title: Synthesis, binding affinity, radiolabeling, and microPET evaluation of 4-(2-substituted-4-substituted)-8-(dialkylamino)-6-methyl-1-substituted-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-ones as ligands for brain corticotropin-releasing factor type-1 (CRF1) receptors.
abstract: Compounds 1-14 were synthesized in a search for high-affinity CRF1 receptor ligands that could be radiolabeled with (11)C or (18)F for use as positron emission tomography (PET) radiotracers. Derivatives of 2 were developed which contained amide N-fluoroalkyl substituents. Compounds [(18)F]24 and [(18)F]25 were found to have appropriate lipophilicities of logP7.4=2.2 but microPET imaging with [(18)F]25 demonstrated limited brain uptake.
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA. Electronic address: jstehou@emory.edu.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Stehouwer
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Chase H
authors.initials: CH
authors.lastname: Bourke
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.affiliation: Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Clinton D
authors.initials: CD
authors.lastname: Kilts
authors.affiliation: Center for Systems Imaging, Department of Radiology and Imaging Sciences, Emory University, WWHC 209, 1841 Clifton Rd NE, Atlanta, GA 30329, USA; Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D005462:Fluorine Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008252:Macaca fascicularis; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry; D049268:Positron-Emission Tomography; D011719:Pyrazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000378:metabolism*; D000099052:CRF Receptor, Type 1
chemical_list: D000631:Aminopyridines; C101531:CRF receptor type 2; D005462:Fluorine Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D010446:Peptide Fragments; D011719:Pyrazines; D019275:Radiopharmaceuticals; D018019:Receptors, Corticotropin-Releasing Hormone; C116607:antisauvagine 30; D000099052:CRF Receptor, Type 1
keywords: CRF-1 receptor; Corticotropin-releasing factor; Fluorine-18; PET imaging; Positron emission tomography