Imaging of glycogen synthase kinase 3

Patent metadata

Field	Value
Publication number	US-10280152-B2
Application number	US-201615563022-A
Country	US
Kind code	B2
Filing date	Mar 30, 2016
Priority date	Mar 30, 2015
Publication date	May 7, 2019
Grant date	May 7, 2019

Abstract

Provided herein are radiolabelled compounds useful for imaging GSK-3 kinase. An exemplary radiolabelled compound provided herein is useful as a radiotracer for imaging GSK-3 kinase using PET imaging. Methods for preparing the radiolabelled compounds and diagnostic methods using the radiolabelled compounds are also provided.

First claim

What is claimed is:

1. A radiolabelled compound of Formula I:

or a salt thereof, wherein:
X is selected from the group consisting of O and NR N ;
NR N is selected from the group consisting of H, C 1-6 alkyl, and C 1-6 haloalkyl;
L is selected from the group consisting of C 1-6 alkylene and C 1-6 haloalkylene;
R 1 is selected from the group consisting of H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and 5-10 membered heteroaryl;
R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, halo, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkylthio; and
wherein the compound of Formula I is radiolabelled.

2. The radiolabelled compound or salt thereof of claim 1 , wherein the compound is radiolabelled with a positron emitting radioisotope selected from 11 C, 13 N, 15 O, 18 F and 124 I; or a gamma emitting radioisotope selected from 123 I, 125 I, and 131 I.

3. The radiolabelled compound or salt thereof of claim 1 , wherein X is NR N .

4. The radiolabeled compound or salt thereof of claim 3 , wherein R N is H.

5. The radiolabelled compound or salt thereof of claim 4 , wherein L is trimethylene (—CH 2 CH 2 CH 2 —).

6. The radiolabelled compound or salt thereof of claim 1 , wherein R 1 is selected from the group consisting of halo, C 1-6 haloalkyl, C 1-6 haloalkoxy, and a 5-6 membered heteroaryl group.

7. The radiolabelled compound or salt thereof of claim 1 , wherein R 2 is hydrogen, R 3 is hydrogen or halo, and R 4 is selected from the group consisting of hydrogen, halo, hydroxy, C 1-6 alkoxy, and C 1-6 haloalkoxy, R 5 is hydrogen or halo, and R 6 is hydrogen.

8. The radiolabelled compound or salt thereof of claim 7 , wherein R 4 is a [ 11 C]-radiolabelled C 1-6 alkoxy.

9. The radiolabeled compound or salt thereof of claim 8 , wherein R 4 is —O 11 CH 3 .

10. The radiolabelled compound or salt thereof of claim 1 , wherein the compound is a compound of Formula III:

wherein:
L is selected from the group consisting of C 1-6 alkylene and C 1-6 haloalkylene;
R 4 and R 5 are each independently selected from the group consisting of halo, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 alkylthio.

11. The radiolabelled compound or salt thereof of claim 1 , wherein the compound is a compound of the following formula:

12. A method of imaging GSK-3 kinase in a cell or tissue sample, the method comprising contacting the cell or tissue sample with the radiolabelled compound or salt thereof of claim 1 , and subsequently imaging the cell or tissue sample.

13. A method of imaging GSK-3 kinase in a subject, comprising administering to the subject the radiolabelled compound or salt thereof of claim 1 , and subsequently imaging the subject.

14. The method of claim 13 , wherein the imaging is PET imaging or SPECT imaging.

15. A method of imaging GSK-3 kinase in a subject, comprising administering to the subject the radiolabelled compound or salt thereof of claim 11 , and subsequently imaging the subject by PET imaging.

Assignees

• Massachusetts Gen Hospital

Inventors

• Vasdev Neil
• Liang Huan Steven

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K51/0474

  complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/12

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

• A61K51/0463

  having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines · CPC title