Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 13; pp. 1624 - 1627
• Main Authors: Dahl, Kenneth, Bernard-Gauthier, Vadim, Nag, Sangram, Varnäs, Katarina, Narayanaswami, Vidya, Mahdi Moein, Mohammad, Arakawa, Ryosuke, Vasdev, Neil, Halldin, Christer
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.07.2019; Elsevier
• Subjects: [11C]SL25.1188; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Fluorine-18; Life Sciences & Biomedicine; MAO-B; Monoamine oxidase; PET; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; [11C]SL25.1188; Monoamine oxidase; MAO-B; Fluorine-18; PET; [C-11]SL25.1188; VIVO EVALUATION; IN-VIVO; HUMAN-BRAIN; [C]SL25.1188
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2019.04.040

[Display omitted] Carbon-11 labeled SL25.1188 is a promising reversible monoamine oxidase-B (MAO-B) radioligand that was recently translated for human positron emission tomography (PET) imaging. Herein, we report the development of a novel fluorinated derivative, namely, [18F](S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([18F]FSL25.1188; [18F]6), as a candidate 18F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [18F]6 was produced and isolated (>6 GBq) with high radiochemical purity (>99%), and molar activity (>100 GBq/µmol at time of injection). Autoradiography studies conducted in post-mortem human brain sections revealed [18F]6 binding in MAO-B rich regions. PET imaging study of [18F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [18F]6 displayed favorable in vivo kinetics, with an early peak in the time-activity curve followed by progressive wash-out from the NHP brain. Specificity of [18F]6 was investigated in a pre-treatment study with l-deprenyl (1.0 mg/kg) wherein reduced radioligand uptake was observed in all MAO-B rich regions. Results from the current preclinical investigation suggests [18F]6 is a promising MAO-B PET radioligand. Further evaluation of [18F]6 and structurally related 18F-analogs are underway to identify an optimized candidate for clinical research studies.