Dataset Information

Development of Novel ¹¹C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

ABSTRACT: Orexin 2 receptors (OX₂R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX₂R in vivo. Herein, we report [¹¹C]1 ([¹¹C]OX₂-2201) and [¹¹C]2 ([¹¹C]OX₂-2202) as novel PET ligands. Both compounds 1 (K_i = 3.6 nM) and 2 (K_i = 2.2 nM) have excellent binding affinity activities toward OX₂R and target selectivity (OX₂/OX₁ > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [¹¹C]1 and [¹¹C]2. PET imaging in rat brains indicated that the low brain uptake of [¹¹C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.

SUBMITTER: Rong J

PROVIDER: S-EPMC10577698 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

Rong Jian J Yamasaki Tomoteru T Li Yinlong Y Kumata Katsushi K Zhao Chunyu C Haider Achi A Chen Jiahui J Xiao Zhiwei Z Fujinaga Masayuki M Hu Kuan K Hu Kuan K Mori Wakana W Zhang Yiding Y Xie Lin L Zhou Xin X Collier Thomas L TL Zhang Ming-Rong MR Liang Steven S

ACS medicinal chemistry letters 20230926 10

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds <b ...[more]

PMID: 37849554

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Project description:Malignant melanoma tends to aggressively metastasize, resulting in it being a potentially lethal form of skin cancer with high mortality rates. The advanced stages of melanoma have a very poor prognosis because of the high tendency for metastasis, and there is therefore, a strong desire to develop efficient technology for the early detection of melanoma. The benzamide structure, which contains aromatic ring and amine group, exhibits a high affinity for melanin, making it a promising agent for targeting melanoma in diagnostic and therapeutic applications. In this study, we synthesized a fluorinated benzamide derivative and chelated it with the radioisotope 68Ga to detect melanoma on positron emission tomography (PET) imaging, and then evaluated its biological properties. We synthesized the new probe 2,2',2,"2"'-(2-(4-(3-(2-((2-(5-fluoropicolinamido)ethyl)(methyl)amino)ethyl)thioureido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (MI-0202C1) for melanoma imaging from 5-fluoropyridine-2-carboxylic acid and conjugated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for chelation with 68Ga. The radiochemical yield and radiochemical purity of the 68Ga chelation complex were confirmed by radio-thin layer chromatography (radio TLC). In vitro cellular uptake of 68Ga-MI-0202C1 was verified in B16F10 cells (murine melanoma). In vivo distribution and small animal PET studies were conducted on mice bearing B16F10 xenografts. The MI-0202C1 was chelated with 68Ga at 90°C for 10 min at pH 5, resulting in a radiochemical yield and radiochemical purity of over 95%. The cellular uptake of 68Ga-MI-0202C1 over 60 min was higher in a group treated with L-tyrosine (2 mM) than in a non-treated group, indicating selective uptake of melanin. 68Ga-MI-0202C1 successfully visualized B16F10 xenografts in microPET imaging performed at 30 and 60 min after intravenous injection, suggesting that 68Ga-MI-0202C1 has considerable potential as a diagnostic probe for melanoma.

Dataset Information

Development of Novel ¹¹C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

Publications

Development of Novel <sup>11</sup>C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

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