RESUMO
A Resin-linker-vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide (18)F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene-bound arylsulfonate linker with [(18)F]-fluoride ion. Three model linker-vector molecules 7a-c containing different alkyl spacer groups were assembled in solution from (4-chlorosulfonylphenyl)alkanoate esters, exploiting a lipase-catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker-vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8a-c with acetate, butyrate and hexanoate spacers, which were characterised by using magic-angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8a,b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4-fluorobutyl)phenylcarbamic acid tert-butyl ester (9) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60%) of the (18) F-labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O-(2-[(18)F]-fluoroethyl)-L-tyrosine ([(18) F]-FET), delivering protected [(18) F]-FET in >90% RCY. Acid deprotection gave [(18)F]-FET in an overall RCY of 41% from the RLV.
Assuntos
Aminoácidos/química , Radioisótopos de Flúor/química , Compostos Radiofarmacêuticos/síntese química , Tirosina/análogos & derivados , Cromatografia Líquida de Alta Pressão , Cinética , Estrutura Molecular , Tomografia por Emissão de Pósitrons , Radioquímica , Compostos Radiofarmacêuticos/química , Tirosina/síntese química , Tirosina/químicaRESUMO
A series of novel TSPO ligands based on the tetracyclic class of translocator protein (TSPO) ligands first described by Okubo et al. was synthesised and evaluated as potential positron emitting tomography (PET) ligands for imaging TPSO in vivo. Fluorine-18 labelling of the molecules was achieved using direct radiolabelling or synthon based labelling approaches. Several of the ligands prepared have promising profiles as potential TSPO PET imaging ligands.
Assuntos
Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA/análise , Receptores de GABA/metabolismo , Animais , Radioisótopos de Flúor/química , Marcação por Isótopo/métodos , Ligantes , Transporte Proteico , Ratos , Receptores de GABA/química , Relação Estrutura-AtividadeRESUMO
A series of novel ligands based on the diaryl anilide (DAA) class of translocator protein (TSPO) ligands was synthesised and evaluated as potential positron emitting tomography (PET) ligands for imaging TPSO in vivo. Fluorine-18 labelling of the molecules was achieved using direct radiolabelling or synthon based labelling approaches. Several of the ligands prepared have promising profiles as potential TSPO PET imaging ligands and will be evaluated further as potential clinical imaging agents.
Assuntos
Anilidas/química , Anilidas/metabolismo , Proteínas de Transporte/análise , Tomografia por Emissão de Pósitrons/métodos , Receptores de GABA-A/análise , Animais , Encéfalo/metabolismo , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Radioisótopos de Flúor , Coração , Ligantes , Ratos , Ratos Wistar , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
A series of tricyclic compounds have been synthesised and evaluated in vitro for affinity against Translocator protein 18 kDa (TSPO) and for preferred imaging properties. The most promising of the compounds were radiolabelled and evaluated in vivo to determine biodistribution and specificity for high expressing TSPO regions. Metabolite profiling in brain and plasma was also investigated. Evaluation in an autoradiography model of neuroinflammation was also carried out for the best compound, 12a ([(18)F]GE-180).
Assuntos
Carbazóis/química , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Receptores de GABA/metabolismo , Animais , Carbazóis/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/metabolismo , Ligantes , Estrutura Molecular , Miocárdio/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
A new approach to the synthesis of 2-fluoro-2-deoxy-d-glucose (FDG, [(19/18)F]-) is described, which employs supported perfluoroalkylsulfonate precursors , where the support consists of insoluble polystyrene resin beads. Treatment of these resins with [(19)F]fluoride ion afforded protected FDG [(19)F]- as the major product, and the identities of the main byproducts were determined. Acidic removal of the acetal protecting groups from [(19)F]- was shown to produce [(19)F]FDG. The method has been applied to the efficient radiosynthesis of the imaging agent [(18)F]FDG, and was shown to produce the radiochemical tracer in good radiochemical yield (average 73%, decay corrected).