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Updated: May 8, 2026
Identification of Orexin and Endocannabinoid Receptors in Adult Zebrafish Using Immunoperoxidase and Immunofluorescence Methods
Published on: June 25, 2019
Evaluation of potential PET imaging probes for the orexin 2 receptors
Changning Wang1, Colin M Wilson, Christian K Moseley
1Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, United States.
Abstract:
A wide range of central nervous system (CNS) disorders, particularly those related to sleep, are associated with the abnormal function of orexin (OX) receptors. Several orexin receptor antagonists have been reported in recent years, but currently there are no imaging tools to probe the density and function of orexin receptors in vivo. To date there are no published data on the pharmacokinetics (PK) and accumulation of some lead orexin receptor antagonists. Evaluation of CNS pharmacokinetics in the pursuit of positron emission tomography (PET) radiotracer development could be used to elucidate the association of orexin receptors with diseases and to facilitate the drug discovery and development. To this end, we designed and evaluated carbon-11 labeled compounds based on diazepane orexin receptor antagonists previously described. One of the synthesized compounds, [(11)C]CW4, showed high brain uptake in rats and further evaluated in non-human primate (NHP) using PET-MR imaging. PET scans performed in a baboon showed appropriate early brain uptake for consideration as a radiotracer. However, [(11)C]CW4 exhibited fast kinetics and high nonspecific binding, as determined after co-administration of [(11)C]CW4 and unlabeled CW4. These properties indicate that [(11)C]CW4 has excellent brain penetrance and could be used as a lead compound for developing new CNS-penetrant PET imaging probes of orexin receptors.
Insights
Researchers developed a novel PET imaging agent, [(11)C]CW4, for visualizing orexin receptors in the brain. While showing good uptake, its fast kinetics and high nonspecific binding suggest it
Area of Science:
- Neuroscience
- Radiochemistry
- Pharmacology
Background:
- Central nervous system (CNS) disorders, especially sleep-related ones, are linked to abnormal orexin (OX) receptor function.
- Current limitations exist in in vivo imaging tools for assessing orexin receptor density and function.
- Lack of published pharmacokinetic data for orexin receptor antagonists hinders drug development.
Purpose of the Study:
- To develop and evaluate novel positron emission tomography (PET) radiotracers for imaging orexin receptors in the brain.
- To assess the central nervous system (CNS) pharmacokinetics of potential orexin receptor antagonists.
- To facilitate the understanding of orexin receptor associations with CNS diseases and aid drug discovery.
Main Methods:
- Design and synthesis of carbon-11 labeled compounds based on known diazepane orexin receptor antagonists.
- Evaluation of a lead compound, [(11)C]CW4, in rodent models for brain uptake.
- Further assessment of [(11)C]CW4 in non-human primates (NHPs) using PET-MR imaging, including pharmacokinetic analysis via co-administration with unlabeled antagonist.
Main Results:
- The synthesized compound [(11)C]CW4 demonstrated high brain uptake in rats.
- PET scans in a baboon showed promising early brain uptake for [(11)C]CW4 as a potential radiotracer.
- [(11)C]CW4 exhibited fast kinetics and significant nonspecific binding, indicating good brain penetrance but requiring further optimization.
Conclusions:
- [(11)C]CW4 shows potential as a lead compound for developing novel CNS-penetrant PET imaging probes targeting orexin receptors.
- The compound's properties suggest its utility in studying orexin receptor distribution and dynamics in vivo.
- Further development is warranted to refine the tracer for improved specificity and slower kinetics in orexin receptor imaging.
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