title: Design, synthesis and evaluation of [(3)H]PF-7191, a highly specific nociceptin opioid peptide (NOP) receptor radiotracer for in vivo receptor occupancy (RO) studies.
abstract: Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6'-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1'-isochroman]-8-yl)propyl)-N-[(3)H]-methylacetamide {[(3)H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki = 0.1 nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (C(b,u)/C(p,u) = 0.29). Subsequent characterization of [(3)H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [(3)H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose-responsive manner. This overall favorable profile indicated that [(3)H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species.
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA. Electronic address: lei.zhang3@pfizer.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neuroscience Research Unit, Pfizer Inc., Cambridge, MA 02139, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Drummond
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brodney
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Cianfrogna
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Drozda
authors.affiliation: Neuroscience Research Unit, Pfizer Inc., Cambridge, MA 02139, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Grimwood
authors.affiliation: Primary Pharmacology Group, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Vanase-Frawley
authors.affiliation: Neuroscience Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02139, USA.
authors.forename: Anabella
authors.initials: A
authors.lastname: Villalobos
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D014316:Tritium / Q000737:chemistry / Q000378:metabolism*; D000094942:Nociceptin Receptor
chemical_list: D018847:Opioid Peptides; D011957:Receptors, Opioid; D014316:Tritium; D000094942:Nociceptin Receptor; C000722285:Oprl1 protein, rat
keywords: NOP receptor; ORL1; PET; Radiotracer; Receptor occupancy