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Preclinical Evaluation of the First Adenosine A₁ Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

ABSTRACT: Central adenosine A₁ receptor (A₁R) is implicated in pain, sleep, substance use disorders, and neurodegenerative diseases, and is an important target for pharmaceutical development. Radiotracers for A₁R positron emission tomography (PET) would enable measurement of the dynamic interaction of endogenous adenosine and A₁R during the sleep-awake cycle. Although several human A₁R PET tracers have been developed, most are xanthine-based antagonists that failed to demonstrate competitive binding against endogenous adenosine. Herein, we explored non-nucleoside (3,5-dicyanopyridine and 5-cyanopyrimidine) templates for developing an agonist A₁R PET radiotracer. We synthesized novel analogues, including 2-amino-4-(3-methoxyphenyl)-6-(2-(6-methylpyridin-2-yl)ethyl)pyridine-3,5-dicarbonitrile (MMPD, 22b), a partial A₁R agonist of sub-nanomolar affinity. [¹¹C]22b showed suitable blood-brain barrier (BBB) permeability and test-retest reproducibility. Regional brain uptake of [¹¹C]22b was consistent with known brain A₁R distribution and was blocked significantly by A₁R but not A_2AR ligands. [¹¹C]22b is the first BBB-permeable A₁R partial agonist PET radiotracer with the promise of detecting endogenous adenosine fluctuations.

SUBMITTER: Guo M

PROVIDER: S-EPMC8327296 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Preclinical Evaluation of the First Adenosine A1 Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.

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Preclinical Evaluation of the First Adenosine A₁ Receptor Partial Agonist Radioligand for Positron Emission Tomography Imaging.