A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging

Area of Science:

• Neuroscience
• Radiochemistry
• Pharmacology

Background:

• Orexin receptors (OXRs) play a crucial role in regulating sleep-wake cycles and motivation.
• Dysregulation of OXRs is implicated in various mood disorders, highlighting their therapeutic potential.
• Investigating OXRs in the living human brain is essential for understanding their function and developing targeted therapies.

Purpose of the Study:

• To develop and characterize a novel positron emission tomography (PET) probe, [¹¹C]CW24, for imaging OXRs in the brain.
• To evaluate the suitability of [¹¹C]CW24 for studying OXR distribution and dynamics in vivo.
• To assess the potential of [¹¹C]CW24 for evaluating orexin-targeting therapeutics.

Main Methods:

• Radiosynthesis and characterization of the novel PET tracer [¹¹C]CW24.
• In vitro binding assays to determine affinity and selectivity of CW24 for OXRs.
• In vivo PET imaging studies in rodent and nonhuman primate models to assess brain uptake, distribution, and pharmacokinetics.
• Evaluation of metabolic stability of [¹¹C]CW24.

Main Results:

• [¹¹C]CW24 demonstrated moderate binding affinity for OX1R and OX2R.
• The tracer exhibited high selectivity for OXRs over 40 other CNS targets.
• [¹¹C]CW24 showed high brain uptake, suitable metabolic stability, and appropriate pharmacokinetic properties in preclinical models.
• The probe displayed favorable distribution and pharmacokinetics for brain PET imaging.

Conclusions:

• [¹¹C]CW24 is a promising novel PET imaging probe for visualizing orexin receptors in the brain.
• The tracer's characteristics support its further evaluation for preclinical and potentially clinical studies of OXR-related functions and disorders.
• [¹¹C]CW24 may serve as a valuable tool for assessing the efficacy of orexin-targeting therapeutics.