Advanced Accelerator Applications, Saint-Genis-Pouilly, France.
Nucl Med Biol. 2013 May;40(4):554-60. doi: 10.1016/j.nucmedbio.2013.02.004. Epub 2013 Mar 20.
Developing positron emission tomography (PET) radiotracers for non-invasive study of the cholinergic system is crucial to the understanding of neurodegenerative diseases. Although several acetylcholinesterase (AChE) PET tracers radiolabeled with carbon-11 exist, no fluorinated radiotracer is currently used in clinical imaging studies. The purpose of the present study is to describe the first fluorinated PET radiotracer for this brain enzyme.
Three structural analogs of huprine, a specific AChE inhibitor presenting high affinity towards AChE in vitro, were synthesized and labeled with fluorine-18 via a mesylate/fluoro-nucleophilic aliphatic substitution: ([(18)F]-FHUa, [(18)F]-FHUb and [(18)F]-FHUc). Initial biological evaluation included in vitro autoradiography in rat with competition with an AChE inhibitor at different concentrations, and microPET-scan on anesthetized rats. In vivo PET studies in anesthetized cat focused on [(18)F]-FHUa.
Although radiosynthesis of these huprine analogs was straightforward, they showed poor brain penetration potential, partially reversed after pharmacological inhibition of P-glycoprotein. These results indicated that current huprine analogs are not suitable for PET mapping of brain AChE receptors, but require physicochemical modulation in order to increase brain penetration.
开发正电子发射断层扫描（PET）放射性示踪剂以无创性研究胆碱能系统对于理解神经退行性疾病至关重要。尽管存在几种用碳-11 放射性标记的乙酰胆碱酯酶（AChE）PET 示踪剂，但目前在临床成像研究中尚未使用氟放射性示踪剂。本研究的目的是描述用于这种脑酶的第一种氟代 PET 放射性示踪剂。
合成了三种结构类似物的 huprine，这是一种体外对 AChE 具有高亲和力的特定 AChE 抑制剂，并通过甲磺酸酯/氟亲核脂肪取代反应用氟-18 进行放射性标记：[（18）F]-FHUa、[（18）F]-FHUb 和 [（18）F]-FHUc。初步的生物学评估包括在大鼠体内进行放射性自显影，并用不同浓度的 AChE 抑制剂进行竞争，以及对麻醉大鼠进行 microPET 扫描。在麻醉猫中进行的体内 PET 研究集中于[（18）F]-FHUa。
尽管这些 huprine 类似物的放射合成很简单，但它们显示出较差的脑穿透潜力，在 P-糖蛋白的药理学抑制后部分逆转。这些结果表明，目前的 huprine 类似物不适合用于大脑 AChE 受体的 PET 映射，需要进行物理化学调节以增加脑穿透。
