Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain

Monoacylglycerol lipase (MAGL) is a gatekeeper in regulating endocannabinoid signaling and has gained sub-stantial attention as a therapeutic target for neurological disorders. We recently discovered a morpholin-3-one derivative as a novel scaffold for imaging MAGL via positron emission tomography (PET). However, its slow kinetics in vivo hampered the application. In this study, structural optimization was conducted and eleven novel MAGL inhibitors were designed and synthesized. Based on the results from MAGL inhibitory potency, in vitro metabolic stability and surface plasmon resonance assays, we identified compound 7 as a potential MAGL PET tracer candidate. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL dis-tribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]7 demonstrated its improved kinetic profile compared to the lead structure. Its high specificity in vivo was proved by using MAGL KO mice. Although further studies confirmed that [11C]7 is a P-glycoprotein (P-gp) substrate in mice, its low P-gp efflux ratio on cells transfected with human protein suggests that it should not be an issue for the clinical translation of [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C] RO7284390) showed promising results warranting further clinical evaluation.Molecular Physiolog

Prevalência de anticorpos anti-Babesia equi em eqüinos no Planalto Catarinense Prevalence of Babesia equi antibodies in horses in the Santa Catarina Plateau, Brazil

Para avaliar a prevalência de anticorpos anti- Babesia equi, através da técnica de imunofluorescência indireta (IFI), foram examinados 397 amostras de soro. As amostras de sangue, para obtenção dos soros, foram coletadas de eqüinos de diferentes idades, raças, sexos, nascidos e criados no Planalto Catarinense, dos municípios de Lages, São Joaquim, Bom Jardim da Serra, Campos Novos, Anita Garibaldi, Curitibanos e Correia Pinto. Os resultados obtidos indicaram a existência de 50,38% de animais sorologicamente reativos para B. equi, na diluição de 1:40. Entre os municípios, os percentuais de animais soropositivos variaram de 18,51% a 64,70%.<br>Serum samples from 397 horses were examined by the indirect immunofluorescence technique. The blood samples were taken from horses of various ages, breeds and both sexes, bred and born in the Santa Catarina State, Brazil, in the counties of Lages, São Joaquim, Bom Jardim da Serra, Campos Novos, Anita Garibaldi, Curitibanos e Correia Pinto. The results indicated a prevalence of 50.38% of positive animals for B. equi at the 1:40 serum dilution. In different counties studied, the prevalence positive animals varied from 18.51% to 64.70%