AUTHOR=Magnussen Janus H. , Ettrup Anders , Lehel Szabolcs , Peters Dan , Dyssegaard Agnete , Thomsen Morten S. , Mikkelsen Jens D. , Knudsen Gitte M. 

TITLE=Characterizing the binding of TC-5619 and encenicline on the alpha7 nicotinic acetylcholine receptor using PET imaging in the pig

JOURNAL=Frontiers in Neuroimaging

VOLUME=3

YEAR=2024

URL=https://www.frontiersin.org/journals/neuroimaging/articles/10.3389/fnimg.2024.1358221

DOI=10.3389/fnimg.2024.1358221

ISSN=2813-1193

ABSTRACT=<p>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 <sup>11</sup>C-NS14492 to characterize binding both with <italic>in vitro</italic> autoradiography and <italic>in vivo</italic> occupancy using positron emission tomography (PET). <italic>In vitro</italic> autoradiography demonstrates significant concentration-dependent binding of <sup>11</sup>C-NS14492, and both TC-5619 and encenicline can block this binding. Of particular significance, our <italic>in vivo</italic> 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.</p>