RESUMEN
The cartilage-targeting strategy is based on the strong affinity of quaternary ammonium (QA) functions for cartilage proteoglycans. We use a bifunctional agent containing QA moiety and a polyazamacrocycle structure able to complex technetium-99m. (99m)Tc-NTP 15-5 was selected for its high stability and its high affinity for proteoglycans in vivo. Labeling conditions of NTP 15-5 were optimized, and a lyophilized kit was developed for radiolabeling of (99m)Tc-NTP 15-5 (radiochemical yields 94.6±1.8%). (99m)Tc-NTP 15-5 was stable and resulted in favorable biological evaluations.
Asunto(s)
Cartílago/diagnóstico por imagen , Cartílago/metabolismo , Compuestos Heterocíclicos con 1 Anillo/aislamiento & purificación , Compuestos de Organotecnecio/aislamiento & purificación , Proteoglicanos/metabolismo , Compuestos de Amonio Cuaternario/aislamiento & purificación , Radiofármacos/aislamiento & purificación , Tecnecio/aislamiento & purificación , Animales , Enfermedades de los Cartílagos/diagnóstico por imagen , Enfermedades de los Cartílagos/metabolismo , Química Farmacéutica , Liofilización/métodos , Compuestos Heterocíclicos con 1 Anillo/sangre , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Indicadores y Reactivos , Compuestos de Organotecnecio/sangre , Compuestos de Organotecnecio/farmacocinética , Compuestos de Amonio Cuaternario/sangre , Compuestos de Amonio Cuaternario/farmacocinética , Cintigrafía , Radiofármacos/sangre , Radiofármacos/farmacocinética , Ratas , Tecnecio/sangre , Tecnecio/farmacocinéticaRESUMEN
The proteasome is a promising target in cancer therapy. However, it is ubiquitous and its inhibitors cause side effects. To target melanoma cells we synthesized new peptide aldehyde and vinylsulfone inhibitors of the proteasome conjugated to the melanin-targeting ligand (MTL) derived from radiotracer [(123)I]-N-(2-diethylaminoethyl)benzamide ([(123)I]BZA) or [(125)I]-N-(4-dipropylaminobutyl)-4-iodobenzamide ([(125)I]BZ18). Influence on the cytotoxicity of the benzamide alkyl side chain length and the composition of the amino acid sequence was assessed. Among the conjugates evaluated, compound 16 and 22 presented the highest cytotoxicity (IC(50), 0.71 and 0.64 µM respectively), which persisted in the presence of an MTL derived from N-(dialkylaminoalkylenyl)benzamide residue.
