Adenosine is a ubiquitous neuromodulator, and adenosine receptor A3 subtype belongs to the G-protein-coupled receptor superfamily. A3 receptor is involved in many important physiological effects and associated with a wide variety of brain, heart and cancer diseases. A3 receptor has become a promising therapeutic target, and a series of 1,2,4-triazolo[4,3,a]quinoxalin-1-one derivatives has been recently developed as new potent and selective A3 antagonists by Colotta et al. A3 receptor is also an attractive imaging target. Here we report the synthesis of carbon-11-labeled 1,2,4-triazolo[4,3,a]quinoxalin-1-one derivatives for use in biomedical imaging technique positron emission tomography (PET) to image A3 adenosine receptor. The reference standards 2-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione, 2-(4-methoxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione, 4-amino-2-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one, 4-amino-2-(4-methoxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one, N-(2-(4-methoxyphenyl)-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)benzamide, N-(2-(4-methoxyphenyl)-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-2,2-diphenylacetamide, and N-(2-(4-methoxyphenyl)-6-nitro-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-2,2-diphenylacetamide were synthesized from 4-methoxyaniline, ethyl 2-chloro-acetoacetate and substituted benzene-1,2-diamines with 3, 5, and 6 steps in 67-75%, 38-47% and 26-35% overall chemical yield, respectively. The precursors 2-(4-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione, 2-(4-hydroxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione, 4-amino-2-(4-hydroxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one, 4-amino-2-(4-hydroxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one, N-(2-(4-hydroxyphenyl)-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)benzamide, N-(2-(4-hydroxyphenyl)-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-2,2-diphenylacetamide, and N-(2-(4-hydroxyphenyl)-6-nitro-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-2,2-diphenylacetamide were synthesized from 4-methoxyaniline, ethyl 2-chloro-acetoacetate and substituted benzene-1,2-diamines with 4, 6, and 7 steps in 54-63%, 30-40% and 22-32% overall chemical yield, respectively. The target tracers 2-(4-[11C]methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione, 2-(4-[11C]methoxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione, 4-amino-2-(4-[11C]methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one, 4-amino-2-(4-[11C]methoxyphenyl)-6-nitro-[1,2,4]triazolo[4,3-a]quinoxalin-1(2H)-one, N-(2-(4-[11C]methoxyphenyl)-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)benzamide, N-(2-(4-[11C]methoxyphenyl)-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-2,2-diphenylacetamide, and N-(2-(4-[11C]methoxyphenyl)-6-nitro-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-2,2-diphenylacetamide were synthesized from their corresponding precursors with [11C]CH3OTf through O-[11C]methylation and isolated by simplified solid-phase extraction (SPE, C18 Sep-Pak) in 30-60% radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB), with 185-370 GBq/�mol specific activity at end of synthesis (EOS).

Synthesis of carbon-11-labeled 1,2,4-triazolo[4,3,<i>a</i>]quinoxalin-1-one derivatives for imaging of A<sub>3</sub> adenosine receptor

247th National Meeting (2014)

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Synthesis of carbon-11-labeled 1,2,4-triazolo[4,3,a]quinoxalin-1-one derivatives for imaging of A3 adenosine receptor

Synthesis of carbon-11-labeled 1,2,4-triazolo[4,3,a]quinoxalin-1-one derivatives for imaging of A₃ adenosine receptor