Synthesis and biological evaluation of novel propargyl amines as potential fluorine-18 labeled radioligands for detection of MAO-B activity

Abstract The aim of this project was to synthesize and evaluate three novel fluorine-18 labeled derivatives of propargyl amine as potential PET radioligands to visualize monoamine oxidase B (MAO-B) activity. The three fluorinated derivatives of propargyl amine (( S )-1-fluoro- N ,4-dimethyl- N -(prop-2-ynyl)-pent-4-en-2-amine ( 5 ), ( S )- N -(1-fluoro-3-(furan-2-yl)propan-2-yl)- N -methylprop-2-yn-1-amine ( 10 ) and ( S )-1-fluoro- N ,4-dimethyl- N -(prop-2-ynyl)pentan-2-amine ( 15 )) were synthesized in multi-step organic syntheses. IC 50 values for inhibition were determined for compounds 5 , 10 and 15 in order to determine their specificity for binding to MAO-B. Compound 5 inhibited MAO-B with an IC 50 of 664 ± 48.08 nM. No further investigation was carried out with this compound. Compound 10 inhibited MAO-B with an IC 50 of 208.5 ± 13.44 nM and compound 15 featured an IC 50 of 131.5 ± 0.71 nM for its MAO-B inhibitory activity. None of the compounds inhibited MAO-A activity (IC 50 > 2 μM). The fluorine-18 labeled analogues of the two higher binding affinity compounds ( 10 and 15 ) ( S )- N -(1-[ 18 F]fluoro-3-(furan-2-yl)propan-2-yl)- N -methylprop-2-yn-1-amine ( 16 ) and ( S )-1-[ 18 F]fluoro- N ,4-dimethyl- N -(prop-2-ynyl)pentan-2-amine ( 18 ) were both prepared from the corresponding precursors 9A, 9B and 14A, 14B by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography experiments on human postmortem brain tissue sections were performed with 16 and 18 . Only compound 18 demonstrated a high selectivity for MAO-B over MAO-A and was, therefore, chosen for further examination by PET in a cynomolgus monkey. The initial uptake of 18 in the monkey brain was 250% SUV at 4 min post injection. The highest uptake of radioactivity was observed in the striatum and thalamus, regions with high MAO-B activity, whereas lower levels of radioactivity were detected in the cortex and cerebellum. The percentage of unchanged radioligand 18 was 30% in plasma at 90 min post injection. In conclusion, compound 18 is a selective inhibitor of MAO-B in vitro and demonstrated a MAO-B specific binding pattern in vivo by PET in monkey. It can, therefore, be considered as a candidate for further investigation in human by PET.