title: Radiosynthesis of [11C]BBAC and [11C]BBPC as potential PET tracers for orexin2 receptors.
abstract: Radiosynthesis of [N-methyl-(11)C](S)-N-([1,1'-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide ([(11)C]BBAC or [(11)C]3) and [N-methyl-(11)C] (S)-N-([1,1'-biphenyl]-2-yl)-1-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)propanoyl)pyrrolidine-2-carboxamide ([(11)C]BBPC or [(11)C]-4), two potential PET tracers for orexin2 receptors are described. Syntheses of non-radioactive standards 3, 4 and corresponding desmethyl precursors 1, 2 were achieved from common intermediate (S)-2-([1,1'-biphenyl]-2-yl)-1-(pyrrolidin-2-yl)ethanone. Methylation using [(11)C]CH(3)OTf in the presence of base in acetone afforded [(11)C]3 and [(11)C]4 in 30±5% yield (EOS) with >99 % radiochemical purities with a specific activity ranged from 2.5±0.5 Ci/μmol (EOB). The logP of [(11)C]3 and [(11)C]4 were determined as 3.4 and 2.8, respectively. The total synthesis time was 30 min from EOB. However, PET scans performed in a rhesus monkey did not show tracer retention or appropriate brain uptake. Hence [(11)C]3 and [(11)C]4 cannot be used as PET tracers for imaging orexin2 receptors.
authors.affiliation: Division of Substance Abuse, Columbia University Medical Center, New York, NY, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Vattoly J
authors.initials: VJ
authors.lastname: Majo
authors.forename: Jaya
authors.initials: J
authors.lastname: Prabhakaran
authors.forename: John
authors.initials: J
authors.lastname: Castrillion
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Diana
authors.initials: D
authors.lastname: Martinez
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D007553:Isotope Labeling; D008253:Macaca mulatta; D064446:Orexin Receptors; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D000577:Amides; D002250:Carbon Radioisotopes; D064446:Orexin Receptors; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide