Dataset Information

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 ?M and 1.406 ?M 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.

SUBMITTER: Bai P

PROVIDER: S-EPMC7179119 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging.

Bai Ping P Bai Sha S Placzek Michael S MS Lu Xiaoxia X Fiedler Stephanie A SA Ntaganda Brenda B Wey Hsiao-Ying HY Wang Changning C

Molecules (Basel, Switzerland) 20200225 5

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 OX1 ...[more]

PMID: 32106419

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging.

Publications

A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging.

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