[18F]ASEM

Emerging evidence supports a hypothesized role for the α7-nicotinic acetylcholine receptor (α7-nAChR) in the pathophysiology of Alzheimer's disease. ¹⁸F-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-¹⁸F-fluorodibenzo[b,d]thiophene 5,5-dioxide) is a radioligand for estimating the availability of α7-nAChR in the brain in vivo with PET. Methods: In this cross-sectional study, 14 patients with mild cognitive impairment (MCI), a prodromal stage to dementia, and 17 cognitively intact, elderly controls completed ¹⁸F-ASEM PET. For each participant, binding in each region of interest was estimated using Logan graphical analysis with a metabolite-corrected arterial input function. Results: Higher ¹⁸F-ASEM binding was observed in MCI patients than in controls across all regions, supporting higher availability of α7-nAChR in MCI. ¹⁸F-ASEM binding was not associated with verbal memory in this small MCI sample. Conclusion: These data support use of ¹⁸F-ASEM PET to examine further the relationship between α7-nAChR availability and MCI.

Understanding unbinding kinetics of protein-ligand systems is of great importance for the design of ligands with desired specificity and safety. In recent years, enhanced sampling techniques have emerged as effective tools for studying unbinding kinetics of protein-ligand systems at the atomistic level. However, in many protein-ligand systems, the ligand unbinding processes are strongly coupled to protein conformational changes and the disclosure of the hidden degrees of freedom closely related to the protein conformational changes so that sampling is enhanced over these degrees of freedom remains a great challenge. Here, we show how potential-scaled molecular dynamics (sMD) and infrequent metadynamics (InMetaD) simulation techniques can be combined to successfully reveal the unbinding mechanism of 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[¹⁸F]fluo-rodibenzo[b,d]thiophene 5,5-dioxide ([¹⁸F]ASEM) from a chimera structure of the α7-nicotinic acetylcholine receptor. By using sMD simulations, we disclosed that the "close" to "open" conformational change of loop C plays a key role in the ASEM unbinding process. By carrying out InMetaD simulations with this conformational change taken into account as an additional collective variable, we further captured the key states in the unbinding process and clarified the unbinding mechanism of ASEM from the protein. Our work indicates that combining sMD and InMetaD simulation techniques can be an effective approach for revealing the unbinding mechanism of a protein-ligand system where protein conformational changes control the unbinding process.