RESUMEN
Decakis(phenylthio)corannulene has been prepared from decachlorocorannulene by direct nucleophilic substitution; electronic structure properties and the X-ray crystal structure were determined and compared to predictions made by ab initio quantum chemical calculations.
RESUMEN
Synthesis and spectral characterization of acecorannulene CpRu+ complexes, in combination with ab initio quantum chemical computations, leads to the hypothesis that eta6-metal binding prefers the exo face in the region of least curvature.
RESUMEN
Three metabotropic glutamate receptor subtype 5 (mGluR5) PET tracers have been labeled with either carbon-11 or fluorine-18 and their in vitro and in vivo behavior in rhesus monkey has been characterized. Each of these tracers share the common features of high affinity for mGluR5 (0.08-0.23 nM vs. rat mGluR5) and moderate lipophilicity (log P 2.8-3.4). Compound 1b was synthesized using a Suzuki or Stille coupling reaction with [11C]MeI. Compounds 2b and 3b were synthesized by a SNAr reaction using a 3-chlorobenzonitrile precursor. Autoradiographic studies in rhesus monkey brain slices using 2b and 3b showed specific binding in cortex, caudate, putamen, amygdala, hippocampus, most thalamic nuclei, and lower binding in the cerebellum. PET imaging studies in monkey showed that all three tracers readily enter the brain and provide an mGluR5-specific signal in all gray matter regions, including the cerebellum. The specific signal observed in the cerebellum was confirmed by the autoradiographic studies and saturation binding experiments that showed tracer binding in the cerebellum of rhesus monkeys. In vitro metabolism studies using the unlabeled compounds showed that 1a, 2a, and 3a are metabolized slower by human liver microsomes than by monkey liver microsomes. In vivo metabolism studies showed 3b to be long-lived in rhesus plasma with only one other more polar metabolite observed.
Asunto(s)
Encéfalo/metabolismo , Antagonistas de Aminoácidos Excitadores/síntesis química , Tomografía de Emisión de Positrones , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Autorradiografía/métodos , Sitios de Unión/efectos de los fármacos , Encéfalo/anatomía & histología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Química Encefálica , Mapeo Encefálico , Radioisótopos de Carbono/farmacocinética , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/clasificación , Antagonistas de Aminoácidos Excitadores/farmacocinética , Radioisótopos de Flúor/farmacocinética , Humanos , Técnicas In Vitro , Macaca mulatta , Imagen por Resonancia Magnética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Estadística como Asunto , Factores de TiempoRESUMEN
The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.