Radiolabeled VYR-206, an Endocannabinoid CBR1 antagonist for assessing of GPCRs activity and cannabinoid CBR1 therapy

• Published in: The Journal of nuclear medicine (1978) Vol. 59; p. 1068
• Main Authors: Rauvolfova, Jana, Strong, Tori, Jackson, Elias, Yang, David, Kim, Edmund, Pham, Lan, Bryant, Jerry
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.05.2018
• Subjects: Activation; Activation analysis; Biosynthesis; Brain; Cannabinoid CB1 receptors; Cannabinoids; Decarboxylation; Homeostasis; Immune system; In vivo methods and tests; Lipids; Metabolic pathways; Neuroimaging; Pharmaceuticals; Phospholipids; Potassium carbonate; Pyrazole; Radiochemistry; Radioisotopes; Receptor mechanisms; Receptors; Rodents; Selective binding; Single photon emission computed tomography; Therapy
• ISSN: 0161-5505; 1535-5667

Objectives: Cannabinoids (CBs) have selective receptors in the brain and immune system that works as a thermostat in the body. These receptors via endocannabinoid (eCB) system may be a useful marker for the assessment of other pathways activation and cannabinoid therapies. Cannabinoid receptors (CBRs) with selective binding affinity in the brain and periphery throughout the body are expressed under many conditions. The eCBs are synthesized and released when activated from membrane phospholipids in response to physiological or pathological stimuli. This key concept adds more complexity to eCB homeostasis and certainly makes them more available both for receptor activation such as GPCRs and for distinct metabolic pathways, such as lipid mediators that may interact, away from the site and time of their biosynthesis. This study was to develop radiolabeled CBR1 antagonist using cyclam as a chelator to assess receptors activation and the efficacy of targeted therapy with cannabinoids. Methods : (VYR-206) 1,4,8,11-tetraazacyclotetradecane-1'-acetyl-[N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] Method: To a solution of N-(Piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 200 mg, 0.43 mmol) dissolved in anhydrous CH3CN (10 mL) was added K2CO3 (200 mg, 1.44 mmol) and BrCH2CO2Et (400 mg, 2.4 mmol) and refluxed 48 hrs. The mixture was cooled and filtered, followed by flash chromatography to yield 1'-Ethylacetyl-[N-(Piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (428 mg, 55 %). Male Sprague-Dawley rats (80g-120g) were obtained from Charles River were used for Biodistrubution studies, In vivo. Biodistribution studies of Tc-99m-VYR-206 (2 μCi/mouse) was conducted at 15 mins, 30 mins and 1 hr after the radiopharmaceutical was injected tail vein region were incubated for 2 hrs. SPECT imaging. Results : Biodistribution studies demonstrated that Tc-99m-VYR-206 showed up in the brain and gut. The brain and gut uptake could be clearly visualized by Tc-99m-VYR-206. It was noted that the brain had high uptake in a rat model using Tc-99m-VYR-206, suggesting decarboxylation might have occurred. Conclusions : Tc-99m-VYR-206 has a potential for the assessment of the efficacy of cannabinoid therapy in many disease states.