RESUMEN
As part of our efforts to develop CB2 PET imaging agents, we investigated 2,5,6-substituted pyridines as a novel class of potential CB2 PET ligands. A total of 21 novel compounds were designed, synthesized, and evaluated for their potency and binding properties toward human and rodent CB1 and CB2. The most promising ligand 6a was radiolabeled with carbon-11 to yield 16 ([(11)C]RSR-056). Specific binding of 16 to CB2-positive spleen tissue of rats and mice was demonstrated by in vitro autogadiography and verified in vivo in PET and biodistribution experiments. Furthermore, 16 was evaluated in a lipopolysaccharid (LPS) induced murine model of neuroinflammation. Brain radioactivity was strikingly higher in the LPS-treated mice than the control mice. Compound 16 is a promising radiotracer for imaging CB2 in rodents. It might serve as a tool for the investigation of CB2 receptor expression levels in healthy tissues and different neuroinflammatory disorders in humans.
Asunto(s)
Medios de Contraste/química , Medios de Contraste/farmacocinética , Tomografía de Emisión de Positrones/métodos , Receptor Cannabinoide CB2/análisis , Animales , Azetidinas/química , Azetidinas/farmacocinética , Células CHO , Cricetulus , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Estabilidad de Medicamentos , Humanos , Masculino , Ratones Endogámicos , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacocinética , Piridinas/química , Ratas Wistar , Receptor Cannabinoide CB1/análisis , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Distribución TisularRESUMEN
OBJECTIVE: Diabetes mellitus has been known to be associated with a high risk of osteoporosis. Rubus coreanus Miquel, a traditional Asian herbal medicine, has various uses, such as antiobesity and antiosteoporosis treatment, among others. We investigated the effect of R. coreanus extracts on diabetic osteoporosis. METHODS: Rats were not treated, or treated with streptozotocin or R. coreanus, or ovariectomized, in various combinations. After 6 weeks of treatment, the rats were killed, and serum biochemistry, histopathology, immunohistochemistry, and semiquantitative reverse transcription polymerase chain reaction were performed. In addition, in vitro studies were performed in MC3T3-E1 and RAW 264.7 cells. RESULTS: Rats treated using R. coreanus showed significant improvement in trabecular bone histopathology. Increased expression of osteocalcin was observed in rats treated with streptozotocin and R. coreanus, whether ovariectomized or not. In addition, the expression levels of cannabinoid receptors 1 and 2 and receptor activator for nuclear factor κß ligand were increased in rats that were ovariectomized and treated with streptozotocin and R. coreanus but decreased in those treated with streptozotocin and R. coreanus alone. These results indicate that the antiosteoporotic effect of R. coreanus in postmenopausal diabetic osteoporosis is attributable to the cannabinoid receptor-dependent maximal up-regulation of osteoblastogenesis. CONCLUSIONS: The present study shows that R. coreanus may rescue diabetic osteoporotic bone loss by simultaneous alteration of activation in osteoblasts and osteoclasts. Furthermore, these effects may be partially influenced by the up-regulation of the endocannabinoid system. In conclusion, dietary R. coreanus may be of use in improving the conditions of diabetic osteoporosis.