# US 10,478,512 B2 · Charge-balanced imaging agents

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- Number: US 10,478,512 B2
- Document ID: US10478512B2
- Status: Granted
- Kind: B2
- Application number: 15/903,783
- Filed: 2018-02-23
- Published: 2018-06-28
- Granted: 2019-11-19
- Earliest claimed: 2009-02-06
- Assignees: Beth Israel Deaconess Medical Center, Inc.; Georgia State University Research Foundation, Inc.
- Applicants: Beth Israel Deaconess Medical Center, Inc.; Georgia State University Research Foundation Inc.
- Inventors: John V. Frangioni; Maged M. Henary
- Web page: https://patentgrep.com/patent/US10478512B2

## CPC

- A61K 49/0032: {Methine dyes, e.g. cyanine dyes}
- A61B 6/00: Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment (instruments measuring radiation intensity for application in the field of nuclear medicine, e.g. in vivo counting, G01T1/161)
- C07D 209/02: condensed with one carbocyclic ring
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 255/02: not condensed with other rings
- C09B 23/0066: {the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)}
- C09B 23/086: {more than five >CH- groups}
- C12Q 1/02: involving viable microorganisms
- G01N 33/582: {with fluorescent label}
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C09B: ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES {, e.g. PIGMENTS}; MORDANTS; LAKES (fermentation or enzyme using processes to synthesise a desired chemical compound C12P)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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

The present invention relates to compositions for and methods of optically imaging tissues or cells using imaging agents having desirable in vivo properties that result in improved signal-to-background ratio.

## Claims

### Claim 1

A method of imaging tissue or cells, the method comprising:
(a) contacting the tissue or cells with an imaging agent comprising a dye;
(b) irradiating the tissue or cells at a wavelength absorbed by the dye;
(c) detecting an optical signal from the irradiated tissue or cells, wherein the signal-to-background ratio of the detected optical signal is at least about 1.1, thereby imaging the tissue or cells;
wherein the dye has the formula V:
wherein:
G is -L-TL, where TL is a targeting ligand comprising at least one binding moiety that binds to a biological target;
L has the formula:
E is absent or S;
Q is (CH2)q or a non-ionic oligomeric or polymeric solubilizing moiety;
J is C(O), C(O)O, or C(O)NH;
R17, R18, R19, and R12 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl;
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C1-6 alkyl, aryl, and heteroaryl, wherein said alkyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halo, cyano, nitro, and C1-4 haloalkyl;
or two adjacent R1, R2, R3, R4, R5, R6, R7, and R8 groups, together with the atoms to which they are attached, form a fused 5-7 membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, cyano, nitro, and C1-4 haloalkyl;
R9, and R10, are independently selected from an ionic group, a non-ionic oligomeric or polymeric solubilizing group, C1-6 alkyl, aryl, and heteroaryl, wherein said alkyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halo, cyano, nitro, and C1-4 haloalkyl;
R11 and R12 are independently selected from C1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R13 and R14 are independently selected from C1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R15 and R16 are independently selected from H and C1-6 alkyl;
R22, R23, R24, R25, R26, and R27 are independently selected from independently an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C1-6 alkyl, aryl, and heteroaryl; and
v is 0, 1, 2, 3, 4, or 5,
wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is an ionic group,
or an ester thereof, which permits covalent conjugation of the fluorophore to targeting ligands.

### Claim 2

A dye, having the formula:
wherein:
G is -L-TL, where TL is a targeting ligand comprisiging at least one binding moiety that binds to a biological target;
L has the formula:
E is absent or S;
Q is (CH2)q or a non-ionic oligomeric or polymeric solubilizing moiety;
J is C(O), C(O)O, or C(O)NH;
R17, R18, R19, and R12 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, cyano, nitro, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl;
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
R1, R2, R3, R4, R5, R6, R7, and R8 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C1-6 alkyl, aryl, and heteroaryl, wherein said alkyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halo, cyano, nitro, and C1-4 haloalkyl;
or two adjacent R1, R2, R3, R4, R5, R6, R7, and R8 groups, together with the atoms to which they are attached, form a fused 5-7 membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, cyano, nitro, and C1-4 haloalkyl;
R9, and R10, are independently selected from an ionic group, a non-ionic oligomeric or polymeric solubilizing group, C1-6 alkyl, aryl, and heteroaryl, wherein said alkyl, aryl, and heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from halo, cyano, nitro, and C1-4 haloalkyl;
R11 and R12 are independently selected from C1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R13 and R14 are independently selected from C1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R15 and R16 are independently selected from H and C1-6 alkyl;
R22, R23, R24, R25, R26, and R27 are independently selected from independently an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C1-6 alkyl, aryl, and heteroaryl; and
v is 0, 1, 2, 3, 4, or 5,
wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 is an ionic group,
or an ester thereof, which permits covalent conjugation of the fluorophore to targeting ligands.

### Claim 3 (depends on 2)

The dye of claim 2, wherein the ester is a N-hydroxysuccinimide ester.

### Claim 4 (depends on 2)

The dye of claim 2, isolated as a salt, acid, or combination thereof.

### Claim 5 (depends on 2)

An imaging agent comprising the dye of claim 2 which is characterized as having detectable fluorescence with a signal-to-background ratio of at least about 1.1.