High-yielding¹⁸F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptakein vivo

Abstract

Probing the mechanism of intranasal oxytocin brain uptake through generation and validation of a novel peptide PET tracer.

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…Research in rodents and monkeys has shown that molecules administered intranasally can be transported to the olfactory bulb within a time-frame of 45-90 min 54,55 , and possibly much faster [56][57][58] . A recent comparison of intranasal and intravenous administration of a new OT receptor tracer in mice supported this hypothesis by showing uptake of the intranasally administered tracer to the olfactory bulb, while increases in this area after the intravenous administration of the tracer were almost negligible 59 . The increases of the concentration of the tracer in the olfactory bulb following its intranasal administration could be observed as soon as 30 min post-dosing, which fits the time-frame of the effects we report in our study.…”

“…The second mechanism postulates that OT reaches the cerebrospinal fluid (CSF) and brain parenchyma via passive diffusion through perineural clefts in the nasal epithelium, which provide a gap in the blood-brain barrier 17 . While some animal work is consistent with the existence of the second mechanism 18 , there is a lack of robust evidence to support the existence of noseto-brain transport in humans 15,19 .…”

Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans

“…Research in rodents and monkeys has shown that molecules administered intranasally can be transported to the olfactory bulb within a time-frame of 45-90 min (61, 62), and possibly much faster (63). A recent comparison of intranasal and infusion administration of a new OT receptor tracer in mice supported this hypothesis by showing uptake of the intranasally administered tracer to the olfactory bulb, while increases in this area after the infusion of the tracer were almost negligible (64). The increases of the concentration of the tracer in the olfactory bulb following its intranasal administration could be observed as soon as 30 minutes post-dosing, which fits the time-frame of the effects we report in our study.…”

“…The second mechanism postulates that the peptide reaches the cerebrospinal fluid (CSF) and brain parenchyma via passive diffusion through perineural clefts in the nasal epithelium, which provide a gap in the blood-brain barrier (19). While some animal work is consistent with the existence of the second mechanism (20), there is a lack of robust evidence to support the existence of nose-tobrain transport in humans (17,21).…”

Penetration of the blood-brain barrier by peripheral neuropeptides: new approaches to enhancing transport and endogenous expression

“…A recent study in mice reported naked plasmid delivery by the intranasal route resulted in significantly elevated levels of plasmid in the olfactory nerves and hypothalamus compared to all other brain regions whose concentrations did not differ from the control region, the cerebellum (Oviedo, et al, 2017). A recently developed radioligand for the oxytocin receptor, when administered intranasally, resulted in enhanced binding in the olfactory bulbs suggesting a direct nose to brain transport via the intranasal route (Beard, et al, 2018). It remains to be determined though, whether the intranasal route leads to improved penetrance of brain parenchyma overall.…”