A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging

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.

Design, Synthesis, and Evaluation of Thienodiazepine Derivatives as Positron Emission Tomography Imaging Probes for Bromodomain and Extra-Terminal Domain Family Proteins

“…As shown in Table , the lipophilicity increased as the alkyl chain extended. Log D 7.4 values of 3a and 6a were tested based on a shake-flask method . The results showed that 6a possesses lipophilicity with Log D 7.4 < 3.5, indicating a high likelihood of achieving sufficient brain permeability.…”

“…The general procedure for log D determination assays as described in our previous literature. , Briefly, 10 μL of 3a or 6a in DMSO solution (10 mM) was mixed with 100 μL of octanol in PBS buffer (pH 7.4) and followed by shaking in a rotator for 1 h at 30 rpm. Incubations are done in duplicates.…”

Development of a Novel Positron Emission Tomography (PET) Radiotracer Targeting Bromodomain and Extra-Terminal Domain (BET) Family Proteins

“…The general procedure for rodent PET/CT studies was described previously ( Bai et al, 2019 , 2020a ). Briefly, the PET/CT scan was carried out by a Triumph Trimodality/SPECT scanner (Gamma Medica, Northridge, CA, United States).…”

Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins

“…Positron emission tomography (PET) imaging is a unique tool that can give the answers to these essential questions about BET BD1 and BD2 in living subjects in a noninvasive way. 25 With a suitable radiotracer, PET imaging would accelerate BET research to aid investigators in diagnosing disease, monitoring treatment, and in drug development. However, developing the PET radioligand targeting BET BD1 and BD2 with high binding affinity and high selectivity is demanding and challenging.…”

“…Provirus studies have found that BRDs (BRD2/3/4) are highly distributed in various tissues and organs, especially in the liver, kidney, and lung, which is consistent with our findings. 25,28,29 As an important application of PET imaging, it could be used for disease diagnosis such as brain disorders and tumors. Because [ 18 F]PB006 has specific binding in peripheral organs such as the lungs and heart, there is potential to apply this probe for tumor imaging such as NUT midline carcinoma.…”