Radiosynthesis of [11C]BBAC and [11C]BBPC as potential PET tracers for orexin2 receptors

• Published in: Bioorganic & medicinal chemistry letters 2012-03, Vol.22 (6), p.2172-2174
• Main Authors: Liu, Fei, Majo, Vattoly J., Prabhakaran, Jaya, Castrillion, John, Mann, J. John, Martinez, Diana, Kumar, J.S. Dileep
• Format: Article
• Language: English
• Subjects: acetone; Amides - chemical synthesis; Amides - metabolism; Amides - pharmacokinetics; Animals; Biological and medical sciences; brain; Brain - diagnostic imaging; Brain - metabolism; Carbon Radioisotopes; Hypocretin; image analysis; Isotope Labeling; Macaca mulatta; Medical sciences; methylation; Orexin; Orexin Receptors; Pharmacology. Drug treatments; Positron emission tomography; Pyrrolidines - chemical synthesis; Pyrrolidines - metabolism; Pyrrolidines - pharmacokinetics; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - metabolism; Radiopharmaceuticals - pharmacokinetics; Radiotracer; receptors; Receptors, G-Protein-Coupled - metabolism; Receptors, Neuropeptide - metabolism; Stereoisomerism; Tissue Distribution; tracer techniques
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.01.114

Radiosynthesis of [N-methyl-11C](S)-N-([1,1′-biphenyl]-2-yl)-1-(2-((1-methyl-1H-benzo[d]imidazol-2-yl)thio)acetyl)pyrrolidine-2-carboxamide ([11C]BBAC or [11C]3) and [N-methyl-11C] (S)-N-([1,1′-biphenyl]-2-yl)-1-(3-(1-methyl-1H-benzo[d]imidazol-2-yl)propanoyl)pyrrolidine-2-carboxamide ([11C]BBPC or [11C]-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 [11C]CH3OTf in the presence of base in acetone afforded [11C]3 and [11C]4 in 30±5% yield (EOS) with >99 % radiochemical purities with a specific activity ranged from 2.5±0.5Ci/μmol (EOB). The logP of [11C]3 and [11C]4 were determined as 3.4 and 2.8, respectively. The total synthesis time was 30min from EOB. However, PET scans performed in a rhesus monkey did not show tracer retention or appropriate brain uptake. Hence [11C]3 and [11C]4 cannot be used as PET tracers for imaging orexin2 receptors.