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
Neuroinflammation, in particular activation of microglia, is thought to play an important role in the progression of neurodegenerative diseases. In activated microglia, the purinergic P2X7 receptor is upregulated. A-740003, a highly affine and selective P2X7 receptor antagonist, is a promising candidate for the development of a radiotracer for imaging of neuroinflammation by positron emission tomography. For this purpose, [(11)C]A-740003 was synthesised and evaluated in vivo with respect to both tracer metabolism and biodistribution. In plasma, a moderate metabolic rate was seen. In healthy rat brain, only marginal uptake of [(11)C]A-740003 was observed and, therefore, metabolites in brain could not be determined. Whether the minimal brain uptake is due to the low expression levels of the P2X7 receptor in healthy brain or to limited transport across the blood-brain barrier has yet to be elucidated.
Asunto(s)
Acetamidas/síntesis química , Encéfalo/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2X/síntesis química , Quinolinas/síntesis química , Radiofármacos/síntesis química , Acetamidas/farmacocinética , Animales , Encéfalo/patología , Isótopos de Carbono/química , Evaluación Preclínica de Medicamentos , Masculino , Antagonistas del Receptor Purinérgico P2X/farmacocinética , Quinolinas/farmacocinética , Radiofármacos/farmacocinética , Ratas , Ratas Wistar , Distribución TisularRESUMEN
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) like sorafenib are important anticancer therapeutics with thus far limited treatment response rates in cancer patients. Positron emission tomography (PET) could provide the means for selection of patients who might benefit from TKI treatment, if suitable PET tracers would be available. The aim of this study was to radiolabel sorafenib (1) with carbon-11 and to evaluate its potential as TKI-PET tracer in vivo. METHODS: Synthetic methods were developed in which sorafenib was labeled at two different positions, followed by a metabolite analysis in rats and a PET imaging study in tumor-bearing mice. RESULTS: [methyl-(11)C]-1 and [urea-(11)C]-1 were synthesized in yields of 59% and 53%, respectively, with a purity of >99%. The identity of the products was confirmed by coinjection on HPLC with reference sorafenib. In an in vivo metabolite analysis [(11)C]sorafenib proved to be stable. The percentage of intact product in blood-plasma after 45 min was 90% for [methyl-(11)C]-1 and 96% for [urea-(11)C]-1, respectively. Due to the more reliable synthesis, further research regarding PET imaging was performed with [methyl-(11)C]-1 in nude mice bearing FaDu (head and neck cancer), MDA-MB-231 (breast cancer) or RXF393 (renal cancer) xenografts. Highest tracer accumulation at a level of 2.52 ± 0.33%ID/g was observed in RXF393, a xenograft line extensively expressing the sorafenib target antigen Raf-1 as assessed by immunohistochemistry. CONCLUSION: In conclusion, we have synthesized [(11)C]sorafenib as PET tracer, which is stable in vivo and has the capability to be used as PET tracer for imaging in tumor-bearing mice.
Asunto(s)
Neoplasias/diagnóstico por imagen , Niacinamida/análogos & derivados , Compuestos de Fenilurea/química , Tomografía de Emisión de Positrones/métodos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Radioquímica , Animales , Radioisótopos de Carbono , Línea Celular Tumoral , Transformación Celular Neoplásica , Masculino , Ratones , Neoplasias/patología , Niacinamida/química , Niacinamida/metabolismo , Niacinamida/farmacocinética , Compuestos de Fenilurea/metabolismo , Compuestos de Fenilurea/farmacocinética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Trazadores Radiactivos , Ratas , SorafenibRESUMEN
INTRODUCTION: To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar. METHODS: Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar. RESULTS: [(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment. CONCLUSIONS: We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.
Asunto(s)
Benzazepinas , Epilepsia/diagnóstico por imagen , Epilepsia/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Quinidina , Quinolinas , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Benzazepinas/sangre , Benzazepinas/química , Benzazepinas/metabolismo , Radioisótopos de Carbono , Enfermedad Crónica , Modelos Animales de Enfermedad , Epilepsia/sangre , Epilepsia/metabolismo , Femenino , Regulación de la Expresión Génica , Cinética , Masculino , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Quinidina/sangre , Quinidina/química , Quinidina/metabolismo , Quinolinas/sangre , Quinolinas/química , Quinolinas/metabolismo , Quinolinas/farmacología , Quinolinas/uso terapéutico , Radioquímica , Ratas , Ratas Sprague-Dawley , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: At present, several positron emission tomography (PET) tracers are in use for imaging P-glycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[11C]verapamil display low brain concentrations with a distribution volume of around 1. [11C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [11C]phenytoin and to characterize its properties as a P-gp tracer. METHODS: [11C]CO was used to synthesize [11C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [11C]phenytoin were studied in rats. Effects of P-gp function on [11C]phenytoin uptake were assessed using predosing with tariquidar. RESULTS: [11C]phenytoin was synthesized via [11C]CO in an overall decay-corrected yield of 22 ± 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [11C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [11C]phenytoin. CONCLUSIONS: Using [11C]CO, the radiosynthesis of [11C]phenytoin could be improved. [11C]phenytoin appeared to be a rather weak P-gp substrate.