RESUMEN
PURPOSE: [(18)F]AZD4694 (2-(2-(18)F-fluoro-6-(methylamino)-3-pyridyl)benzofuran-5-ol) is a radioligand suitable for imaging of amyloid beta deposits in the living human brain using positron emission tomography (PET). Here, we report the preparation and pharmacokinetic profile of its carbon-11 (t1/2 = 20.4 min) labeled isotopolog [(11)C]AZD4694 and compare [(11)C]AZD4694 with the hitherto most widely applied amyloid PET radioligand [(11)C]Pittsburgh Compound B (PiB). PROCEDURES: The immediate unlabeled precursor to [(11)C]AZD4694 was prepared in a four-step convergent synthesis. Subsequent N-(11)C-methylation of this precursor with [(11)C]methyl iodide yielded [(11)C]AZD4694, which after isolation and formulation was injected into cynomolgus monkeys. The radioactivity in nonhuman primate brain following injection of [(11)C]AZD4694 and [(11)C]PiB was measured using PET. RESULTS: [(11)C]AZD4694 was prepared in a 60 % incorporation yield. In a head to head comparison with [(11)C]PiB, it appeared that [(11)C]AZD4694 displayed slightly lower nonspecific binding in white matter than [(11)C]PiB as well as more rapid pharmacokinetics in the brain. CONCLUSIONS: The advantageous pharmacokinetic profile and low nonspecific binding render [(11)C]AZD4694 a promising PET radioligand for imaging of amyloid beta in the human brain with PET.
Asunto(s)
Péptidos beta-Amiloides/síntesis química , Péptidos beta-Amiloides/farmacocinética , Benzofuranos/síntesis química , Benzofuranos/farmacocinética , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/farmacocinética , Macaca fascicularis/metabolismo , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Compuestos de Anilina/sangre , Compuestos de Anilina/farmacocinética , Animales , Benzofuranos/sangre , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Humanos , Hidrocarburos Fluorados/sangre , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Radiofármacos/sangre , Tiazoles/sangre , Tiazoles/farmacocinética , Factores de TiempoRESUMEN
The penetration of the free radical trapping neuroprotectant NXY-059 into the brain has been examined in rats subjected to permanent middle cerebral artery occlusion (pMCAO). NXY-059 (125 mg/kg bolus followed by 125 mg/kg/h) was infused for 4 h 45 min starting 15 min after right pMCAO or sham operation. At 5 h, there was a similar plasma total NXY-059 concentration (micromol/L) in both groups [sham: 623 +/- 44 (6); pMCAO: 605 +/- 43 (5)] and a similar drug concentration (nmol/g) in the right cortex [sham: 6.92 +/- 1.05 (6); pMCAO: 6.14 +/- 2.18 (6)]. A subsequent experiment in normal rats, infusing NXY-059 at both a similar and higher concentration (252 mg/kg bolus and 252 mg/kg/h), demonstrated that the concentration of NXY-059 in cortex increased linearly with respect to the plasma concentration. These data demonstrate that NXY-059 does penetrate brain tissue in control animals and ischemic tissue of animals subjected to pMCAO.
