Synthesis and preclinical evaluation of [18F]FSL25.1188, a reversible PET radioligand for monoamine oxidase-B. Issue 13 (1st July 2019)

• Record Type: Journal Article
• Authors: Dahl, Kenneth; Bernard-Gauthier, Vadim; Nag, Sangram; Varnäs, Katarina; Narayanaswami, Vidya; Mahdi Moein, Mohammad; Arakawa, Ryosuke; Vasdev, Neil; Halldin, Christer
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 13(2019)
• Page Start: 1624
• Page End: 1627
• Publication Date: 2019-07-01
• Subjects: MAO-B -- Monoamine oxidase -- [11C]SL25.1188 -- Fluorine-18 -- PET; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.040
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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, [ 18 F]( S )-3-(6-(3-fluoropropoxy)benzo[ d ]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one ([ 18 F]FSL25.1188; [ 18 F]6 ), as a candidate 18 F-labeled MAO-B radioligand, and, its subsequent preclinical evaluation in non-human primates (NHP). [ 18 F]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 [ 18 F]6 binding in MAO-B rich regions. PET imaging study of [ 18 F]6 in NHP showed high brain uptake (SUV > 2.5) as well as a regional brain radioactivity distribution in accordance with MAO-B expression. [ 18 F]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 [ 18 F]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 [ 18 F]6 is a promising MAO-B PET radioligand. Further evaluation of [ 18 F]6 and structurally related 18 F-analogs are underway to identify an optimized candidate for clinical research studies.