Charge-balanced imaging agents

Patent metadata

Field	Value
Publication number	US-10478512-B2
Application number	US-201815903783-A
Country	US
Kind code	B2
Filing date	Feb 23, 2018
Priority date	Feb 6, 2009
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

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.

First claim

What is claimed is:

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;
R 17 , R 18 , R 19 , and R 12 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl;
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C 1-6 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 C 1-4 haloalkyl;
or two adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 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 C 1-4 haloalkyl;
R 9 , and R 10 , are independently selected from an ionic group, a non-ionic oligomeric or polymeric solubilizing group, C 1-6 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 C 1-4 haloalkyl;
R 11 and R 12 are independently selected from C 1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R 13 and R 14 are independently selected from C 1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R 15 and R 16 are independently selected from H and C 1-6 alkyl;
R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are independently selected from independently an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C 1-6 alkyl, aryl, and heteroaryl; and
v is 0, 1, 2, 3, 4, or 5,
wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is an ionic group,
or an ester thereof, which permits covalent conjugation of the fluorophore to targeting ligands.

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;
R 17 , R 18 , R 19 , and R 12 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl;
q is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently selected from H, an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C 1-6 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 C 1-4 haloalkyl;
or two adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 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 C 1-4 haloalkyl;
R 9 , and R 10 , are independently selected from an ionic group, a non-ionic oligomeric or polymeric solubilizing group, C 1-6 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 C 1-4 haloalkyl;
R 11 and R 12 are independently selected from C 1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R 13 and R 14 are independently selected from C 1-4 alkyl optionally substituted with 1, 2, or 3 halo;
R 15 and R 16 are independently selected from H and C 1-6 alkyl;
R 22 , R 23 , R 24 , R 25 , R 26 , and R 27 are independently selected from independently an ionic group, a non-ionic oligomeric or polymeric solubilizing group, halo, C 1-6 alkyl, aryl, and heteroaryl; and
v is 0, 1, 2, 3, 4, or 5,
wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is an ionic group,
or an ester thereof, which permits covalent conjugation of the fluorophore to targeting ligands.

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

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

5. 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.

Assignees

• Beth Israel Deaconess Medical Ct Inc
• Univ Georgia State Res Found

Inventors

• Frangioni John V
• Henary Maged M

Classifications

• A61K49/0032 Primary

  Methine dyes, e.g. cyanine dyes · CPC title

• C09B23/0066

  the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid) · CPC title

• C07D209/42

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C09B23/086

  more than five >CH- groups · CPC title

• C07D209/02

  condensed with one carbocyclic ring · CPC title