Synthesis and evaluation of [<sup>18sup>F]fluororasagiline, a novel positron emission tomography (PET) radioligand for monoamine oxidase B (MAO-B)

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• 作者：S. Nag<sup>asup><sup> ; sup><sup>sangram.nag@ki.sesup> ; L. Lehmann<sup>bsup> ; G. Kettschau<sup>bsup> ; T. Heinrich<sup>bsup> ; A. Thiele<sup>bsup> ; A. Varrone<sup>asup> ; B. Gulyas<sup>asup> ; C. Halldin<sup>asup>
• 关键词：PET ; positron emission tomography ; MAO ; monoamino oxidase ; MAOI ; monoamino oxidase inhibitor ; PD ; Parkinson&rsquo ; s disease ; AD ; Alzheimer&rsquo ; s disease ; NMR ; nuclear magnetic resonance ; UPLC ; ultra performance liquid chromatograpy ; HPLC ; high performan
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 May, 2012
• 卷：20
• 期：9
• 页码：3065-3071
• 文件大小：711 K

摘要

The aim of this study was to synthesize and evaluate a novel fluorine-18 labeled analogue of rasagiline (<strong class="boldFont">6strong>) as a PET radioligand for monoamine oxidase B (MAO-B). The corresponding non-radioactive fluorine-19 ligand, (1S,2S)-2-fluoro-N-(prop-2-yn-1-yl)indan-1-amine (<strong class="boldFont">4strong>), was characterized in in vitro assays.

The precursor compound (3aS,8aR)-3-(prop-2-yn-1-yl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2,2-dioxide (<strong class="boldFont">3strong>) and reference standard <strong class="boldFont">4strong> were synthesized in multi-step syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used in order to determine IC<sub>50sub> values for compound <strong class="boldFont">4strong> by use of an enzymatic assay employing kynuramine as substrate. Radiolabeling was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulphamidate group. Human whole hemisphere autoradiography (ARG) was performed with [<sup>18sup>F]fluororasagiline. Blocking experiments with pirlindole (MAO-A), l-deprenyl and rasagiline (MAO-B) were conducted to demonstrate the specificity of the binding. A positron emission tomography (PET) study was carried out in a cynomolgus monkey where time activity curves for whole brain and regions with high and low MAO-B activity were recorded. Radiometabolites were measured in monkey plasma using gradient HPLC.

Compound <strong class="boldFont">4strong> inhibited MAO-B with an IC<sub>50sub> of 27 nM and MAO-A with an IC<sub>50sub> of 2.3 渭M. Radiolabeling of precursor <strong class="boldFont">3strong> and subsequent hydrolysis of the protecting group towards (1S,2S)-2-[<sup>18sup>F]fluoro-N-(prop-2-yn-1-yl)indan-1-amine (<strong class="boldFont">6strong>) was successfully accomplished with an radiochemical yield of 40-70%, a radiochemical purity higher than 99%and a specific radioactivity higher than 200 GBq/渭mol. ARG demonstrated selective binding for [<sup>18sup>F]fluororasagiline (<strong class="boldFont">6strong>) to MAO-B containing brain regions, for example, striatum. The initial uptake in the monkey brain was 250%SUV at 4 min post injection. The highest amounts of radioactivity were observed in the striatum and thalamus as expected whereas in the cortex and cerebellum lower levels were observed. Metabolite studies demonstrated 30%unchanged radioligand at 90 min post injection.

Our investigations demonstrated that the new ligand [<sup>18sup>F]fluororasagiline (<strong class="boldFont">6strong>) binds specifically to MAO-B in vitro and has a MAO-B specific binding pattern in vivo. Thus, it could serve as a novel potential candidate for human PET studies.