PSMA targeted fluorescent agents for image guided surgery

Patent metadata

Field	Value
Publication number	US-11021450-B2
Application number	US-202016820052-A
Country	US
Kind code	B2
Filing date	Mar 16, 2020
Priority date	Mar 19, 2009
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

Compositions and methods for visualizing tissue under illumination with near-infrared radiation, including compounds comprising near-infrared, closed chain, sulfo-cyanine dyes and prostate specific membrane antigen ligands are disclosed.

First claim

That which is claimed:

1. A compound having the structure:

wherein:
Z is tetrazole or CO 2 Q;
each Q is independently selected from hydrogen or a protecting group;
FG is a fluorescent dye moiety which emits in the visible or near infrared spectrum;

each R is independently H or C 1 -C 4 alkyl;
V is —C(O)—;
W is —NRC(O);
Y is —C(O);
a is 1, 2, 3, or 4;
m is 1, 2, 3, 4, 5, or 6;
n is 1, 2, 3, 4, 5 or 6;
p is 0, 1, 2, or 3, and when p is 2 or 3, each R 1 may be the same or different;
R 1 is H, C 1 -C 6 alkyl, C 6 -C 12 aryl, or alkylaryl having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms;
R 2 and R 3 are independently H, CO 2 H, or CO 2 R 4 , where R 4 is a C 1 -C 6 alkyl, C 6 -C 12 aryl, or alkylaryl having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms, wherein when one of R 2 and R 3 is CO 2 H or CO 2 R 4 , the other is H.

2. A compound according to claim 1 having the structure:

3. A compound according to claim 2 having the structure:

4. A compound according to claim 1 , wherein R 3 is CO 2 H and R 2 is H or R 2 is CO 2 H and R 3 is H.

5. A compound according to claim 1 , wherein R 2 is CO 2 R 4 and R 3 is H or R 3 is CO 2 R 4 , and R 2 is H.

6. A compound according to claim 1 , wherein R 2 is H, and R 3 is H.

7. A compound according to claim 1 , wherein R 4 is C 6 -C 12 aryl, or alkylaryl having 1 to 3 separate or fused rings and from 6 to about 18 ring carbon atoms.

8. A compound according to claim 1 , wherein R 1 is C 6 -C 12 aryl.

9. A compound according to claim 8 wherein R 1 is phenyl.

10. A compound according to claim 1 , wherein FG is a fluorescent dye moiety which emits in the near infrared spectrum.

11. A compound according to claim 1 , wherein FG is selected from the group consisting of a polymethine dye, a coumarin dye, a xanthene dye, and a boron-dipyrromethene dye.

12. A compound according to claim 1 , wherein FG has a structure selected from the group consisting of:

13. A compound according to claim 1 selected from the group consisting of:

14. A method of imaging one or more cells, organs or tissues by exposing the cell to or administering to an organism an effective amount of a compound according to claim 1 , where the compound includes a fluorescent dye moiety suitable for imaging.

15. A method for sorting cells by exposing the cells to a compound according to claim 1 , where the compound includes a fluorescent dye moiety, followed by separating cells which bind the compound from cells which do not bind the compound.

16. A method for intraoperative tumor mapping comprising administering an effective amount of a compound according to claim 1 , where the compound includes a fluorescent dye moiety.

17. A kit comprising a compound according to claim 1 .

18. The compound according to claim 1 , wherein the protecting group is selected from the group consisting of benzyl, p-methoxybenzyl, tertiary butyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, and triphenylmethyl.

19. The compound according to claim 11 , wherein the polymethine dye is selected from the group consisting of a carbocyanine dye, a indocarbocyanine dye, an oxacarbocyanine dye, a thiacarbocyanine dye, and a merocyanine dye.

20. The compound according to claim 19 , wherein the polymethine dye comprises an indocarbocyanine.

21. The compound according to claim 11 , wherein the xanthene dye is selected from the group consisting of a fluorescein dye and a coumarin dye.

Assignees

• Univ Johns Hopkins

Inventors

• Pomper Martin G
• Mease Ronnie C
• Chen Ying
• Ray Sangeeta

Classifications

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title

• A61K49/0032

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

• C07D311/82

  Xanthenes · CPC title

• A61K51/0453

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title