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 O;
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)—;
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;
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 The 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.
3. A The 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.
4. A The compound according to claim 1 , wherein R 2 is H, and R 3 is H.
5. A The 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.
6. A The compound according to claim 1 , wherein R 1 is C 6 -C 12 aryl.
7. A The compound according to claim 6 wherein R 1 is phenyl.
8. A The compound according to claim 1 , wherein FG is a fluorescent dye moiety which emits in the near infrared spectrum.
9. The compound according to claim 4 , wherein FG is selected from the group consisting of a polymethine dye, a coumarin dye, a xanthene dye, and a boron-dipyrromethane dye.
10. A The compound according to claim 1 , wherein FG has a structure selected from the group consisting of:
11. A The compound according to claim 1 , wherein the compound is selected from the group consisting of:
12. A method of imaging one or more cells, organs, or tissues, the method comprising: (i) 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, (ii) irradiating the cell or the organism, and (iii) imaging the cell or the organism.
13. A method for sorting cells, the method comprising: (i) exposing the cells to a compound according to claim 1 , where the compound includes a fluorescent dye moiety, (ii) irradiating the cells, (iii) imaging the cells, and (iv) separating cells which bind the compound from cells which do not bind the compound.
14. A method for intraoperative tumor mapping in an organism in need thereof, the method comprising (i) administering an effective amount of a compound according to claim 1 to the organism, where the compound includes a fluorescent dye moiety, (ii) irradiating the organism, and (iii) imaging the organism to map the tumor.
15. A kit comprising a compound according to claim 1 .
16. 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.
17. The compound according to claim 9 , 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.
18. The compound according to claim 17 , wherein the polymethine dye comprises an indocarbocyanine.
19. The compound according to claim 9 , wherein the xanthene dye comprises a fluorescein dye.