RESUMO
The translocator protein (TSPO) ligand 2-(6,8-dichloro-2-(4-ethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-N-(2-fluoropyridin-3-yl)-N-methylacetamide (PBR170), is a novel imidazopyridineacetamide with high affinity (2.6 nm) and selectivity for the TSPO. The synthesis of [(11)C]PBR170 was accomplished by N-methylation of the corresponding desmethyl precursor with [(11)C]methyl iodide in the presence of sodium hydroxide in dimethylformamide. [(11)C]PBR170 was produced in 30-45% radiochemical yield (decay-corrected, based on [(11)C]methyl iodide) with a radiochemical purity >98% and a specific activity of 90-190 GBq/µmol after 35 min of synthesis time.
Assuntos
Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Piridinas/síntese química , Piridinas/farmacocinética , Receptores de GABA/metabolismo , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Marcação por Isótopo/métodos , Especificidade de Órgãos , Ligação Proteica , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [(11)C]methionine has prompted the development of a new (18)F-labeled methionine derivative S-(3-[(18)F]fluoropropyl)homocysteine ([(18)F]FPHCys). The L and D enantiomers of [(18)F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [(18)F]fluoride substitution using K(2.2.2) and potassium oxalate, followed by acid hydrolysis on a Tracerlab FX(FN) synthesis module. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys were isolated in 20 ± 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[(18)F]FPHCys are taken up by the L-transporter system. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [(18)F]-L-FPHCys and [(18)F]-D-FPHCys, respectively, at 2 h postinjection.
Assuntos
Homocisteína/análogos & derivados , Neoplasias Experimentais/diagnóstico por imagem , Compostos Radiofarmacêuticos/síntese química , Sistema A de Transporte de Aminoácidos/antagonistas & inibidores , Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/antagonistas & inibidores , Sistema L de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-3-yl)- N, N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.
Assuntos
Imidazóis/química , Pirazóis/química , Piridinas/síntese química , Piridinas/farmacocinética , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Receptores de GABA-A/metabolismo , Animais , Fêmur/efeitos dos fármacos , Radioisótopos de Flúor , Ligantes , Estrutura Molecular , Bulbo Olfatório/efeitos dos fármacos , Especificidade de Órgãos/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Piridinas/química , Pirimidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
The major component (35-65%) of the volatile oil obtained by steam distillation of the leaves of Melaleuca triumphalis has been identified as (rel)-1beta-pentyl-1alpha,6alpha-dihydroxy-3,3,5,5-tetramethylcyclohexa-2,4-dione (trivial name triumphalone). Relative stereochemistry was established by nuclear Overhauser experiments and X-ray studies on the 2-(3,5-dinitrobenzoic acid) derivative. The remainder of the oil was composed of mono- and sesquiterpene hydrocarbons and alcohols. On prolonged standing the presence of a rearrangement product of triumphalone was observed which was characterized as (rel)-1beta-pentyl-1alpha,3alpha-dihydroxy-4,4,6,6-tetramethylcyclohexa-2,5-dione (trivial name isotriumphalone), presumably arising from an acid catalyzed shift of the pentyl group from C-1 to C-2.