Synthesis and in vivo evaluation of [O-methyl-¹¹C] 2-(4-methoxyphenyl)-N-methylbenzyl-N-(1-methylpiperidin-4-yl)acetamide as an imaging probe for 5-HT_2A receptors

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide (AC90179, 4), a highly potent and selective competitive 5-HT_2A antagonist, was labeled by [¹¹C]-methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p-tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and > 99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C]4 Penetrates the blood-brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C]4 cannot be used as PET ligand for imaging 5-HT _2A receptors.