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

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.