Radiotracer derivatives of trimethoprim for diagnostic imaging

Patent metadata

Field	Value
Publication number	US-10398790-B2
Application number	US-201615572632-A
Country	US
Kind code	B2
Filing date	May 10, 2016
Priority date	May 10, 2015
Publication date	Sep 3, 2019
Grant date	Sep 3, 2019

Abstract

The present invention provides radiolabeled trimethoprim which are useful in imaging tests such as PET scans. The compounds show robust bacterial uptake in vitro and identify infections from inflammation or tumor when administered to a subject. The compounds show rapid and sensitive detection of Ec DHFR containing tumors from control tumors and background tissue. In one aspect, a compound having the structure of formula (I) is provided or a pharmaceutically acceptable salt or prodrug thereof, wherein R is defined herein. Also provided are compositions containing these compounds, positron emission tomography reporter probe comprising these compounds, and methods of imaging a bacterial infection, tracking or monitoring bacteria, distinguishing a bacterial infection from inflammation or tumor, monitoring genetically fused protein expression, and monitoring genetically engineered cells in clinical scenarios such as immunotherapy for cancer treatment.

First claim

What is claimed is:

1. A compound of formula (I):

wherein:
R is —O—C 11 —(C 1 to C 6 alkyl), an O—C 11 -glycol, —O—(C 1 to C 6 alkyl)— 18 F, —OCH 2 —( 18 F substituted phenyl), —OCH 2 CH 2 —( 18 F-substituted triazole), —OCH 2 CH 2 —( 18 F-substituted tetrazole), 18 F-substituted boron-dipyrromethene, —O(CH 2 CH 2 O) n CH 2 CH 2 — 18 F, —OCH 2 CH 2 CH 2 NHC(O)(CH 2 CH 2 O) n —CH 2 CH 2 — 18 F, -L 1 - 68 Ga, -L 1 - 64 Cu, -L 1 - 99m Tc, radioactive halogen, 211 At, -L 1 - 10 B, -L 1 - 32 P, -L- 1 - 90 Y, -L 1 - 103 Pd, -L 1 - 131 Cs, -L 1 - 153 Sm, —L 1 - 177 Lu, -L 1 - 211 At, -L 1 - 212 Bi, -L 1 - 212 Po, -L 1 - 212 Pb, -L 1 - 223 Ra, or -L 1 - 225 Ac;
n is 1-3;
L 1 is a linker;

or a pharmaceutically acceptable salt or prodrug thereof.

2. The compound of claim 1 , wherein said radioactive halogen is 18 F, 123 I, 125 I, 124 I, 131 I, 32 Cl, 33 Cl, 34 Cl, 74 Br, 75 Br, 76 Br, 77 Br, or 78 Br.

3. The compound of claim 1 , wherein R is O 11 CH 3 .

4. The compound of claim 1 , wherein R is 18 F.

5. The compound of claim 1 , wherein L 1 is DTPA, HEHA, NOTA, DOTA, CHX-A, or TCMC.

6. The compound of claim 1 , which is:

7. The compound of claim 1 , which is:

8. The compound of claim 1 , which is:

9. The compound of claim 1 , which is:

10. The compound of claim 1 which is:

11. The compound of claim 1 , of the following structure:

wherein:
n is 1 to 6; and

Y is

12. The compound of claim 1 , wherein 64 Cu, 68 Ga, 10 B, 32 P, 90 Y, 103 Pd, 131 Cs, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Po, 212 Pb, 223 Ra, or 225 Ac is chelated.

13. The compound of claim 12 , wherein the chelation is performed using:

14. The compound of claim 12 , wherein the chelation is performed using:

15. The compound of claim 12 , wherein the chelation is performed using:

wherein, R 2 is, independently, H or CH 2 CO 2 H.

16. The compound of claim 12 , wherein the chelation is performed using:

17. The compound of claim 12 , wherein the chelation is performed using:

wherein, R 3 is, independently, H or NH 2 .

18. The compound of claim 12 , wherein the chelation is performed using:

wherein, R 4 is, independently, H, —(CH 2 ) 2 CO 2 H, CH 2 OH, or phenyl.

19. The compound of claim 12 , wherein the chelation is performed using:

wherein, R 5 is H or —(CH 2 ) 2 CO 2 H.

20. The compound of claim 12 , wherein the chelation is performed using:

21. The compound of claim 12 , wherein the chelation is performed using:

22. The compound of claim 1 , wherein R is:

wherein, R 6 is alkyl or alkoxy.

23. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

24. A method of imaging a bacterial infection in a subject, said method comprising:
(a) administering an effective amount of claim 1 to said subject; and
(b) tracking said compound.

25. A method of tracking or monitoring bacteria in a subject, said method comprising:
(a) administering an effective amount of claim 1 to said subject; and
(b) tracking said compound.

26. A method of treating a bacterial infection in a subject, said method comprising:
(a) administering an antibiotic to said subject;
(b) administering an effective amount of claim 1 to said subject; and
(c) tracking said compound.

27. The method of claim 24 , wherein said bacteria is E. coli, S. aureus, P. aureginosa, Enterobacter, Haemophilus, Klebsiella, Morganella, Proteus, Providencia, Salmonella, Serratia, Streptococcus A, Streptococcus B, Streptococcus C, Streptococcus G, Mycobacterium TB, or any combination thereof.

28. The method of claim 24 , wherein said effective amount is about 1 to about 50 mCi.

29. The method of claim 24 , wherein said bacteria comprises gastrointestinal tract bacteria.

30. The method of claim 24 , wherein said subject is an animal or human.

31. The compound of claim 1 , that is:

or a pharmaceutically acceptable salt or prodrug thereof.

Assignees

• Univ Pennsylvania

Inventors

• Sellmyer Mark
• Mach Robert H
• Mankoff David A
• Lee Iljung

Classifications

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/49

  with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• A61K51/0453

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title