound 0118.

### Claim 26 (depends on 20)

The computing system of claim 20, wherein the radiotracer identifier identifies at least one of an amount, a concentration or a distribution of the radiolabeled analog of compound 0118 in the tissue of interest of a patient represented in the image data and visually presents the identified at least one of the amount, the concentration or the distribution.

### Claim 27 (depends on 20)

The computing system of claim 20, wherein the presence of the radiolabeled analog of compound 0118 in the tissue of interest indicates presence of a cancer having a galectin-1 molecular target, which is a cancer treatable by compound 0118.

### Claim 28

A radiotracer, comprising:
an analog of compound 0118; and
a radiolabel.

### Claim 29 (depends on 28)

The radiotracer of claim 28, wherein the radiotracer is therapeutic.

### Claim 30

A radiolabeled analog of compound 0118, comprising:
a central calix[4]arene core; and
a hydrophobic substituent at the upper rim of the calix[4]arene,
wherein the substituent is one of a radioiodinated or a radiobrominated derivative accessible via radiohalodestannylation from a corresponding tributylstannyl precursor.

### Claim 31

A radiolabeled analog of compound 0118, comprising:
a central calix[4]arene core; and
a hydrophilic substituent at a lower rim,
wherein the substituent is a radiolabel.

### Claim 32 (depends on 31)

The radiolabeled analog of compound 0118 of claim 31, wherein the radiolabel includes an [18F]fluoroalkyltriazole moiety.

### Claim 33

A radiolabeled analog of compound 0118 according to formula I:
comprising:
a central calix[4]arene core; and
a substituent R at an equatorial position on a methylene bridge of the calix[4]arene core.

### Claim 34 (depends on 33)

The radiolabeled analog of compound 0118 of claim 33, wherein the substituent R is from a group consisting of an [18F]fluoroalkyl chain or an [18F]fluoroalkyltriazole moiety.

### Claim 35

A non-radioactive analogue of compound 0118 according to formula
comprising:
a central calix[4]arene core; and
substituent R at an equatorial position on a methylene bridge of the calix[4]arene core.

### Claim 36 (depends on 35)

The radiolabeled analog of compound 0118 of claim 35, wherein the substituent R is linear or branched alkyl, alkynyl, alkenyl cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, alkoxy, thioalkoxy, cycloaklalkoxy, or heterocycloalkylalkoxy.

### Claim 37 (depends on 36)

The radiolabeled analog of compound 0118 of claim 36, wherein a group R includes halogen, hydroxyl, sulfhydryl, amide, ester, (poly)ether, phosphonate, sulfonate and/or heteroaryl.

### Claim 38

A macromolecular structure containing two or more tethered moieties of a non-radioactive analogue of compound 0118 according to formula I:
wherein the individual calix[4]arene subunits are attached to each other via a linker extending from the equatorial substituent R on the methylene bridge of the calix[4]arene core.

### Claim 39 (depends on 38)

The macromolecular structure of claim 38, wherein the linker consists of branched and/or straight polyethylene(PEG)-chains of variable chain length, which in turn may be attached to a dendrimeric core structure and/or a suitable No-compatible polymer.

### Claim 40 (depends on 35, 38)

A macromolecular structure according to claim 38, wherein the linkers and/or polymeric support are made from a bio-degradable material allowing controlled release of therapeutically active modified compound 0118 entities, which includes both monomeric compound 0118 analogues according to formula I and therapeutically active di- and multimeric structures according to claims 35, 38, and 39.

### Claim 41 (depends on 33)

Both non-radioactive and radiolabelled analogues of compound 0118 according to claim 33, wherein the application is therapeutic.

### Claim 42 (depends on 41)

The analogues according to claim 41, wherein the analogues include nonradioactive analogues of the analogues of compound 0118.

### Claim 43 (depends on 41)

A therapeutic method to inhibit angiogenesis in a patient, comprising administration of therapeutically effective amounts and formulations of analogues of compound 0118 according to claim 41.

### Claim 44 (depends on 43)

The therapeutic method according to claim 43, wherein the therapeutic application is inhibition of tumorigenesis in a patient.

### Claim 45 (depends on 44)

The therapeutic method according to claim 44, wherein the therapeutic application in patients is inhibition of diabetic retinopathy, inhibition of neovascular glaucoma, inhibition of rheumatoid arthritis, inhibition of restenosis, and inhibition of diabetic retinopathy.