An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates

Smith, Aaron L.; Walum, Hasse; Connor-Stroud, Fawn; Freeman, Sara M.; Inoue, Kiyoshi; Parr, Lisa A.; Goodman, Mark M.; Young, Larry J.

doi:10.1016/j.bmc.2016.10.035

Cited by 8 publications

(4 citation statements)

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“…A potential alternative for future studies is to make use of recently available selective antagonists which penetrate into the CSF (Smith et al, 2017). When combined with precise microinjection techniques it would be possible to selectively block OT receptors in various brain regions, and assess both behavioral and neurophysiological changes induced by IN, AE, or peripheral administration of OT.…”

Section: Studies Of Oxytocin In Non-human Primatesmentioning

confidence: 99%

“…As previously described, rodents and NHPs show considerable differences in the expression and pharmacological properties of OXTRs, which limits our ability to extrapolate findings from rodents to humans and NHPs. A potential alternative for future studies is to make use of recently available selective antagonists which penetrate into the CSF (Smith et al, 2017). When combined with precise microinjection techniques it would be possible to selectively block OT receptors in various brain regions, and assess both behavioral and neurophysiological changes induced by IN, AE, or peripheral administration of OT.…”

Section: Studies Of Oxytocin In Non-human Primatesmentioning

confidence: 99%

See 1 more Smart Citation

Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

Putnam

Young²,

Gothard

2018

American J Primatol

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Oxytocin (OT), a neuropeptide that acts in the brain as a neuromodulator, has been long known to shape maternal physiology and behavior in mammals, however its role in regulating social cognition and behavior in primates has come to the forefront only in the recent decade. Many of the current perspectives on the role of OT in modulating social behavior emerged first from studies in rodents, where invasive techniques with a high degree of precision have permitted the mechanistic dissection of OT-related behaviors, as well as their underlying neural circuits in exquisite detail. In parallel, behavioral and imaging studies in humans have suggested that brain OT may similarly influence human social behavior and neural activity. These studies in rodents and humans have spurred interest in the therapeutic potential of targeting the OT system to remedy deficits in social cognition and behavior that are present across numerous psychiatric disorders. Yet there remains a tremendous gap in our mechanistic understanding of the influence of brain OT on social neural circuitry between rodents and man. In fact, very little is known regarding the neural mechanisms by which exogenous or endogenous OT influences human social cognition, limiting its therapeutic potential. Here we discuss how non-human primates (NHPs) are uniquely positioned to now bridge the gaps in knowledge provided by the precise circuit-level approaches widely used in rodent models and the behavioral, imaging, and clinical studies in humans. This review provides a perspective on what has been achieved, and what can be expected from exploring the role of OT in shaping social behaviors in NHPs in the coming years.

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Section: Studies Of Oxytocin In Non-human Primatesmentioning

confidence: 99%

Section: Studies Of Oxytocin In Non-human Primatesmentioning

confidence: 99%

Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

Putnam

Young²,

Gothard

2018

American J Primatol

Self Cite

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“…There is a substantial need for the discovery of specific radio-ligands, small antagonists, or agonists of OTR that could penetrate the brain and that we can use to image OTR in vivo in the human brain using positron emission topography. Our group evaluated a potent and selective oxytocin receptor antagonist in nonhuman primate and showed that it mildly penetrated the brain (Smith et al 2016). These results are promising and further research on small potent molecules that penetrate the brain can be important to pursue in the human population.…”

Section: Oxytocin System Origin Structure Synthesis and Releasementioning

confidence: 99%

A Precision Medicine Approach to Oxytocin Trials

Andari

Hurlemann

Young

2017

Behavioral Pharmacology of Neuropeptides: Oxytocin

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In this chapter, we introduce a new area of social pharmacology that encompasses the study of the role of neuromodulators in modulating a wide range of social behaviors and brain function, with the interplay of genetic and epigenetic factors. There are increasing evidences for the role of the neuropeptide oxytocin in modulating a wide range of social behaviors, in reducing anxiety, and in impacting the social brain network. Oxytocin also promotes social functions in patients with neuropsychiatric disorders, such as autism and reduces anxiety and fear in anxiety disorders. In this chapter, we will emphasize the importance of integrating basic research and clinical human research in determining optimal strategies for drug discoveries for social dysfunctions and anxiety disorders. We will highlight the significance of adopting a precision medicine approach to optimize targeted treatments with oxytocin in neuropsychiatry. Oxytocin effects on social behavior and brain function can vary from one individual to another based on external factors, such as heterogeneity in autism phenotype, childhood experiences, personality, attachment style, and oxytocin receptor polymorphisms. Hence, targeted therapies for subgroups of patients can help alleviating some of the core symptoms and lead to a better future for these patients and their families.

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“…14,15 For in vivo SPECT imaging, Gallium-67 labelled OT has been reported. 16 Recently, several candidate molecules were evaluated for in vivo imaging of the central OTR; [17][18][19][20][21][22] however, despite some encouraging in vitro results, PET imaging studies showed either no significant brain uptake or a limited CNS distribution that did not correspond to the expected OTR distribution.…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and evaluation of 1‐substituted 3‐(2,3‐dihydro‐1H‐inden‐2‐yl)‐6‐(1‐ethylpropyl)‐(3R,6R)‐2,5‐piperazinedione derivatives as PET tracers for imaging the central oxytocinergic system

Marzano

Jakobsen

Salinas

et al. 2017

Labelled Comp Radiopharmac

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Oxytocin is known to be implicated in a variety of functions, such as learning, stress, anxiety, feeding, and pain perception. Oxytocin is also important for social memory and attachment, human bonding, sexual and maternal behaviour, and aggression. Human disorders characterized by aberrant social interactions, such as autism and schizophrenia, may also involve abnormal oxytocin levels. GSK712043, GSK711320, and GSK664004, three antagonists exhibiting subnanomolar affinity for the human oxytocin receptor (hOTR) and high selectivity over vasopressin receptors were successfully labelled with carbon-11 with suitable yields (0.5-1GBq @EOS), high molar activity (275-700 GBq/μmol), and radiochemical purities. The in vivo regional uptake of these radiotracers was determined in porcine brain. [ C]GSK711320 baseline scan showed no significant brain uptake, and limited initial uptake was observed following administration of [ C]GSK712043 or [ C]GSK664004. The [ C]GSK712043 and [ C]GSK664004 kinetics were slow and peaked at around 2%ID/L at 90 minutes post-injection. For both tracers, the distribution of activity was homogeneous throughout the brain. All the tracers showed high uptake in the pituitary gland, especially [ C]GSK711320; however, its uptake could not be blocked by pretreatment with the known OTR antagonist, L368,899. In vivo evaluation of these candidates demonstrated that they are not suitable as central OTR PET imaging agents.

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An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates

Cited by 8 publications

References 53 publications

Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

Bridging the gap between rodents and humans: The role of non‐human primates in oxytocin research

A Precision Medicine Approach to Oxytocin Trials

Radiosynthesis and evaluation of 1‐substituted 3‐(2,3‐dihydro‐1H‐inden‐2‐yl)‐6‐(1‐ethylpropyl)‐(3R,6R)‐2,5‐piperazinedione derivatives as PET tracers for imaging the central oxytocinergic system

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