RESUMO
P-glycoprotein is an efflux transporter located in the blood-brain barrier. (R)-[11C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer's disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[18F]fluoroethylverapamil ([18F]1) and (R)-O-[18F]fluoroethylnorverapamil ([18F]2) has been described. [18F]1 was obtained in reaction of (R)-norverapamil with the volatile [18F]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% ± 1.2%. [18F]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% ± 9.9%. Both tracers, [18F]1 and [18F]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [18F]1 and [18F]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6- and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [18F]1 and [18F]2, PET scans in Mdr1a/b(-/-), Bcrp1(-/-), and WT mice were acquired, in which [18F]2 showed a more specific brain uptake in Mdr1a/b(-/-) mice and no increased signal in Bcrp1(-/-) mice. [18F]2 was selected as the best performing tracer and should be evaluated further in clinical studies.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Fármacos do Sistema Nervoso Central/farmacologia , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Masculino , Camundongos Knockout , Estrutura Molecular , Quinolinas/farmacologia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos Wistar , Distribuição Tecidual , Verapamil/síntese química , Verapamil/farmacologia , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
The present study was performed to design oral controlled delivery systems for the water-soluble drug, verapamil hydrochloride, using natural and semisynthetic polymers as carriers in the forms of 1- and 3-layer matrix tablets. Verapamil hydrochloride 1-layer matrix tablets containing hydroxypropylmethylcellulose, tragacanth, and acacia either alone or mixed were prepared by direct compression technique. 3-layer matrix tablets were prepared by compressing the polymers as release retardant layers on both sides of the core containing the drug. The prepared tablets were subjected to in vitro drug release studies. Tragacanth when used as the carrier in the formulation of 1- and 3-layer matrices produced satisfactory release prolongation either alone or in combination with the other 2 polymers. On the other hand, acacia did not show enough prolonging efficiency in 1- and 3-layer matrix tablets. The results also showed that the location of the polymers in the 3-layer tablets has a pronounced effect on the drug release. Kinetic analysis of drug release from matrices exhibiting sustained release indicated that release was predominantly attributable to the contribution made by Fickian diffusion, while the erosion/relaxation mechanisms had a minor role in the release.