Labeled inhibitors of prostate specific membrane antigen (PSMA) biological evaluation, and use of imaging agents

Patent metadata

Field	Value
Publication number	US-10039845-B2
Application number	US-201715639445-A
Country	US
Kind code	B2
Filing date	Jun 30, 2017
Priority date	Jun 26, 2007
Publication date	Aug 7, 2018
Grant date	Aug 7, 2018

Abstract

The prostate-specific membrane antigen (PSMA) is increasingly recognized as a viable target for imaging and therapy of cancer. Various 99mTc/Re-labeled compounds were prepared by attaching known Tc/Re chelating agents to an amino-functionalized PSMA inhibitor with or without a variable length linker moiety. Ex vivo biodistribution and in vivo imaging demonstrated the degree of specific binding to engineered PSMA+ PC3 PIP tumors.

First claim

What is claimed is:

1. A compound of formula II:

wherein:
AA 1 and AA 2 are each independently a natural or unnatural amino acid;
R′ is —CO—NR x R y —, —CS—NR x R y —, COR x , CSR x , C(NR x )R x , —S(O) p R x —, or —CO 2 —NR x R y —; wherein R x is optionally substituted aryl or optionally substituted alkyl and R y is H, optionally substituted aryl or optionally substituted alkyl;
R″ is H or optionally substituted alkyl;
X and Z are each independently C 1 -C 8 alkylene, C 2 -C 8 alkenylene, C 2 -C 8 alkynylene, C 1 -C 8 heteroalkylene, C 2 -C 8 heteroalkenylene, C 2 -C 8 heteroalkynylene, or a bond, each of which may be substituted with 0-5 R A ;
W is —C(═O)—;
Y is —O—, —S(O) p —, —NH—, —NR B —, —CH═CH—, —CR B ═CH—, —CH═CR B —, —NH—CO—, —NH—CO 2 —, —NR B —CO—, —NR B —CO 2 —; —CO—NH—, —CO 2 —NH—, —CO—NR B —, —CO 2 —NR B —, or a bond;
p is 0, 1, or 2;
R A , for each occurrence, is halogen, hydroxy, amino, cyano, nitro, CO 2 H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted mono or dialkylamino, optionally substituted alkylthio, optionally substituted alkylsulfinyl, optionally substituted alkylsulfonyl, optionally substituted mono- or dialkylcarboxamide, optionally substituted aryl, or optionally substituted heteroaryl; and
R B , for each occurrence, is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted mono or dialkylamino, optionally substituted alkylthio, optionally substituted aryl, or optionally substituted heteroaryl.

2. The compound of claim 1 , wherein AA 1 and AA 2 are each independently lysine, glutamic acid, tyrosine, or cysteine.

3. The compound of claim 1 , wherein R′ is —CO—NR x R y —, —CS—NR x R y —, COR x , or CSR x .

4. The compound of claim 1 , wherein X is C 1 -C 8 alkylene, which may be substituted with 0-5 R A ; and R A for each occurrence, is halogen, hydroxy, amino, cyano, nitro, or CO 2 H.

5. The compound of claim 1 , wherein Z is C 1 -C 8 alkylene, which may be substituted with 0-5 R A ; and R A for each occurrence, is halogen, hydroxy, amino, cyano, nitro, or CO 2 H.

6. The compound of claim 1 , wherein the aryl or alkyl of R x is substituted with

7. The compound of claim 1 further comprising a metal, wherein the metal is Tc, Re, Ga, Cu, Y, Ac, Bi or In.

8. The compound of claim 7 , wherein the metal is a radioactive isotope.

9. The compound of claim 8 , wherein the metal is Tc-99m, Re-188, Re-186, Ga-68, Cu-64, Y-90, Y-86, Ac-225, Bi-213, In-111, Tc-94m, Sm-153, Ho-166, Lu-177, Cu-67, or Dy-166.

10. A method of imaging in a subject, comprising the steps of:
administering a radiolabeled compound according to claim 8 , or a pharmaceutically acceptable salt thereof;
contacting cells or tissues with the compound;
detecting the compound in the cells or tissue; and
imaging the compound in the cells or tissue.

11. The method of claim 10 , wherein the metal is Tc-99m, Re-188, Re-186, Ga-68, Cu-64, Y-90, Y-86, Ac-225, Bi-213, In-111, Tc-94m, Sm-153, Ho-166, Lu-177, Cu-67, or Dy-166.

12. The method of claim 10 , wherein the imaging method is suitable for imaging PSMA inhibitors.

13. The method of claim 10 , wherein the imaging method is suitable for imaging of cancer, tumor or neoplasm.

14. The method of claim 13 , wherein the cancer is selected from eye or ocular cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, stomach cancer, liver cancer, pancreatic cancer, lung cancer, corpus uteri, ovary cancer, prostate cancer, testicular cancer, renal cancer, brain/ens cancer, throat cancer, skin melanoma, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer, larynx cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangiomas, and lymphangiogenesis.

15. The method of claim 10 , wherein the radiolabeled compound is stable in vivo.

16. The method of claim 10 , wherein the radiolabeled compound is detected by positron emission tomography (PET) or single photon emission computed tomography (SPECT).

17. The method of claim 10 , wherein the subject is a human, rat, mouse, cat, dog, horse, sheep, cow, monkey, avian, or amphibian.

18. The method of claim 10 , wherein the cell is in vivo or in vitro.

Assignees

• Univ Johns Hopkins

Inventors

• Pomper Martin G
• Ray Sangeeta
• Mease Ronnie C
• Foss Catherine Anne

Classifications

• G01N33/57555

  of the prostate · CPC title

• A61K31/4402

  only substituted in position 2, e.g. pheniramine, bisacodyl · CPC title

• C07D257/00

  Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms · CPC title

• A61K31/145

  having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) (isothiourea A61K31/155) · CPC title

• C07D213/38

  having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom · CPC title