RESUMEN
Glycine transporter type-1 (GlyT1) has been proposed as a target for drug development for schizophrenia. PET imaging with a GlyT1 specific radiotracer will allow for the measurement of target occupancy of GlyT1 inhibitors, and for in vivo investigation of GlyT1 alterations in schizophrenia. We conducted a comparative evaluation of two GlyT1 radiotracers, [(11) C]GSK931145, and [(18) F]MK-6577, in baboons. Two baboons were imaged with [(11) C]GSK931145 and [(18) F]MK-6577. Blocking studies with GSK931145 (0.3 or 0.2 mg/kg) were conducted to determine the level of tracer specific binding. [(11) C]GSK931145 and [(18) F]MK-6577 were synthesized in good yield and high specific activity. Moderately fast metabolism was observed for both tracers, with â¼ 30% of parent at 30 min post-injection. In the brain, both radiotracers showed good uptake and distribution profiles consistent with regional GlyT1 densities. [(18) F]MK-6577 displayed higher uptake and faster kinetics than [(11) C]GSK931145. Time activity curves were well described by the two-tissue compartment model. Regional volume of distribution (VT ) values were higher for [(18) F]MK-6577 than [(11) C]GSK931145. Pretreatment with GSK931145 reduced tracer uptake to a homogeneous level throughout the brain, indicating in vivo binding specificity and lack of a reference region for both radiotracers. Linear regression analysis of VT estimates between tracers indicated higher specific binding for [(18) F]MK-6577 than [(11) C]GSK931145, consistent with higher regional binding potential (BPND ) values of [(18) F]MK-6577 calculated using VT from the baseline scans and non-displaceable distribution volume (VND ) derived from blocking studies. [(18) F]MK-6577 appears to be a superior radiotracer with higher brain uptake, faster kinetics, and higher specific binding signals than [(11) C]GSK931145.
Asunto(s)
Benzamidas , Radioisótopos de Carbono , Glicinérgicos , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Radiofármacos , Sulfonamidas , Animales , Benzamidas/síntesis química , Benzamidas/química , Benzamidas/farmacocinética , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Mapeo Encefálico , Radioisótopos de Carbono/farmacocinética , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Femenino , Glicinérgicos/síntesis química , Glicinérgicos/química , Glicinérgicos/farmacocinética , Cinética , Modelos Lineales , Imagen por Resonancia Magnética , Estructura Molecular , Papio , Tomografía de Emisión de Positrones , Radiofármacos/síntesis química , Radiofármacos/química , Radiofármacos/farmacocinética , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Series of indole-2-carboxamide and cycloalkeno[1,2-b]indole derivatives were synthesized and evaluated in order to determine the necessary structural requirements for a high inhibition of human LDL copper-induced peroxidation. Various modulations were systematically performed on the indole and cycloalkeno[1,2-b]indole nuclei as well as on the carboxamide moiety. The best compounds (3c, 3e, 7c, 7f, 7h, 7g, and 7o) are between 5 and 30 times more active than probucol itself. Two of these compounds (3c and 7o) were selected for complementary in vitro and in vivo investigations, which have shown additional properties of interest for the treatment and the prevention of atherosclerosis injuries. Compound 3c was found to have some antiinflammatory properties while compound 7o was proved to protect endothelial cells from the direct cytotoxicity of oxidized LDL with some additional calcium channel blocking properties.