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
An enantioselective method for the synthesis of α-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important α-methyl substituted carboxylic acids in high ee and overall yields of up to 76%.
