Sabri Osama, Kendziorra Kai, Wolf Henrike, Gertz Hermann-Josef, Brust Peter
Department of Nuclear Medicine, University of Leipzig, Stephanstrasse 11, Leipzig, Germany.
Eur J Nucl Med Mol Imaging. 2008 Mar;35 Suppl 1:S30-45. doi: 10.1007/s00259-007-0701-1.
To clarify whether changes in the cholinergic transmission occur early in the course of Alzheimer's disease (AD), we carried out positron emission tomography (PET) with the radioligand 2-[(18)F]F-A-85380, which is supposed to be specific for alpha4beta2 nicotinic acetylcholine receptors (nAChRs).
We included patients with moderate to severe AD and patients with amnestic mild cognitive impairment (MCI), presumed to present preclinical AD.
Both patients with AD and MCI showed significant reductions in alpha4beta2 nAChRs in brain regions typically affected by AD pathology. These findings indicate that a reduction in alpha4beta2 nAChRs occurs during early symptomatic stages of AD. The alpha4beta2 nAChR availability in these regions correlated with the severity of cognitive impairment, indicating a stage sensitivity of the alpha4beta2 nAChR status.
Together, our results provide evidence for the potential of 2-[(18)]F-A-85380 nAChR PET in the diagnosis of patients at risk for AD. Because of the extraordinary long acquisition time with 2-[(18)F]F-A-85380, we developed the new alpha4beta2 nAChR-specific radioligands (+)- and (-)-[(18)F]norchloro-fluoro-homoepibatidine (NCFHEB) and evaluated them preclinically. (-)-[(18)F]NCFHEB shows twofold higher brain uptake and significantly shorter acquisition times. Therefore, (-)-[(18)F]NCFHEB should be a suitable radioligand for larger clinical investigations.
为了阐明胆碱能传递的变化是否在阿尔茨海默病（AD）病程早期就已出现，我们使用放射性配体2-[(18)F]F-A-85380进行了正电子发射断层扫描（PET），该放射性配体被认为对α4β2烟碱型乙酰胆碱受体（nAChRs）具有特异性。
我们纳入了中度至重度AD患者以及遗忘型轻度认知障碍（MCI）患者，后者被认为处于临床前期AD阶段。
AD患者和MCI患者在通常受AD病理影响的脑区中，α4β2 nAChRs均显著减少。这些发现表明，α4β2 nAChRs的减少发生在AD的早期症状阶段。这些区域中α4β2 nAChR的可用性与认知障碍的严重程度相关，表明α4β2 nAChR状态具有阶段敏感性。
总之，我们的结果为2-[(18)]F-A-85380 nAChR PET在诊断AD高危患者中的潜力提供了证据。由于使用2-[(18)F]F-A-85380时采集时间极长，我们开发了新的α4β2 nAChR特异性放射性配体(+)-和(-)-[(18)F]去氯氟高表巴蒂啶（NCFHEB）并对其进行了临床前评估。(-)-[(18)F]NCFHEB的脑摄取量高出两倍，采集时间显著缩短。因此，(-)-[(18)F]NCFHEB应该是适合进行更大规模临床研究的放射性配体。
