RESUMO
Gastrin-releasing peptide receptors (GRP-Rs, also known as bombesin 2 receptors) are overexpressed in a variety of human cancers, including prostate cancer, and therefore they represent a promising target for in vivo imaging of tumors using positron emission tomography (PET). Structural modifications of the non-peptidic GRP-R antagonist PD-176252 ((S)-1a) led to the identification of the fluorinated analog (S)-3-(1H-indol-3-yl)-N-[1-[5-(2-fluoroethoxy)pyridin-2-yl]cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide ((S)-1m) that showed high affinity and antagonistic properties for GRP-R. This antagonist was stable in rat plasma and towards microsomal oxidative metabolism in vitro. (S)-1m was successfully radiolabeled with fluorine-18 through a conventional radiochemistry procedure. [18F](S)-1m showed high affinity and displaceable interaction for GRP-Rs in PC3 cells in vitro.
Assuntos
Indóis/farmacologia , Compostos de Fenilureia/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores da Bombesina/antagonistas & inibidores , Triptofano/análogos & derivados , Animais , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Radioisótopos de Flúor , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacocinética , Ligantes , Microssomos Hepáticos/metabolismo , Oxirredução , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Triptofano/síntese química , Triptofano/farmacologiaRESUMO
In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.
Assuntos
Piperazinas/síntese química , Tomografia por Emissão de Pósitrons , Propanóis/síntese química , Pirazinas/síntese química , Compostos Radiofarmacêuticos , Receptores de Serotonina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Células CHO , Isótopos de Carbono , Cricetulus , Células HEK293 , Humanos , Cinética , Ligantes , Estrutura Molecular , Fenóis/farmacologia , Piperazinas/química , Propanóis/química , Pirazinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Sulfonamidas/farmacologia , Suínos , Distribuição TecidualRESUMO
We report the synthesis of compounds structurally related to the high-affinity dopamine D4 receptor ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-methoxybenzamide (1e). All compounds were specifically designed as potential PET radioligands for brain D4 receptor visualization, having lipophilicity within a range for brain uptake and weak non-specific binding (0.75