RESUMEN
Two potent SP1-7 peptidomimetics have been successfully radiolabeled via [11C]CO2-fixation with excellent yields, purity, and molar activity. l-[11C]SP1-7-peptidomimetic exhibited promising ex vivo biodistribution profile. Metabolite analysis showed that l-[11C]SP1-7-peptidomimetic is stable in brain and spinal cord, whereas rapid metabolic degradation occurs in rat plasma. Metabolic stability can be significantly improved by substituting l-Phe for d-Phe, preserving 70% more of intact tracer and resulting in better brain and spinal cord tracer retention. Positron emission tomography (PET) scanning confirmed moderate brain (1.5 SUV; peak at 3 min) and spinal cord (1.0 SUV; peak at 10 min) uptake for l- and d-[11C]SP1-7-peptidomimetic. A slight decrease in SUV value was observed after pretreatment with natural peptide SP1-7 in spinal cord for l-[11C]SP1-7-peptidomimetic. On the contrary, blocking using cold analogues of l- and d-[11C]tracers did not reduce the tracers' brain and spinal cord exposure. In summary, PET scanning of l- and d-[11C]SP1-7-peptidomimetics confirms rapid blood-brain barrier and blood-spinal-cord barrier penetration. Therefore, further validation of these two tracers targeting SP1-7 is needed in order to define a new PET imaging target and select its most appropriate radiopharmaceutical.
Asunto(s)
Imagen Molecular/métodos , Peptidomiméticos/farmacocinética , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Sustancia P/metabolismo , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/metabolismo , Radioisótopos de Carbono/química , Evaluación Preclínica de Medicamentos , Inyecciones Intravenosas , Masculino , Modelos Animales , Peptidomiméticos/administración & dosificación , Peptidomiméticos/química , Permeabilidad , Radiofármacos/administración & dosificación , Radiofármacos/química , Ratas , Ratas Wistar , Médula Espinal/diagnóstico por imagen , Médula Espinal/metabolismo , Distribución TisularRESUMEN
[(18)F]FDDNP is a positron emission tomography (PET) tracer for determining amyloid plaques and neurofibrillary tangles in the brain in vivo. In order to quantify binding of this tracer properly, a metabolite-corrected plasma input function is required. The purpose of the present study was to develop a sensitive method for measuring [(18)F]FDDNP and its radiolabelled metabolites in plasma. The second aim was to assess whether these radiolabelled metabolites enter the brain. In humans, there was extensive metabolism of [(18)F]FDDNP. After 10 min, more than 80% of plasma radioactivity was identified as polar (18)F-labelled fragments, probably formed from N-dealkylation of [(18)F]FDDNP. These labelled metabolites were reproduced in vitro using human hepatocytes. PET studies in rats showed that these polar metabolites can penetrate the blood-brain barrier and result in uniform brain uptake.