RESUMO
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.
Assuntos
Granisetron/síntese química , Isoquinolinas/síntese química , Tomografia por Emissão de Pósitrons , Quinuclidinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Antagonistas do Receptor 5-HT3 de Serotonina/síntese química , Animais , Autorradiografia , Mapeamento Encefálico , Radioisótopos de Carbono , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Granisetron/sangue , Granisetron/química , Granisetron/farmacologia , Células HEK293 , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Isoquinolinas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Palonossetrom , Quinuclidinas/sangue , Quinuclidinas/química , Quinuclidinas/farmacologia , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacologia , Ratos Wistar , Receptores 5-HT3 de Serotonina/metabolismo , Antagonistas do Receptor 5-HT3 de Serotonina/sangue , Antagonistas do Receptor 5-HT3 de Serotonina/farmacologiaRESUMO
A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT(3) receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3-ethoxyquinoxalin-2-carboxylic acid by coupling with appropriate amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and 1-hydroxybenzotriazole (HOBt). The 5-HT(3) receptor antagonism was evaluated in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methy-5-HT, which was expressed in the form of pA(2) values. Compound 6h (3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone was found to be the most active compound, which expressed a pA(2) value of 7.7. In forced swim test, the compounds with higher pA(2) value exhibited good anti-depressant-like activity and compounds with lower pA(2) value failed to show activity as compared to the vehicle-treated group.