## 2 Radiolabeled Tacrine and Its Derivatives Used in Alzheimer's Disease
### Radiotracers Based on Tacrine Derivatives
For this radioconjugate and its parent tacrine-based complexing agent CN-NH(CH\({}_{2}\))\({}_{7}\)Tac, computer docking studies were also performed. The biodistribution study showed a higher uptake of [\({}^{99m}\)Tc]Tc(NS\({}_{3}\))(CN-NH(CH\({}_{2}\))\({}_{7}\)Tac in the liver than in the kidney, indicating the clearance of the radioconjugate mainly through the hepatic route. High uptake was also observed in the lung, but uptake in the brain was relatively low, nevertheless demonstrating the ability of the [\({}^{99m}\)Tc]Tc(NS\({}_{3}\))(CN-NH(CH\({}_{2}\))\({}_{7}\)Tac radioconjugate to cross the blood-brain barrier. Radioconjugates based on the same tacrine derivatives, containing the radionuclide \({}^{99m}\)Tc complexed by 6-hydrazinonicotinamide (HYNIC) and \({}^{68}\)Ga complexed by macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), are presented in another work by [PERSON] et al. [34]. All synthesized [\({}^{99m}\)Tc]Tc-Hynic-(tricine)\({}_{2}\)NH(CH\({}_{2}\))\({}_{n}\)tacrine ([\({}^{99m}\)Tc]Tc-Hynic-NH(CH\({}_{2}\))\({}_{n}\)Tac) (Figure 3B), where n was in the range from two to nine, and [\({}^{68}\)Ga]Ga-DOTA-NH(CH\({}_{2}\))\({}_{n}\)tacrine ([\({}^{68}\)Ga]Ga-DOTA-NH(CH\({}_{2}\))\({}_{n}\)Tac), where n was seven, eight or nine (Figure 3C), turned out to be completely stable in cysteine and histidine solutions (challenge experiments), in human serum and in cerebrospinal fluid. The lipophilicity parameter was determined for all radioconjugates, and the determined log D parameters showed that all [\({}^{99m}\)Tc]Tc-Hynic-NH(CH\({}_{2}\))\({}_{n}\)Tac and [\({}^{68}\)Ga]Ga-DOTA-NH(CH\({}_{2}\))\({}_{n}\)Tac radioconjugates are definitely hydrophilic compounds. Furthermore, the radioconjugates containing the [\({}^{68}\)Ga]Ga-DOTA complex were significantly more hydrophilic than the radioconjugates containing the [\({}^{99m}\)Tc]Tc-Hynic complex. For the two radioconjugates (one from each series, [\({}^{99m}\)Tc]Tc-Hynic-NH(CH\({}_{2}\))\({}_{9}\)Tac and [\({}^{68}\)Ga]Ga-DOTA-NH(CH\({}_{2}\))\({}_{9}\)Tac, containing nine methylene CH\({}_{2}\) groups in the aliphatic chain) with the most appropriate physicochemical properties (the highest possible lipophilicity parameter), cholinesterase inhibitory activity tests, biodistribution studies in mice and molecular modelling studies were carried out. Studies of the biological activity of the radioconjugates [99 mTc]Tc-Hynic-NH(CH\({}_{2}\))\({}_{9}\)Tac and [68 Ga]Ga-DOTA-NH(CH\({}_{2}\))\({}_{9}\)Tac showed that these compounds have equally strong inhibitory properties against acetylcholinesterase (AChE) and buryrycholinesterase (BuChE) as the reference compound tacrine. The in vivo biodistribution study showed the uptake of both radioconjugates in the brain, spleen, lungs, heart, kidneys and liver; however, the uptake of [68 Ga]Ga-DOTA-NH(CH\({}_{2}\))\({}_{9}\)Tac in the brain was very low. In general, the uptake of the [99 mTc]Tc-Hynic-NH(CH\({}_{2}\))\({}_{9}\)Tac radiocarbonugate was significantly higher in all analyzed organs (its uptake in the brain was four times greater than that of the gallium radioconjugate). According to the authors, the low efficiency of crossing the blood-brain barrier of the tested radioconjugates may be due to their hydrophilic nature, and, for example, in the case of the gallium radioconjugates, the use of a chelator less hydrophilic than DOTA could increase the lipophilicity of the radioconjugate. Studies on radioconjugates, still based on the same tacrine derivatives, in which five various chelators were used to complex the \({}^{68}\)Ga radionuclide, were presented in the work of [PERSON] et al. (2015).