Abstract
The orexin receptor (OX) is critically involved in motivation and sleep−wake regulation and holds promising therapeutic potential in various mood disorders. To further investigate the role of orexin receptors (OXRs) in the living human brain and to evaluate the treatment potential of orexin-targeting therapeutics, we herein report a novel PET probe ([11C]CW24) for OXRs in the brain. CW24 has moderate binding affinity for OXRs (IC50 = 0.253 μM and 1.406 μM for OX1R and OX2R, respectively) and shows good selectivity to OXRs over 40 other central nervous system (CNS) targets. [11C]CW24 has high brain uptake in rodents and nonhuman primates, suitable metabolic stability, and appropriate distribution and pharmacokinetics for brain positron emission tomography (PET) imaging. [11C]CW24 warrants further evaluation as a PET imaging probe of OXRs in the brain.
Highlights
Orexin (OX) is a hypothalamic hypocretin peptide that mediates multiple functions such as arousal, attention, neuroendocrine, water balance, and pain modulation [1,2,3,4,5,6]
Orexin receptors (OXRs) are differently expressed throughout the brain
~50% reduction in the was found when the blocking dose post-injection of IPSU was of increased to 2.0 (5.0 mg/kg) mouse brain
Summary
Orexin (OX) is a hypothalamic hypocretin peptide that mediates multiple functions such as arousal, attention, neuroendocrine, water balance, and pain modulation [1,2,3,4,5,6]. The orexin system has two peptide members, orexin-A and orexin-B with 33 amino acids and 28 amino acids, respectively [7]. Orexin receptors (OXRs) have two subtypes (OX1 R and OX2 R). Orexin-A has similar binding affinities to OX1 R and OX2 R, while orexin-B has a 10-fold higher affinity for OX2 R compared with. OXRs are differently expressed throughout the brain. OX1 R is mainly expressed in the prefrontal and infralimbic cortex, hippocampus, paraventricular thalamic nucleus, and locus coeruleus [8]
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