Radiosynthesis and evaluation of [¹¹C]EMPA as a potential PET tracer for orexin 2 receptors

EMPA is a selective antagonist of orexin 2 (OX₂) receptors. Previous literature with [³H]-EMPA suggest that it may be used as an imaging agent for OX₂ receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11. Radiosynthesis of [¹¹C]N-ethyl-2-(N-(6-methoxypyridin-3- yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([ ¹¹C]EMPA), and evaluation as a potential PET tracer for OX ₂ receptors is described. Synthesis of an appropriate non-radioactive O-desmethyl precursor was achieved from EMPA with sodium iodide and chlorotrimethylsilane. Selective O-methylation using [¹¹C]CH ₃I in the presence of cesium carbonate in DMSO at room temp afforded [¹¹C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [¹¹C]CH₃I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36 min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [¹¹C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.