Magnussen Janus H, Ettrup Anders, Lehel Szabolcs, Peters Dan, Dyssegaard Agnete, Thomsen Morten S, Mikkelsen Jens D, Knudsen Gitte M
Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Front Neuroimaging. 2024 Mar 27;3:1358221. doi: 10.3389/fnimg.2024.1358221. eCollection 2024.
The alpha7 nicotinic acetylcholine receptor (α7-nAChR) has has long been considered a promising therapeutic target for addressing cognitive impairments associated with a spectrum of neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, despite this potential, clinical trials employing α7-nAChR (partial) agonists such as TC-5619 and encenicline (EVP-6124) have fallen short in demonstrating sufficient efficacy. We here investigate the target engagement of TC-5619 and encenicline in the pig brain by use of the α7-nAChR radioligand C-NS14492 to characterize binding both with autoradiography and occupancy using positron emission tomography (PET). autoradiography demonstrates significant concentration-dependent binding of C-NS14492, and both TC-5619 and encenicline can block this binding. Of particular significance, our investigations demonstrate that TC-5619 achieves substantial α7-nAChR occupancy, effectively blocking approximately 40% of α7-nAChR binding, whereas encenicline exhibits more limited α7-nAChR occupancy. This study underscores the importance of preclinical PET imaging and target engagement analysis in informing clinical trial strategies, including dosing decisions.
α7烟碱型乙酰胆碱受体（α7-nAChR）长期以来一直被认为是治疗一系列神经和精神疾病（包括阿尔茨海默病和精神分裂症）相关认知障碍的一个有前景的治疗靶点。然而，尽管有这种潜力，但使用α7-nAChR（部分）激动剂（如TC-5619和依西美坦（EVP-6124））的临床试验在证明足够疗效方面却不尽人意。我们在此通过使用α7-nAChR放射性配体C-NS14492，利用放射自显影和正电子发射断层扫描（PET）进行占有率分析，研究TC-5619和依西美坦在猪脑中的靶点结合情况。放射自显影显示C-NS14492具有显著的浓度依赖性结合，并且TC-5619和依西美坦都能阻断这种结合。特别重要的是，我们的研究表明TC-5619实现了相当程度的α7-nAChR占有率，有效地阻断了约40%的α7-nAChR结合，而依西美坦表现出更有限的α7-nAChR占有率。这项研究强调了临床前PET成像和靶点结合分析在为临床试验策略（包括给药决策）提供信息方面的重要性。
