Deuther-Conrad Winnie, Fischer Steffen, Hiller Achim, Nielsen Elsebet Østergaard, Timmermann Daniel Brunicardi, Steinbach Jörg, Sabri Osama, Peters Dan, Brust Peter
Institute of Interdisciplinary Isotope Research, Leipzig, Germany.
Eur J Nucl Med Mol Imaging. 2009 May;36(5):791-800. doi: 10.1007/s00259-008-1031-7. Epub 2009 Jan 10.
The outstanding diversity of cellular properties mediated by neuronal and nonneuronal alpha7 nicotinic acetylcholine receptors (alpha7 nAChR) points to the diagnostic potential of quantitative nuclear molecular imaging of alpha7 nAChR in neurology and oncology. It was our goal to radiolabel the alpha7 nAChR agonist 4-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3.2.2]nonane (NS10743) and to assess the selectivity of [(18)F]NS10743 binding site occupancy in animal experiments.
[(18)F]NS10743 was synthesized by nucleophilic substitution of the nitro precursor. In vitro receptor affinity and selectivity were assessed by radioligand competition and autoradiography. The radiotracer properties were evaluated in female CD-1 mice by brain autoradiography and organ distribution. Target specificity was validated after treatment with SSR180711 (10 mg/kg, intraperitoneal), and metabolic stability was investigated using radio-HPLC.
The specific activity of [(18)F]NS10743 exceeded 150 GBq/micromol at a radiochemical purity >99%. In vitro, NS10743 and [(18)F]NS10743 showed high affinity and specificity towards alpha7 nAChR. The brain permeation of [(18)F]NS10743 was fast and sufficient with values of 4.83 and 1.60% injected dose per gram and brain to plasma ratios of 3.83 and 2.05 at 5 and 60 min after radiotracer administration. Brain autoradiography and organ distribution showed target-specific accumulation of [(18)F]NS10743 in brain substructures and various alpha7 nAChR-expressing organs. The radiotracer showed a high metabolic stability in vivo with a single polar radiometabolite, which did not cross the blood-brain barrier.
The good in vitro and in vivo features of [(18)F]NS10743 make this radioligand a promising candidate for quantitative in vivo imaging of alpha7 nAChR expression and encourage further investigations.
神经元和非神经元α7烟碱型乙酰胆碱受体（α7 nAChR）介导的细胞特性具有显著多样性，这表明α7 nAChR的定量核分子成像在神经病学和肿瘤学中具有诊断潜力。我们的目标是用放射性标记α7 nAChR激动剂4-[5-(4-氟苯基)-[1,3,4]恶二唑-2-基]-1,4-二氮杂双环[3.2.2]壬烷（NS10743），并在动物实验中评估[(18)F]NS10743结合位点占据的选择性。
[(18)F]NS10743通过硝基前体的亲核取代反应合成。通过放射性配体竞争和放射自显影评估体外受体亲和力和选择性。通过脑放射自显影和器官分布在雌性CD-1小鼠中评估放射性示踪剂特性。用SSR180711（10 mg/kg，腹腔注射）处理后验证靶点特异性，并用放射性高效液相色谱法研究代谢稳定性。
[(18)F]NS10743的比活度在放射化学纯度>99%时超过150 GBq/μmol。在体外，NS10743和[(18)F]NS10743对α7 nAChR表现出高亲和力和特异性。[(18)F]NS10743的脑渗透率快且充足，在注射放射性示踪剂后5分钟和60分钟时，每克脑的摄取量分别为注射剂量的4.83%和1.60%，脑与血浆的比值分别为3.83和2.
