Design, synthesis and evaluation of [3H]PF-7191, a highly specific nociceptin opioid peptide (NOP) receptor radiotracer for in vivo receptor occupancy (RO) studies

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 22; pp. 5219 - 5223
• Main Authors: Zhang, Lei, Drummond, Elena, Brodney, Michael A., Cianfrogna, Julie, Drozda, Susan E., Grimwood, Sarah, Vanase-Frawley, Michelle A., Villalobos, Anabella
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.11.2014; Elsevier
• Subjects: Animals; Brain - metabolism; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical - methods; Life Sciences & Biomedicine; NOP receptor; Opioid Peptides - chemistry; Opioid Peptides - metabolism; ORL1; PET; Pharmacology & Pharmacy; Physical Sciences; Protein Binding - physiology; Radiotracer; Rats; Receptor occupancy; Receptors, Opioid - metabolism; Science & Technology; Tritium - chemistry; Tritium - metabolism; ORL1; Radiotracer; Receptor occupancy; NOP receptor; PET; LOCALIZATION; CNS; FQ; PARAMETERS; DISCOVERY; POSITRON-EMISSION-TOMOGRAPHY; ORL1 RECEPTOR; CENTRAL-NERVOUS-SYSTEM
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.09.069

[Display omitted] 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-[3H]-methylacetamide {[3H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki=0.1nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (Cb,u/Cp,u=0.29). Subsequent characterization of [3H](+)-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 [3H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose–responsive manner. This overall favorable profile indicated that [3H](+)-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.