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US-12617768-B2 - Radiolabeled cannabinoid receptor 2 ligand

US12617768B2US 12617768 B2US12617768 B2US 12617768B2US-12617768-B2

Abstract

The present invention relates to a compound of formula (I) wherein R 1 , R 2 , and R 3 are defined as in the description and in the claims. The compound of formula (I) can be used as a radiolabeled ligand.

Inventors

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

Assignees

  • HOFFMANN-LA ROCHE INC.
  • ETH ZUERICH

Dates

Publication Date
20260505
Application Date
20240521
Priority Date
20180627

Claims (10)

  1. 1 . A method of imaging a CB2 receptor in a patient or a sample comprising: (a) administering to said patient or contacting the sample with a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is CH; 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 positron-emitting radionuclide; and (b) imaging the compound in the patient or in the sample using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  2. 2 . The method of claim 1 , wherein the positron emission tomography (PET) is used for imaging.
  3. 3 . The method of claim 2 , wherein in the compound of formula (I) both R 1 and R 2 comprise at least one radionuclide or R 3 comprises a radionuclide.
  4. 4 . The method of claim 2 , wherein in the compound of formula (I) at least one radionuclide is 18 F or 11 C.
  5. 5 . The method of claim 4 , wherein in the compound of formula (I) R 3 is —CH 2 —CH 2 —CH 2 18 F or —CD 2 -CD 2 -CD 2 18 F.
  6. 6 . The method of claim 4 , wherein the compound of formula (I) is selected from: 3-( 18 F) Fluoropropyl 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate and (1,1,2,2,3,3-Hexadeuterio-3-( 18 F) fluoropropyl) 2-ethyl-2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate or a pharmaceutically acceptable salt thereof.
  7. 7 . The method of claim 1 , wherein the compound is:
  8. 8 . A method of imaging a CB2 receptor in a patient or a sample comprising: (a) administering to said patient or contacting the sample with a compound having the structure: and (b) imaging the compound in the patient or in the sample using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  9. 9 . The method of claim 8 , wherein the positron emission tomography (PET) is used for imaging.
  10. 10 . The method of claim 8 , wherein the single-photon emission computed tomography (SPECT) is used for imaging.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/125,655 filed Dec. 17, 2020, issued as U.S. Pat. No. 11,999,710, which is a continuation of International Application No. PCT/EP2019/066799 having an International Filing Date of 25 Jun. 2019, which claims the benefit of priority to European Patent Application No. 18180154.9, filed 27 Jun. 2018, the contents of which applications are hereby incorporated by reference in their entirety. The present invention relates to a radiolabeled Cannabinoid Receptor 2 ligand. The invention relates in particular to a compound of formula (I): whereinR1 and R2 are both ethyl at the same time; andR3 is 3-fluoropropyl;provided that at least one of R1, R2 and R3 comprises at least one radionuclide;or a pharmaceutically acceptable salt thereof. The cannabinoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, termed Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). The CB1 receptor has a wide range of expression. It is mainly expressed in the central nervous (i.e. amygdala cerebellum, hippocampus) system and to a lesser amount in the periphery. CB2, which is encoded by the CNR2 gene, is mostly expressed peripherally, on cells of the immune system, such as macrophages, B- and, T-cells (Ashton, J. C. et al. Curr Neuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J Pharmacol 2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, 14(23), 2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 receptor is also present in the brain where it is found primarily on microglia and not on neurons (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2), 240-51). The interest in CB2 receptor agonists has been steadily on the rise during the last decade (currently 30-40 patent applications/year) due to the fact that several of the early compounds have been shown to have beneficial effects in pre-clinical models for a number of human diseases including chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol 2008, 153(2), 182-8), neuroinflammation (Cabral, G. A. et al. J Leukoc Biol 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62), systemic fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36; Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6) and liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83). Ischemia/reperfusion (I/R) injury is the principal cause of tissue damage occurring in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries, and organ transplantation, as well as a major mechanism of end-organ damage complicating the course of circulatory shock of various etiologies. All these conditions are characterized by a disruption of normal blood supply resulting in an insufficient tissue oxygenation. Re-oxygenation e.g., reperfusion is the ultimate treatment to restore normal tissue oxygenation. However the absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in further tissue damage. The damage of reperfusion injury is due in part to the inflammatory response of damaged tissues. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane. Remote ischemic preconditioning (RIPC) represents a strategy for harnessing the body's endogenous protective capabilities against the injury incurred by ischemia and reperfusion. It describes the intriguing phenomenon in which transient non-lethal ischemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of “lethal” ischemia reperfusion injury in a remote organ or tissue. The actual mechanism through which transient ischemia and reperfusion of an organ or tissue confers protection is currently unknown although several hypotheses have been proposed. The humoral hypothesis proposes that the endogenous substance (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, Angiotensin I or some other as yet unidentified humoral factors) generated in the remote organ or tissue enters the blood stream and activates its respective receptor in the target tissue thereby recruiting the various intracellular pathways of cardioprotection implicated in ischemic preconditioning. Recent data indicate that endocannabinoids and their receptors, in part