A Novel 18 F-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 [C]AS2471907 as a PET radiotracer to image 11β-HSD1 in the brain of nonhuman primates and humans. However, the radiosynthesis of [C]AS2471907 was unreliable and low-yielding. Here, we report the development of the F-labeled version [F]AS2471907, including the synthesis of two iodonium ylide precursors and the optimization of F-radiosynthesis. Preliminary PET experiments, composed of a baseline scan of [F]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 [F]AS2471907 and its specific binding in the brain. The iodonium ylide precursors were prepared in a 7-step synthetic route with an optimized overall yield of ~2%. [F]AS2471907 was synthesized in good radiochemical purity, with the ortho regioisomer of iodonium ylide providing greater radiochemical yield as compared to the para regioisomer. In monkey brain, [F]AS2471907 displayed high uptake and heterogenous distribution, while administration of the 11β-HSD1 inhibitor ASP3662 significantly reduced uptake, thus demonstrating the binding specificity of [F]AS2471907. Given the longer half-life of F-18 and feasibility for central production and distribution, [F]AS2471907 holds great promise to be a valuable PET radiotracer to image 11β-HSD1 in the brain.