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ACS Chem Neurosci. 2019 May 15;10(5):2450-2458. doi: 10.1021/acschemneuro.8b00715. Epub 2019 Feb 19.

A Novel 18F-Labeled Radioligand for Positron Emission Tomography Imaging of 11β-Hydroxysteroid Dehydrogenase (11β-HSD1): Synthesis and Preliminary Evaluation in Nonhuman Primates.

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PET Center, Department of Radiology and Biomedical Imaging , Yale University School of Medicine , 801 Howard Ave , New Haven , Connecticut 06520-8048 , United States.
Department of Nuclear Medicine, West China Hospital , Sichuan University , Chengdu , Sichuan 610041 , China.


11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of cortisone to cortisol and controls a key pathway in the regulation of stress. Studies have implicated 11β-HSD1 in metabolic diseases including type 2 diabetes and obesity, as well as stress-related disorders and neurodegenerative diseases, such as depression and Alzheimer's disease (AD). We have previously developed [11C]AS2471907 as a PET radiotracer to image 11β-HSD1 in the brain of nonhuman primates and humans. However, the radiosynthesis of [11C]AS2471907 was unreliable and low-yielding. Here, we report the development of the 18F-labeled version [18F]AS2471907, including the synthesis of two iodonium ylide precursors and the optimization of 18F-radiosynthesis. Preliminary PET experiments, composed of a baseline scan of [18F]AS2471907 and a blocking scan with the reversible 11β-HSD1 inhibitor ASP3662 (0.3 mg/kg), was also conducted in a rhesus monkey to verify the pharmacokinetics of [18F]AS2471907 and its specific binding in the brain. The iodonium ylide precursors were prepared in a seven-step synthetic route with an optimized overall yield of ∼2%. [18F]AS2471907 was synthesized in good radiochemical purity, with the ortho regioisomer of iodonium ylide providing greater radiochemical yield as compared with the para regioisomer. In monkey brain, [18F]AS2471907 displayed high uptake and heterogeneous distribution, while administration of the 11β-HSD1 inhibitor ASP3662 significantly reduced radiotracer uptake, thus demonstrating the binding specificity of [18F]AS2471907. Given the longer half-life of F-18 and feasibility for central production and distribution, [18F]AS2471907 holds great promise to be a valuable PET radiotracer to image 11β-HSD1 in the brain.


11-beta hydroxysteroid dehydrogenase type 1; 11β-HSD1; AS2471907; nonhuman primates; positron emission tomography; radiofluorination

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