## 2 Radiolabeled Tacrine and Its Derivatives Used in Alzheimer's Disease
### Molecular Modeling Studies of Tacrine Derivatives--Cholinesterase Interaction  
The study of the crystal structure of _Torpedo californica_ acetylcholinesterase (_Tc_AChE) made possible, for the first time at atomic resolution, the visualization of the acetylcholine (ACh) binding pocket [37; 38; 39]. The binding pocket is a narrow and deep gorge approximately 5 A wide and 20 A long and lined (in approximately 40-60%) with rings of 14 conserved aromatic residues: Y70, W84, F120, Y121, Y130, W233, W279, F288, F290, F330, F331, Y334, W432 and Y442 [28]. It penetrates into the enzyme more than halfway and expands near the bottom to form a cavity called the active binding site, containing the catalytic triad S200, E327 and H440 (Figure 7 in ref. [37]). Five amino acids, Tyr70, Asp72, Tyr121, Trp279 and Tyr334, located at the entrance to the gorge, constitute the peripheral anionic site (PAS) binding for AChE [38]. A large number of aromatic residues in the gorge walls and bases in the gorge bottom result in many different hydrophobic and \"anionic\" interaction sites in the binding pocket, located separately or overlapping with the active sites of the ACh-binding enzyme (the ACh binding site in AChE contains from six to nine negative charges). The aromatic nature of the gorge influences the high degree of binding of a given substrate and thus the high catalytic activity of the enzyme. _Tc_AChE has a very large dipole moment, which is greatly influenced by the presence of five acidic amino acids located around the entrance to the gorge. The axis of the AChE dipole moment is oriented along the axis of the gorge's active sites. Along the gorge, along the entire length of the active sites, there is a potential gradient that can effectively pull the substrate appearing at the gorge mouth (Y121, F330) down the gorge.  
Computational studies of the interaction of some tacrine derivatives as well as potential radiotracers based on them (Table 3) with acetyl- and/or butyrylcholinesteraseerase were discussed in the works of [PERSON] et al. [33; 34], [PERSON] et al. [35] and [PERSON] et al. [36]. The conjugates and radioconjugates selected for the molecular docking studies are listed in Table 3.  
Molecular modeling studies made it possible to determine the structure of the inhibitor-cholinesterase system and to determine and locate individual interactions between the components of this system responsible for the action of the inhibitor on the enzyme. Detailed information about the nature and location of individual interactions of the inhibitor with the amino acids forming the enzyme's binding pocket is provided in the cited publications.  
In general, all tested inhibitors had similar components, namely tacrine, a longer or shorter linker in the form of a hydrocarbon chain and, optionally, a radionuclide complex. Therefore, their fit into the cholinesterase binding pocket and their interactions with AChE and BChE were similar. A fragment of tacrine (as well as a tacrine analog with a cyclopentane ring) was located at the bottom of the gorge, and the main interaction here was the interaction with the catalytic triad. The hydrocarbon chain was located along the gorge and formed hydrophobic interactions with the aromatic rings of the amino acids present in  
\begin{table}
\begin{tabular}{c c c} \hline \hline  & \multicolumn{2}{c}{**Molecular Docking Studies to**} \\ \cline{2-3}  & **AChE [Ref.]** & **BChE [Ref.]** \\ \hline \hline  & & \\ \(N\)H & \(N\)N & \(N\  
the gorge wall. The radionuclide complex is usually located outside or at the entry to the gorge of the binding pocket and interacted through peripheral anionic sites.