# US 11,999,710 B2 · Radiolabeled cannabinoid receptor 2 ligand > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,999,710 B2 - Document ID: US11999710B2 - Status: Granted - Kind: B2 - Application number: 17/125,655 - Filed: 2020-12-17 - Published: 2021-04-22 - Granted: 2024-06-04 - Earliest claimed: 2018-06-27 - Assignees: Hoffmann-La Roche Inc.; Eth Zuerich - Applicants: Hoffmann-La Roche Inc.; Eth Zuerich - Inventors: Simon M. Ametamey; Luca Gobbi; Uwe Grether; Julian Kretz; Dieter Muri; Ahmed Haider Wahauib - Web page: https://patentgrep.com/patent/US11999710B2 ## CPC - A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom} - C07D 401/04: directly linked by a ring-member-to-ring-member bond - A61K 51/0459: {having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine} - C07B 59/002: {Heterocyclic compounds} - G01N 33/60: involving radioactive labelled substances - G01N 33/948: {Sedatives, e.g. cannabinoids, barbiturates (opiates G01N33/9486)} - C07B 2200/05: Isotopically modified compounds, e.g. labelled - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F) - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) ## 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. ## Claims ### Claim 1 A compound of formula (I) wherein A is CH or N; R1 and R2 are both ethyl at the same time; and R3 is fluoropropyl or hexadeuteriofluoropropyl; provided that at least one of R1, R2 and R3 comprises at least one radionuclide; or a pharmaceutically acceptable salt thereof. ### Claim 2 (depends on 1) The compound of claim 1, wherein A is CH. ### Claim 3 (depends on 1) The compound of claim 1, wherein both R1 and R2 comprise at least one radionuclide or R3 comprises a radionuclide. ### Claim 4 (depends on 1) The compound of claim 1, wherein the at least one radionuclide is independently selected from 3H, 18F and 11C. ### Claim 5 (depends on 1) The compound of claim 1, wherein R1 and R2 are both —C3HH—C3HH2 at the same time. ### Claim 6 (depends on 1) The compound of claim 1, wherein R3 is —CH2—CH2—CH218F or —CD2-CD2-CD218F. ### Claim 7 (depends on 1) The compound of claim 1 selected from the group consisting of: 3-(18F)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-(18F)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. ### Claim 8 (depends on 1) 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. ### Claim 9 (depends on 1) 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. ### Claim 10 (depends on 9) The method of claim 9, wherein the disease is characterized by a change in the expression of the CB2 receptor in said subject or tissue compared to the expression of the CB2 receptors in the healthy subject or tissue. ### Claim 11 (depends on 9) The method of claim 9, wherein the diagnosing comprises the step of comparing the expression of the CB2 receptor in the subject or tissue to the expression of the CB2 receptor in a healthy subject or tissue. ### Claim 12 (depends on 1) A method for identifying a compound that binds to a CB2 receptor comprising the following steps: (a) contacting the compound suspected to bind to the CB2 receptor with a sample comprising a CB2 receptor and a compound of claim 1; and (b) monitoring whether the compound suspected to bind to the CB2 receptor influences the binding of the compound of claim 1 to the CB2 receptor. ### Claim 13 (depends on 12) The method of claim 12 further comprising a step of measuring the binding strength to the CB2 receptor of the compound suspected to bind to the CBb 2 receptor. ### Claim 14 (depends on 12) The method of claim 12 further comprising measuring the binding constant to the CB2 receptor of the compound suspected to bind selectively to the CB2 receptor. ### Claim 15 (depends on 1) A method for identifying a cellular receptor as a CB2 receptor comprising the following steps: (a) contacting a sample suspected to comprise a CB2 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 CB2 ligand and monitoring whether said known CB2 ligand has displaced the compound of claim 1 from its binding site. ### Claim 16 (depends on 1) A method for measuring in a sample the percentage of CB2 receptors occupied by a compound suspected to bind to the CB2 receptor when said compound is put in contact with the sample, comprising the following steps: (a) contacting a sample comprising at least one CB2 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 CB2 receptor; and (d) calculating the percentage of the CB2 receptors that is occupied by the compound suspected to bind to the CB2 receptor. ### Claim 17 (depends on 1) A method for determining a dose of a CB2 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 CB2 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 CB2 ligand; and (d) calculating the percentage of CB2 receptors that is occupied by the CB2 ligand and determining the dose/occupancy relationship. ### Claim 18 (depends on 1) A method for determining whether a disease is characterized by a change in the expression of the CB2 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 CB2 receptors. ### Claim 19 (depends on 8) The method of claim 8, wherein positron emission tomography (PET), single-photon emission computed tomography (SPECT) or autoradiography is used for the imaging. ### Claim 20 (depends on 1) A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof. ### Claim 21 (depends on 9) 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. ### Claim 22 A process for the manufacture of a compound comprising the following steps: (a) reacting a compound of formula (A) with a nucleophilic [18F]fluoride reagent; or (b) reacting a compound of formula (B) with 3H2; wherein LG is a leaving group; A is CH or N; R1 and R2 are both ethyl at the same time; and R3 is fluoropropyl or hexadeuteriofluoropropyl; provided that at least one of R1, R2 and R3 comprises at least one radionuclide. ### Claim 23 (depends on 17) The method of claim 17, wherein the vertebrate is a human subject.