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 selected from the group consisting of:
2. A composition comprising a compound of claim 1 ; wherein the composition is adapted for visualization of tissue under illumination with near-infrared radiation.
3. The composition of claim 2 , wherein the composition is adapted for administration to a subject.
4. The composition of claim 3 , wherein the composition comprises a unit dosage form of the compound.
5. The composition of claim 4 , wherein the unit dosage form delivers to the subject an amount of the compound between about 0.01 and about 8 mg/kg.
6. The composition of claim 5 , wherein the unit dosage form delivers to the subject an amount of the compound of about 0.01 mg/kg, about 0.05 mg/kg, about 0.10 mg/kg, about 0.20 mg/kg, about 0.3 mg/kg, about 0.35 mg/kg, about 0.40 mg/kg, about 0.45 mg/kg, about 0.50 mg/kg, about 0.55 mg/kg, about 0.60 mg/kg, about 0.65 mg/kg, about 0.70 mg/kg, about 0.75 mg/kg, about 0.80 mg/kg, about 0.90 mg/kg, about 1 mg/kg, about 2, mg/kg, about 4 mg/kg, about 6 mg/kg, or about 8 mg/kg.
7. The composition of claim 2 , wherein the composition is in a single dose form.
8. The composition of claim 2 , wherein the composition is in dry form.
9. The composition of claim 2 , wherein the composition is lyophilized in a sterile container.
10. The composition of claim 2 , wherein the composition is contained within a sterile container.
11. The composition of claim 10 , wherein the sterile container comprises a machine detectable identifier.
12. The composition of claim 2 , further comprising one or more pharmaceutically acceptable excipients in an oral dosage form.
13. The composition of claim 2 , further comprising one or more pharmaceutically acceptable carriers in an injectable dosage form.
14. The composition of claim 2 , further comprising one or more pharmaceutically acceptable excipients in a dosage form for direct delivery to a surgical site.
15. A method for visualization of tissue expressing PSMA, the method comprising administering to a subject a composition of a compound of claim 1 ;
wherein the compound is administered in an amount sufficient for imaging tissue under illumination with near-infrared radiation;
imaging the tissue under illumination with near-infrared radiation; and
obtaining at least one image of tissue from the subject.
16. The method of claim 15 , wherein the composition comprises a unit dosage form of the compound.
17. The method of claim 16 , wherein the unit dosage form delivers to the subject an amount of the compound from about 0.01 mg/kg and about 8 mg/kg.
18. The method of claim 15 , wherein the composition is sterile, non-toxic, and adapted for administration to a subject.
19. The method of claim 15 , further comprising obtaining the image during administration, after administration, or both during and after administration of the composition.
20. The method of claim 15 , further comprising intravenously injecting a composition comprising the compound into the subject.
21. The method of claim 20 , wherein the composition is injected into a circulatory system of the subject.
22. The method of claim 15 , further comprising visualizing a subject area on which surgery is or will be performed.
23. The method of claim 22 , further comprising performing a surgical procedure of the subject area based on the visualization of the area.
24. The method of claim 22 , further comprising viewing a subject area on which an ophthalmic, arthroscopic, laparoscopic, cardiothoracic, muscular, or neurological procedure is or will be performed.
25. The method of claim 15 , further comprising diagnosing the subject with a condition or disease based on the visualization of the tissue expressing PSMA.
26. The method of claim 15 , further comprising obtaining ex vivo images of at least a portion of the subject.
27. The method of claim 15 , wherein the tissue being visualized comprises tumor tissue.
28. The method of claim 15 , wherein the tissue being visualized comprises cancerous tissue.
29. The method of claim 15 , wherein the tissue being visualized comprises prostate tissue.
30. The method of claim 15 , wherein the tissue being visualized comprises prostate tumor tissue.
31. The method of claim 15 , wherein the tissue being visualized comprises nerve tissue.
32. The method of claim 15 , wherein the tissue being visualized comprises clear cell renal cell carcinoma.
33. A compound of formula (I):
wherein:
each Q is independently hydrogen, a metal ion, a negative charge, or a protecting group;
a, h, m, and n are each independently an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6;
s is 1;
r is 0 or 1;
q is 0 or 1;
p is an integer selected from the group consisting of 0, 1, 2, and 3, and when p is 2 or 3, each R and R 1 can be the same or different;
R′ is halogenated benzyl;
R and R 1 are each independently hydrogen, C 1 -C 6 substituted or unsubstituted alkyl, C 6 -C 12 substituted or unsubstituted aryl, C 6 -C 12 substituted or unsubstituted heteroaryl, or C 6 -C 16 alkyaryl;
R 2 , R 3 , and R 3 ′ are each independently hydrogen, C 1 -C 4 substituted or unsubstituted alkyl, —CO 2 H, —CO 2 Q, or —CO 2 R 4 , wherein R 4 is a C 1 -C 6 substituted or unsubstituted alkyl, C 6 -C 12 substituted or unsubstituted aryl, C 6 -C 12 substituted or unsubstituted heteroaryl, or C 6 -C 16 alkyaryl, wherein if one of R 2 and R 3 is —CO 2 H, or —CO 2 R 4 , then the other is H;
R 3 ′
Tz is a triazole containing moiety selected from the group consisting of:
wherein L 1 is
and L 2 is
wherein:
X 1 is —NRC(O)—, —NRC(O)NR—, —NRC(S)NR, or —NRC(O)O—;
X 2 is —C(O)NR—, —NRC(O)NR—, —NRC(S)NR—, or —OC(O)NR—;
R 5 is H, —CO 2 H, or —CO 2 R 6 , wherein R 6 is C 1 -C 6 alkyl, C 6 -C 12 aryl, or C 6 -C 16 alkyaryl; b is 1, 2, 3, or 4; and d is 1, 2, 3, or 4;
Y is —C(O)—, —NRC(O)—, —NRC(S)—, —OC(O)—;
W is a bond, —(CH 2 —O) t —, —NRC(O)—, —NRC(O)NR—, —NRC(S)NR—, —NRC(O)O—, —OC(O)NR—, —OC(O)—, —C(O)NR—, or —C(O)O—, wherein t is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
G is
FG is a fluorescent dye moiety that emits in the near-infrared spectrum; V is —C(O)—, —NRC(O)—, —NRC(S)—, or —OC(O)—, and g is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6;
under the condition that when r is 0, then q and s are both 0 or both 1;
or a pharmaceutically acceptable salt thereof.
34. The compound of claim 33 , wherein R′ is bromobenzyl.
35. A composition comprising a compound of claim 33 , wherein the composition is adapted for visualization under illumination with near-infrared radiation.
36. A method for visualization of tissue expressing PSMA, the method comprising administering to the subject a composition comprising a compound of claim 33 , wherein the compound is administered in an amount sufficient for imaging tissue under illumination with near-infrared radiation; and obtaining at least one image of the subject.