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

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

doi:10.3389/fnimg.2024.1358221

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

Front Neuroimaging. 2024 Mar 27:3:1358221. doi: 10.3389/fnimg.2024.1358221. eCollection 2024.

Authors

Janus H Magnussen^{1

2}, Anders Ettrup¹, Szabolcs Lehel³, Dan Peters⁴, Agnete Dyssegaard¹, Morten S Thomsen^{1

5}, Jens D Mikkelsen^{1

6}, Gitte M Knudsen^{1

7}

Affiliations

¹ Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.
² Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³ PET and Cyclotron Unit, Rigshospitalet, Copenhagen, Denmark.
⁴ DanPET AB, Malmö, Sweden.
⁵ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶ Institute of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Abstract

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

Keywords: alpha7; autoradiography; cognitive impairment; nicotinic acetylcholine receptors; occupancy study; positron emission tomography (PET).

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was partially supported by the Lundbeck Foundation and the Novo Nordisk Foundation.