RESUMEN
Serotonin-gated ionotropic 5-HT3 receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT3 receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use. To enable us to better understand the actions of these drugs in vivo, we report the synthesis of 8-fluoropalonosetron (15) that has a binding affinity (Ki = 0.26 ± 0.05 nM) similar to the parent drug (Ki = 0.21 ± 0.03 nM). We radiolabeled 15 by nucleophilic 18F-fluorination of an unsymmetrical diaryliodonium palonosetron precursor and achieved the radiosynthesis of 1-(methyl-11C)-N-granisetron ([11C]2) through N-alkylation with [11C]CH3I, respectively. Both compounds [18F]15 (chemical and radiochemical purity >95%, specific activity 41 GBq/µmol) and [11C]2 (chemical and radiochemical purity ≥99%, specific activity 170 GBq/µmol) were evaluated for their utility as positron emission tomography (PET) probes. Using mouse and rat brain slices, in vitro autoradiography with both [18F]15 and [11C]2 revealed a heterogeneous and displaceable binding in cortical and hippocampal regions that are known to express 5-HT3 receptors at significant levels. Subsequent PET experiments suggested that [18F]15 and [11C]2 are of limited utility for the PET imaging of brain 5-HT3 receptors in vivo.
Asunto(s)
Granisetrón/síntesis química , Isoquinolinas/síntesis química , Tomografía de Emisión de Positrones , Quinuclidinas/síntesis química , Radiofármacos/síntesis química , Antagonistas del Receptor de Serotonina 5-HT3/síntesis química , Animales , Autorradiografía , Mapeo Encefálico , Radioisótopos de Carbono , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Granisetrón/sangre , Granisetrón/química , Granisetrón/farmacología , Células HEK293 , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Humanos , Isoquinolinas/sangre , Isoquinolinas/química , Isoquinolinas/farmacología , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Palonosetrón , Quinuclidinas/sangre , Quinuclidinas/química , Quinuclidinas/farmacología , Radiofármacos/sangre , Radiofármacos/farmacología , Ratas Wistar , Receptores de Serotonina 5-HT3/metabolismo , Antagonistas del Receptor de Serotonina 5-HT3/sangre , Antagonistas del Receptor de Serotonina 5-HT3/farmacologíaRESUMEN
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
Research towards the non-invasive imaging of atherosclerotic plaques is of high clinical priority as early recognition of vulnerable plaques may reduce the incidence of cardiovascular events. The fibroblast activation protein alpha (FAP) was recently proposed as inflammation-induced protease involved in the process of plaque vulnerability. In this study, FAP mRNA and protein levels were investigated by quantitative polymerase chain reaction and immunohistochemistry, respectively, in human endarterectomized carotid plaques. A published boronic-acid based FAP inhibitor, MIP-1232, was synthetized and radiolabeled with iodine-125. The potential of this radiotracer to image plaques was evaluated by in vitro autoradiography with human carotid plaques. Specificity was assessed with a xenograft with high and one with low FAP level, grown in mice. Target expression analyses revealed a moderately higher protein level in atherosclerotic plaques than normal arteries correlating with plaque vulnerability. No difference in expression was determined on mRNA level. The radiotracer was successfully produced and accumulated strongly in the FAP-positive SK-Mel-187 melanoma xenograft in vitro while accumulation was negligible in an NCI-H69 xenograft with low FAP levels. Binding of the tracer to endarterectomized tissue was similar in plaques and normal arteries, hampering its use for atherosclerosis imaging.