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

[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....

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Published inBioorganic & 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
LanguageEnglish
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
Online AccessGet full text

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Abstract [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.
AbstractList 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-[H-3]-methylacetamide{[H-3]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (K-i = 0.1 nM), excellent selectivity over other opioid receptors (>1000 x) and good brain permeability in rats (C-b,C-u/C-p,C-u = 0.29). Subsequent characterization of [H-3](+)-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 [H-3](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose-responsive manner. This overall favorable profile indicated that [H-3](+)-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. (C) 2014 Elsevier Ltd. All rights reserved.
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.
[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.
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.
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-[ super(3)H]-methylacetamide {[ super(3)H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (K sub(i) = 0.1 nM), excellent selectivity over other opioid receptors (>1000) and good brain permeability in rats (C sub(b,u)/C sub(p,u) = 0.29). Subsequent characterization of [ super(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 [ super(3)H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose-responsive manner. This overall favorable profile indicated that [ super(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.
Author Cianfrogna, Julie
Brodney, Michael A.
Villalobos, Anabella
Drummond, Elena
Vanase-Frawley, Michelle A.
Zhang, Lei
Drozda, Susan E.
Grimwood, Sarah
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  givenname: Anabella
  surname: Villalobos
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Keywords ORL1
Radiotracer
Receptor occupancy
NOP receptor
PET
LOCALIZATION
CNS
FQ
PARAMETERS
DISCOVERY
POSITRON-EMISSION-TOMOGRAPHY
ORL1 RECEPTOR
CENTRAL-NERVOUS-SYSTEM
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Snippet [Display omitted] Herein we report the identification of...
Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)...
Herein we report the identification of...
Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6'-fluoro-8...
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SubjectTerms 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
Title Design, synthesis and evaluation of [3H]PF-7191, a highly specific nociceptin opioid peptide (NOP) receptor radiotracer for in vivo receptor occupancy (RO) studies
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