Synthesis and Evaluation of Radioligands for Imaging Brain Nociceptin/Orphanin FQ Peptide (NOP) Receptors with Positron Emission Tomography

Pike, Victor W.; Rash, Karen; Chen, Zhaogen; Pedregal, Concepciòn; Statnick, Michael A.; Kimura, Yasuyuki; Hong, Jinsoo; Zoghbi, Sami S.; Fujita, Masahiro; Toledo, Miguel Ángel; Dı́az, Nuria; Gackenheimer, Susan L.; Tauscher, Johannes; Barth, Vanessa N.; Innis, Robert B.

doi:10.1021/jm101487v

Cited by 62 publications

(73 citation statements)

References 36 publications

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“…These findings raise the intriguing possibility that LY2940094 may be effective in the treatment of patients with BED and/or obesity. Given the existence of a PET ligand for NOP receptors (Pike et al, 2011;Pedregal et al, 2012) and the demonstrated safety of LY2940094 in human clinical investigation (Post et al, 2014), LY2940094 can be used to study the role of NOP receptors in eating disorders and metabolic complications.…”

Section: Discussionmentioning

confidence: 99%

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Statnick

Chen

Ansonoff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Nociceptin/orphanin FQ (N/OFQ), a 17 amino acid peptide, is the endogenous ligand of the ORL1/nociceptin-opioid-peptide (NOP) receptor. N/OFQ appears to regulate a variety of physiologic functions including stimulating feeding behavior. Recently, a new class of thienospiro-piperidine-based NOP antagonists was described. One of these molecules, LY2940094 has been identified as a potent and selective NOP antagonist that exhibited activity in the central nervous system. Herein, we examined the effects of LY2940094 on feeding in a variety of behavioral models. Fasting-induced feeding was inhibited by LY2940094 in mice, an effect that was absent in NOP receptor knockout mice. Moreover, NOP receptor knockout mice exhibited a baseline phenotype of reduced fasting-induced feeding, relative to wild-type littermate controls. In lean rats, LY2940094 inhibited the overconsumption of a palatable high-energy diet, reducing caloric intake to control chow levels. In dietary-induced obese rats, LY2940094 inhibited feeding and body weight regain induced by a 30% daily caloric restriction. Last, in dietary-induced obese mice, LY2940094 decreased 24-hour intake of a high-energy diet made freely available. These are the first data demonstrating that a systemically administered NOP receptor antagonist can reduce feeding behavior and body weight in rodents. Moreover, the hypophagic effect of LY2940094 is NOP receptor dependent and not due to off-target or aversive effects. Thus, LY2940094 may be useful in treating disorders of appetitive behavior such as binge eating disorder, food choice, and overeating, which lead to obesity and its associated medical complications and morbidity.

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Section: Discussionmentioning

confidence: 99%

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Statnick

Chen

Ansonoff

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…To assess the applicability of the method to clinical data, we applied the genomic plot to the following brain PET tracers: 1)[ 11 C]WAY100635, targeting the serotonin 5-HT 1A receptor (Pike et al, 1996); 2)[ 11 C]Ro15-4513 targeting the GABA α5 receptor (Lingford-Hughes et al, 2002); 3)[ 11 C]LY2795050 targeting the kappa opioid receptor (Zheng et al, 2013); 4)[ 18 F]FIMX, targeting the metabotropic glutamate receptor 1 (Xu et al, 2013); 5)[ 11 C]NOP-1A targeting the nociceptin/orphanin FQ peptide receptor (Pike et al, 2011); 6)[ 11 C](R)rolipram, targeting the phosphodiesterase 4 enzyme (Fujita et al, 2005); 7)[ 11 C]Raclopride, targeting the dopamine D2 receptors (Ehrin et al, 1985). …”

Section: Methodsmentioning

confidence: 99%

Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot

et al. 2016

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PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.

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“…At a translational level, the use of radiolabeled molecules that bind the NOP receptor in the brain (Hostetler et al, 2013; Kimura et al, 2011; Linz et al, 2014; Lohith et al, 2014; Lohith et al, 2012; Pedregal et al, 2012; Pike et al, 2011; Thomsen et al, 2000) could provide insight into the association between N/OFQ-NOP receptor levels, human learning and memory, and brain disorders (e.g. Posttraumatic stress disorder, Alzheimer, Parkinson, etc.).…”

Section: Nociceptin and The Nociceptin Receptor In Learning And Mementioning

confidence: 99%

Nociceptin and the nociceptin receptor in learning and memory

Andero

2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Summary There are many processes in which the neuropeptide nociceptin/orphanin FQ (N/OFQ or nociceptin) is involved in the brain. The role of nociceptin in learning and memory holds promise in modulating these processes in health and disease in the human brain. This review summarizes the body of research focused on N/OFQ and its specific receptor, the nociceptin receptor (NOP receptor), in learning and memory, and its potential mechanisms of action, in which acetylcholine, NMDA receptor and noradrenaline may be critical. Finally, the association between NOP receptor and Posttraumatic stress disorder (PTSD), a psychiatric disorder with altered fear learning, is examined as one of the potential outcomes resulting from pathological consequences of dysregulation of N/OFQ-NOP receptor in the brain.

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Synthesis and Evaluation of Radioligands for Imaging Brain Nociceptin/Orphanin FQ Peptide (NOP) Receptors with Positron Emission Tomography

Cited by 62 publications

References 36 publications

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

Measuring specific receptor binding of a PET radioligand in human brain without pharmacological blockade: The genomic plot

Nociceptin and the nociceptin receptor in learning and memory

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