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In vivo evaluation of limiting brain penetration of probes for ?(2C)-adrenoceptor using small-animal positron emission tomography.

ABSTRACT: To evaluate in vivo brain penetration of ?(2C)-adrenoceptor (?(2C)-AR) antagonists as a therapeutic agent, we synthesized two new (11)C-labeled selective ?(2C)-AR antagonists 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-aryl-7-methoxybenzofuran ([(11)C]MBF) and acridin-9-yl-[4-(4-methylpiperazin-1-yl)phenyl]amine ([(11)C]JP-1302) as ?(2C)-AR-selective positron emission tomography (PET) probes. The radiochemical yield, specific activity, and radiochemical purity of these probes was appropriate for injection. To evaluate whether the brain penetration of these probes is related to the function of two major drug efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), we performed PET studies using wild-type and P-gp/Bcrp knockout mice. In wild-type mice, the radioactivity level after injection with [(11)C]MBF initially increased and effluxed immediately from the brain, whereas that with [(11)C]JP-1302 was distributed throughout the brain. However, the regional distribution of radioactivity after injection with [(11)C]JP-1302 in the brain was different from that of ?(2C)-ARs. In P-gp/Bcrp knockout mice, uptake of [(11)C]MBF was approximately 3.7-fold higher and that of [(11)C]JP-1302 was approximately 1.6-fold higher than those in wild-type mice. These results indicate that brain penetration of the two PET probes was affected by modulation of P-gp and Bcrp functions.

SUBMITTER: Kawamura K

PROVIDER: S-EPMC3368684 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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In vivo evaluation of limiting brain penetration of probes for α(2C)-adrenoceptor using small-animal positron emission tomography.

Kawamura Kazunori K Akiyama Megumi M Yui Joji J Yamasaki Tomoteru T Hatori Akiko A Kumata Katsushi K Wakizaka Hidekatsu H Takei Makoto M Nengaki Nobuki N Yanamoto Kazuhiko K Fukumura Toshimitsu T Zhang Ming-Rong MR

ACS chemical neuroscience 20100602 7

To evaluate in vivo brain penetration of α(2C)-adrenoceptor (α(2C)-AR) antagonists as a therapeutic agent, we synthesized two new (11)C-labeled selective α(2C)-AR antagonists 4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2-aryl-7-methoxybenzofuran ([(11)C]MBF) and acridin-9-yl-[4-(4-methylpiperazin-1-yl)phenyl]amine ([(11)C]JP-1302) as α(2C)-AR-selective positron emission tomography (PET) probes. The radiochemical yield, specific activity, and radiochemical purity of these probes wa ...[more]

PMID: 22778842

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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

In vivo evaluation of limiting brain penetration of probes for ?(2C)-adrenoceptor using small-animal positron emission tomography.

Publications

In vivo evaluation of limiting brain penetration of probes for α(2C)-adrenoceptor using small-animal positron emission tomography.

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