RESUMO
INTRODUCTION: Developing positron emission tomography (PET) ligands for imaging metabotropic glutamate receptor type 1 (mGluR1) is important for studying its role in the central nervous system. N-cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074) exhibited high binding affinity for mGluR1 (K(i)=4.8 nM), and selectivity over other mGluRs in vitro. The purpose of this study was to label YM-202074 with carbon-11 and to evaluate in vitro and in vivo characteristics of [(11)C]YM-202074 as a PET ligand for mGluR1 in rodents. METHODS: [(11)C]YM-202074 was synthesized by N-[(11)C]methylation of its desmethyl precursor with [(11)C]methyl iodide. The in vitro and in vivo brain regional distributions were determined in rats using autoradiography and PET, respectively. RESULTS: [(11)C]YM-202074 (262-630 MBq, n=5) was obtained with radiochemical purity of >98% and specific activity of 27-52 GBq/mumol at the end of synthesis, starting from [(11)C]CO(2) of 19.3-21.5 GBq. In vitro autoradiographic results showed that the high specific binding of [(11)C]YM-202074 for mGluR1 was presented in the cerebellum, thalamus and hippocampus, which are known as mGluR1-rich regions. In ex vivo autoradiography and PET studies, the radioligand was specifically distributed in the cerebellum, although the uptake was low. Furthermore, the regional distribution was fairly uniform in the whole brain by pretreatment with JNJ16259685 (a mGluR1 antagonist). However, radiometabolite(s) was detected in the brain. CONCLUSIONS: From these results, especially considering the low brain uptake and the influx of radiometabolite(s) into brain, [(11)C]YM-202074 may not be a useful PET ligand for in vivo imaging of mGluR1 in the brain.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores de Glutamato Metabotrópico/metabolismo , Tiazóis/síntese química , Tiazóis/metabolismo , Animais , Benzimidazóis/química , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ligantes , Imageamento por Ressonância Magnética , Masculino , Camundongos , Ratos , Especificidade por Substrato , Tiazóis/químicaRESUMO
The aim of this study was to evaluate N-benzyl-N-[11C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC) as a new translocator protein (18 kDa) [TSPO, formerly known as the peripheral-type benzodiazepine receptor (PBR)] positron emission tomography (PET) ligand in normal mice and unilateral kainic acid (KA)-lesioned rats. DAC is a derivative of AC-5216, which is a potent and selective PET ligand for the clinical investigation of TSPO. The binding affinity and selectivity of DAC for TSPO were similar to those of AC-5216, and DAC was less lipophilic than AC-5216. The distribution pattern of [11C]DAC was in agreement with TSPO distribution in rodents. No radioactive metabolite of [11C]DAC was found in the mouse brain, although it was metabolized rapidly in mouse plasma. Using small-animal PET, we examined the in vivo binding of [11C]DAC for TSPO in KA-lesioned rats. [11C]DAC and [11C]AC-5216 exhibited similar brain uptake in the lesioned and nonlesioned striatum, respectively. The binding of [11C]DAC to TSPO was increased significantly in the lesioned striatum, and [(11)C]DAC showed good contrast between the lesioned and nonlesioned striatum (the maximum ratio was about threefold). In displacement experiments, the uptake of [11C]DAC in the lesioned striatum was eventually blocked using an excess of either unlabeled DAC or PK11195 injected. [11C]DAC had high in vivo specific binding to TSPO in the injured rat brain. Therefore, [11C]DAC is a useful PET ligand for TSPO imaging, and its specific binding to TSPO is suitable as a new biomarker for brain injury.
Assuntos
Lesões Encefálicas/diagnóstico por imagem , Purinas/metabolismo , Purinas/farmacologia , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/farmacologia , Receptores de GABA/metabolismo , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/metabolismo , Radioisótopos de Carbono/farmacologia , Cromatografia Líquida de Alta Pressão , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Caínico/toxicidade , Ligantes , Masculino , Camundongos , Tomografia por Emissão de Pósitrons , Purinas/química , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Ratos , Ratos Sprague-Dawley , Receptores de GABA/química , Distribuição TecidualRESUMO
[(18)F]FEAC ([(18)F]4a) and [(18)F]FEDAC ([(18)F]4b) were developed as two novel positron emission tomography (PET) ligands for peripheral-type benzodiazepine receptor (PBR). [(18)F]4a and [(18)F]4b were synthesized by fluoroethylation of precursors 8a and 8b with [(18)F]FCH(2)CH(2)Br ([(18)F]9), respectively. Small-animal PET scan for a neuroinflammatory rat model showed that the two radioligands had high uptakes of radioactivity in the kainic acid-infused striatum, a brain region where PBR density was increased.
Assuntos
Química Farmacêutica/métodos , Radioisótopos de Flúor/farmacologia , Tomografia por Emissão de Pósitrons/instrumentação , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Receptores de GABA-A/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Desenho de Fármacos , Humanos , Inflamação , Ligantes , Masculino , Modelos Químicos , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Oseltamivir phosphate (Tamiflu, 1.H(3)PO(4) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 (2) with potent activity inhibiting neuraminidase. In this study, for the first time, we synthesized carbon-11-labeled oseltamivir ([(11)C]1) and Ro 64-0802 ([(11)C]2) as two novel positron emission tomography probes and demonstrated that [(11)C]1 had twofold higher radioactivity concentration in the mouse brains than [(11)C]2.
