title: Synthesis and evaluation of candidate PET radioligands for corticotropin-releasing factor type-1 receptors.
abstract: BACKGROUND
  A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold.
  
  
  METHODS
  CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [(125)I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [(3)H]BMS-728300.
  
  
  RESULTS
  The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [(3)H]BMS-728300 and the two (18)F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [(18)F]BMS-721313, [(18)F]BMS-732098 and [(11)C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro.
  
  
  CONCLUSIONS
  Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.
authors.affiliation: Department of Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.affiliation: Department of Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892, USA; Department of Radiology, Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA 94305-5484, USA.
authors.forename: Frederick T
authors.initials: FT
authors.lastname: Chin
authors.affiliation: Department of Radiochemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Dischino
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Department of Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Deskus
authors.affiliation: Department of Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Mattson
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Masao
authors.initials: M
authors.lastname: Imaizumi
authors.affiliation: Department of Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Rick
authors.initials: R
authors.lastname: Pieschl
authors.affiliation: Department of Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Department of Veterinary Sciences, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Dulac
authors.affiliation: Department of Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.affiliation: Department of Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Department of Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm. B3 C346A, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D008024:Ligands; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011854:Radiochemistry; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D014018:Tissue Distribution; D000099052:CRF Receptor, Type 1
chemical_list: D008024:Ligands; D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: Autoradiography; Corticotropin‐releasing factor (CRF); Positron emission tomography (PET); Rhesus monkey; [(11)C]BMS-709460; [(18)F]BMS-721313; [(18)F]BMS-732098