Charged-balanced imaging agents

Patent metadata

Field	Value
Publication number	US-9687567-B2
Application number	US-201514681068-A
Country	US
Kind code	B2
Filing date	Apr 7, 2015
Priority date	Feb 6, 2009
Publication date	Jun 27, 2017
Grant date	Jun 27, 2017

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 independently selected from H, C 1-6 alkyl, a moiety comprising a linking group, and a moiety comprising a targeting ligand;
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
n is −1, 0 or +1,
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.

2. A dye, having the formula V:

wherein:
G is independently selected from H, C 1-6 alkyl, a moiety comprising a linking group, and a moiety comprising a targeting ligand;
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
n is −1, 0 or +1,
wherein the ester is a conjugate of one or more of an ionic group and/or the linking group.

3. An ester conjugate of a dye, having the formula V:

wherein:
G is independently selected from H, C 1-6 alkyl, a moiety comprising a linking group, and a moiety comprising a targeting ligand;
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
n is −1, 0 or +1,
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;
wherein the ester conjugate permits covalent conjugation of the fluorophore to targeting ligands.

4. The ester conjugate of claim 3 , wherein the ester is an N-hydroxysuccinimide ester.

Assignees

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

Inventors

• Frangioni John V
• Henary Maged M

Classifications

• C07D255/02

  not condensed with other rings · CPC title

• G01N33/582

  with fluorescent label · CPC title

• C12Q1/02

  involving viable microorganisms · CPC title

• C09B23/086

  more than five >CH- groups · CPC title

• A61K49/0032 Primary

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