Radiolabeled cannabinoid receptor 2 ligand

Patent metadata

Field	Value
Publication number	US-11999710-B2
Application number	US-202017125655-A
Country	US
Kind code	B2
Filing date	Dec 17, 2020
Priority date	Jun 27, 2018
Publication date	Jun 4, 2024
Grant date	Jun 4, 2024

Abstract

The present invention relates to a compound of formula (I)wherein R1, R2, and R3 are defined as in the description and in the claims. The compound of formula (I) can be used as a radiolabeled ligand.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is CH or N;
R 1 and R 2 are both ethyl at the same time; and
R 3 is fluoropropyl or hexadeuteriofluoropropyl;
provided that at least one of R 1 , R 2 and R 3 comprises at least one radionuclide;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein A is CH.

3. The compound of claim 1 , wherein both R 1 and R 2 comprise at least one radionuclide or R 3 comprises a radionuclide.

4. The compound of claim 1 , wherein the at least one radionuclide is independently selected from 3 H, 18 F and 11 C.

5. The compound of claim 1 , wherein R 1 and R 2 are both —C 3 HH—C 3 HH 2 at the same time.

6. The compound of claim 1 , wherein R 3 is —CH 2 —CH 2 —CH 2 18 F or —CD 2 -CD 2 -CD 2 18 F.

7. The compound of claim 1 selected from the group consisting of:
3-( 18 F)Fluoropropyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate;
(1,1,2,2,3,3-Hexadeuterio-3-( 18 F)fluoro-propyl) 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate; and
3-Fluoropropyl 2-(1,2-ditritioethyl)-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-3,4-ditritio-butanoate;
or a pharmaceutically acceptable salt thereof.

8. A method of imaging a CB2 receptor in a patient or sample comprising:
administering to a patient or contacting a sample with a compound of claim 1 ; and
imaging the compound in the patient or in the sample.

9. A method of diagnosing a disease in a patient or tissue, comprising:
administering a compound of claim 1 to the subject or the tissue and a healthy subject or tissue.

10. The method of claim 9 , wherein the disease is characterized by a change in the expression of the CB 2 receptor in said subject or tissue compared to the expression of the CB 2 receptors in the healthy subject or tissue.

11. The method of claim 9 , wherein the diagnosing comprises the step of comparing the expression of the CB 2 receptor in the subject or tissue to the expression of the CB 2 receptor in a healthy subject or tissue.

12. A method for identifying a compound that binds to a CB 2 receptor comprising the following steps:
(a) contacting the compound suspected to bind to the CB 2 receptor with a sample comprising a CB 2 receptor and a compound of claim 1 ; and
(b) monitoring whether the compound suspected to bind to the CB 2 receptor influences the binding of the compound of claim 1 to the CB 2 receptor.

13. The method of claim 12 further comprising a step of measuring the binding strength to the CB 2 receptor of the compound suspected to bind to the CB b 2 receptor.

14. The method of claim 12 further comprising measuring the binding constant to the CB 2 receptor of the compound suspected to bind selectively to the CB 2 receptor.

15. A method for identifying a cellular receptor as a CB 2 receptor comprising the following steps:
(a) contacting a sample suspected to comprise a CB 2 receptor with a compound of claim 1 ;
(b) monitoring whether the binding of the compound of claim 1 has occurred; and
(c) optionally further contacting the sample with another known CB 2 ligand and monitoring whether said known CB 2 ligand has displaced the compound of claim 1 from its binding site.

16. A method for measuring in a sample the percentage of CB 2 receptors occupied by a compound suspected to bind to the CB 2 receptor when said compound is put in contact with the sample, comprising the following steps:
(a) contacting a sample comprising at least one CB 2 receptor with a compound of claim 1 to determine a baseline signal;
(b) contacting the sample with a dose of said compound suspected to bind to the CB2 receptor and a compound of claim 1 ;
(c) monitoring the displacement of the compound of claim 1 by the compound suspected to bind to the CB 2 receptor; and
(d) calculating the percentage of the CB 2 receptors that is occupied by the compound suspected to bind to the CB 2 receptor.

17. A method for determining a dose of a CB 2 ligand that needs to be administered to a vertebrate in need thereof comprising the following steps:
(a) administering to the vertebrate a compound of claim 1 and determining a baseline signal;
(b) administering to the vertebrate different doses of CB 2 ligand and concomitantly administering to the vertebrate a compound of claim 1 ;
(c) monitoring the displacement of the compound of claim 1 by the different doses of CB 2 ligand; and
(d) calculating the percentage of CB 2 receptors that is occupied by the CB 2 ligand and determining the dose/occupancy relationship.

18. A method for determining whether a disease is characterized by a change in the expression of the CB 2 receptor comprising the following steps:
(a) contacting a sample or administering to a subject affected with said disease and a healthy sample or a healthy subject with a compound of claim 1 ;
(b) monitoring in both samples or subjects whether the binding of the compound of claim 1 has occurred; and
(c) comparing in both samples or subjects the amount of compound of claim 1 that is bound to the CB 2 receptors.

19. The method of claim 8 , wherein positron emission tomography (PET), single-photon emission computed tomography (SPECT) or autoradiography is used for the imaging.

20. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. The method of claim 9 , wherein the disease is pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.

22. A process for the manufacture of a compound comprising the following steps:
(a) reacting a compound of formula (A)

with a nucleophilic [ 18 F]fluoride reagent; or
(b) reacting a compound of formula (B)

with 3 H 2 ;
wherein LG is a leaving group;
A is CH or N;
R 1 and R 2 are both ethyl at the same time; and
R 3 is fluoropropyl or hexadeuteriofluoropropyl;
provided that at least one of R 1 , R 2 and R 3 comprises at least one radionuclide.

23. The method of claim 17 , wherein the vertebrate is a human subject.

Assignees

• Hoffmann La Roche
• Eth Zuerich

Inventors

• Ametamey Simon M
• Gobbi Luca
• Grether Uwe
• Kretz Julian
• Muri Dieter
• Haider Wahauib Ahmed

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• C07B2200/05

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

• A61K51/0455 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title