FIBROBLAST ACTIVATION PROTEIN (FAP)-TARGETED IMAGING AND THERAPY
The present teachings relate generally to conjugates and methods for imaging a tumor microenvironment in a patient, and to conjugates and methods for imaging cancer-associated fibroblasts (CAFs) in the tumor microenvironment of a patient. The present teachings relate generally to method of making conjugates comprising a fibroblast activation protein (FAP) inhibitor.
1 . A conjugate, or a pharmaceutically acceptable salt thereof, having a structure
B-L-X,
wherein B comprises a fibroblast activation protein (FAP) inhibitor;
L comprises a bivalent linker; and
X comprises a near infrared (NIR) dye, a radioactive imaging agent, or a therapeutic agent effective against cancer cells and/or cancer-associated fibroblasts (CAF).
2 . The conjugate of claim 1 , wherein B has a structure
wherein R 1 and R 2 are the same or different, and are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 4 alkyl;
R 3 is a C 1 -C 4 alkyl, nitrile, or isonitrile;
R 4 , R 5 , and R 6 are the same or different, and are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 4 alkyl; and
n is an integer from 1 to 8.
3 .- 6 . (canceled)
7 . The conjugate of claim 2 , or a pharmaceutically acceptable salt thereof, wherein B has a structure
8 . (canceled)
9 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker comprises at least one amino acid in the D- or L-configuration, or a derivative thereof, selected from the group consisting of Lys, Asn, Thr, Ser, Ile, Met, Pro, His, Gln, Arg, Gly, Asp, Glu, Ala, Val, Phe, Leu, Tyr, Cys, and Trp.
10 .- 15 . (canceled)
16 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker comprises a moiety of the formula
wherein m is an integer from 0 to 9, p is an integer from 3 to 10, q is an integer from 3 to 100.
17 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker comprises a portion selected from the group consisting of
wherein
each of R 7 and R 8 is independently H or C 1 -C 6 alkyl;
t is an integer from 1 to 8.
18 .- 20 . (canceled)
21 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L comprises a structure
22 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker comprises a portion selected from the group consisting of
wherein R 6 is H or C 1 -C 6 alkyl.
23 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, comprising the formula
24 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X comprises a fluorescent dye, or a NIR dye.
25 . (canceled)
26 . The conjugate of claim 24 , or a pharmaceutically acceptable salt thereof, wherein the fluorescent dye is fluorescein maleimide or fluorescein isothiocyanate (FITC).
27 . The conjugate of claim 24 , or a pharmaceutically acceptable salt thereof, wherein the NIR dye is S0456.
28 . (canceled)
29 . (canceled)
30 . The conjugate of claim 1 having a structure
or a pharmaceutically acceptable salt thereof.
31 . (canceled)
32 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is a chelating agent of the formula
33 . The conjugate of claim 32 , or a pharmaceutically acceptable salt thereof, wherein X comprises a radioactive metal isotope coordinated to the chelating agent.
34 . A conjugate having a structure
wherein L comprises a bivalent linker; and
X comprises a near infrared (NIR) dye.
35 . (canceled)
36 . A method of surgically removing cancer-associated fibroblasts (CAFs) from a patient, the method comprising:
delivering a conjugate to a tumor microenvironment of the patient, the tumor microenvironment comprising at least one CAF, the conjugate having a structure
wherein L comprises a bivalent linker and X comprises a near infrared (NIR) dye;
causing the NIR dye to fluoresce through an application of an optical stimulus thereto; and
cutting CAF-containing tissue of the patient based on a result of the fluorescence.
37 . (canceled)
38 . The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is a drug selected from the group consisting of a vinca alkaloid, a cryptophycin, bortezomib, thiobortezomib, a tubulysin, aminopterin, rapamycin, paclitaxel, docetaxel, doxorubicin, daunorubicin, everolimus, a-amanatin, verucarin, didemnin B, geldanomycin, purvalanol A, ispinesib, budesonide, dasatinib, an epothilone, a maytansine, and a tyrosine kinase inhibitor.
39 .- 47 . (canceled)
48 . A conjugate of the formula
or a pharmaceutically acceptable salt thereof.
49 . The conjugate of claim 48 , or a pharmaceutically acceptable salt thereof, wherein the conjugate comprises a radioactive metal isotope selected from the group consisting of 111 In, 99m Tc, 64 Cu, 67 Cu, 67 Ga and 68 Ga coordinated thereto.
50 . (canceled)
51 . A conjugate of the formula
or pharmaceutically acceptable salt thereof.
52 . (canceled)
53 . A pharmaceutical composition comprising a conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable excipient.
54 . A method of treating cancer in a subject, comprising,
a. administering to the subject an effective amount of a conjugate or composition according to claim 1 ; or a pharmaceutically acceptable salt thereof.
55 .- 62 . (canceled)
63 . A method of imaging a population of cells in vitro, comprising
a. contacting the cells with a conjugate according to claim 1 , to provide labelled cells, and
b. visualizing the labelled cells.
64 . (canceled)
65 . (canceled)
66 . A method of imaging a population of cells in vivo, comprising
a. administering to a patient an effective amount of a conjugate according to claim 1 , or a pharmaceutically acceptable salt thereof, to provide labelled cells; and
b. visualizing the labelled cells by imaging.
67 . (canceled)
68 . (canceled)