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1.
Mol Imaging Biol ; 21(1): 113-121, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-29869061

RESUMEN

PURPOSE: There is an urgent need for the development of novel positron emission tomography (PET) tracers for glioma imaging. In this study, we developed a novel PET probe ([18F]VUIIS1018A) by targeting translocator protein (TSPO), an imaging biomarker for glioma. The purpose of this preclinical study was to evaluate this novel TSPO probe for glioma imaging. PROCEDURES: In this study, we synthesized [19F]VUIIS1018A and the precursor for radiosynthesis of [18F]VUIIS1018A. TSPO binding affinity was confirmed using a radioligand competitive binding assay in C6 glioma cell lysate. Further, dynamic imaging studies were performed in rats using a microPET system. These studies include displacement and blocking studies for ligand reversibility and specificity evaluation, and compartment modeling of PET data for pharmacokinetic parameter measurement using metabolite-corrected arterial input functions and PMOD. RESULTS: Compared to previously reported TSPO tracers including [18F]VUIIS1008 and [18F]DPA-714, the novel tracer [18F]VUIIS1018A demonstrated higher binding affinity and BPND. Pretreatment with the cold analog [19F]VUIIS1018A could partially block tumor accumulation of this novel tracer. Further, compartment modeling of this novel tracer also exhibited a greater tumor-to-background ratio, a higher tumor binding potential and a lower brain binding potential when compared with other TSPO probes, such as [18F]DPA-714 and [18F]VUIIS1008. CONCLUSIONS: These studies illustrate that [18F]VUIIS1018A can serve as a promising TSPO PET tracer for glioma imaging and potentially imaging of other solid tumors.


Asunto(s)
Neoplasias Encefálicas/diagnóstico , Radioisótopos de Flúor/farmacocinética , Glioma/diagnóstico , Tomografía de Emisión de Positrones/métodos , Pirazoles/farmacocinética , Pirimidinas/farmacocinética , Animales , Neoplasias Encefálicas/patología , Proteínas Portadoras/agonistas , Proteínas Portadoras/metabolismo , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Glioma/patología , Ligandos , Imagen por Resonancia Magnética , Masculino , Ratas , Ratas Wistar , Receptores de GABA-A/metabolismo , Células Tumorales Cultivadas
2.
Eur J Med Chem ; 150: 1-8, 2018 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-29505933

RESUMEN

Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [18F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[18F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([18F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [18F]DPA-714. We evaluated the performance of [18F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BPND), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [18F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.


Asunto(s)
Modelos Animales de Enfermedad , Inflamación/diagnóstico , Isquemia/diagnóstico , Sondas Moleculares/química , Radiofármacos/química , Receptores de GABA/análisis , Animales , Relación Dosis-Respuesta a Droga , Radioisótopos de Flúor , Humanos , Inflamación/metabolismo , Isquemia/metabolismo , Masculino , Ratones , Estructura Molecular , Tomografía de Emisión de Positrones , Pirazoles , Pirimidinas , Trazadores Radiactivos , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Distribución Tisular
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