title: Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors.
abstract: EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [(3)H]-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 [(11)C]N-ethyl-2-(N-(6-methoxypyridin-3-yl)-2-methylphenylsulfonamido)-N-(pyridin-3-ylmethyl)acetamide ([(11)C]EMPA), and evaluation as a potential PET tracer for OX2 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 [(11)C]CH3I in the presence of cesium carbonate in DMSO at room temp afforded [(11)C]EMPA in 1.5-2.5% yield (non-decay corrected relative to trapped [(11)C]CH3I at EOS) with ≥95% chemical and radiochemical purities. The total synthesis time was 34-36min from EOB. Studies in rodent suggested that uptake in tissue was dominated by nonspecific binding. However, [(11)C]EMPA also showed poor uptake in both rats and baboon as measured with PET imaging.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Building 149, 13th Street, Suite 2301, Charlestown, MA 02129, USA.
authors.forename: Changning
authors.initials: C
authors.lastname: Wang
authors.forename: Christian K
authors.initials: CK
authors.lastname: Moseley
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Carlin
authors.forename: Colin M
authors.initials: CM
authors.lastname: Wilson
authors.forename: Ramesh
authors.initials: R
authors.lastname: Neelamegam
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
mesh_terms: D000631:Aminopyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes / Q000737:chemistry; D002254:Carbonates / Q000737:chemistry; D002586:Cesium / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors / Q000378:metabolism; D010215:Papio; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D012974:Sodium Iodide / Q000737:chemistry; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014297:Trimethylsilyl Compounds / Q000737:chemistry
chemical_list: D000631:Aminopyridines; D002250:Carbon Radioisotopes; D002254:Carbonates; C546023:N-ethyl-2-((6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)amino)-N-pyridin-3-ylmethyl-acetamide; D000068796:Orexin Receptor Antagonists; D064446:Orexin Receptors; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D014297:Trimethylsilyl Compounds; D002586:Cesium; C039293:trimethylchlorosilane; D012974:Sodium Iodide; C545311:cesium carbonate