PSMA targeted fluorescent agents for image guided surgery
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.
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.