## 2 Radiolabeled Tacrine and Its Derivatives Used in Alzheimer's Disease
### Radiotracers Based on Tacrine Derivatives
The chelators used for the synthesis of the \({}^{68}\)Ga-radioconjugates were 2,2\({}^{\prime}\)-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA-NHS), 2,2\({}^{\prime}\)-(7-(1-carboxy-4-((4-isothiocyanatechbenzyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA-Br-NCS), 2,2\({}^{\prime}\),2\({}^{\prime\prime}\)-(10-(1-carboxy-4-((4-isothiocyanatechbenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacycldodecane-1,4,7-triyl)triacetic acid (DOTAGA-Br-NCS), [(R)-2-Amino-3-(4-isothiocyanatechyphenyl)propyl]trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (DTPA-CHX-Br-NCS) and N1,N7-bis((3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridin-2-yl)methyl)-4-(3-((3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridin-2-yl)methyl)amino)-3-oxopropyl)-4-(3-(3-(4-isothiocyanatechphenyl)thioureido)propanamido)heptanediamide (THP-Br-NCS). In order to obtain the highest possible lipophilicity of the synthesized radioconjugates (recommended for radiopreparations capable of crossing the blood-tissue and blood-brain barriers), a tacrine derivative containing nine methylene groups in the aliphatic hydrocarbon chain was used for the synthesis of the \({}^{68}\)Ga-radioconjugates. All obtained radioconjugates (Figure 4) met the physicochemical properties required for radiopharmaceuticals. The tested inhibitory properties of the radioconjugates turned out to be no less than those of tacrine, which confirmed that the attachment of the radionuclide complex to tacrine through an appropriate linker does not change the biological properties of tacrine. Moreover, the [68 Ga]Ga-THP-NH(CH\({}_{2}\))\({}_{9}\)Tac radioconjugate showed a much stronger activity towards both AChE and BuChE than the parent tacrine compound. Lipophilicity tests showed that all newly synthesized radioconjugates were significantly less hydrophilic, and two of them, [68 Ga]Ga-NODAGA-Br-NH(CH\({}_{2}\))\({}_{9}\)Tac and [68 Ga]Ga-THP-NH(CH\({}_{2}\))\({}_{9}\)Tac, were already hydrophobic. These radioconjugates were selected for the biodistribution studies and molecular docking studies. The in vivo biodistribution studies in rats showed clearly different profiles. The [68 Ga]Ga-NODAGA-Br-NH(CH\({}_{2}\))\({}_{9}\)Tac compound, apart from a relatively large accumulation in the excretory organs (kidneys and liver), accumulated in other organs (lungs, blood, heart and spleen) in small amounts. The compound [68 Ga]Ga-THP-NH(CH\({}_{2}\))\({}_{9}\)Tac circulated in the blood in large quantities and accumulated in comparable amounts in the excretory organs (kidneys, liver and spleen) as well as in the lungs and heart. Unfortunately, the uptake of both radioconjugates in the brain was low and insufficient from the point of view of potential application of these radioconjugates as a tool for the early diagnosis of [PERSON]'s disease. Particularly noteworthy is the high uptake of the radioconjugate [68 Ga]Ga-THP-NH(CH\({}_{2}\))\({}_{9}\)Tac in the lungs, which indicates its specificity for this organ, and due to the presence of cholinesterase in the glial tissue of the lungs, it allows for the use of this radioconjugate as a tool for imaging pathological conditions of the lungs. In a review article focusing on potential radiotracers based on tacrine and its analogues, it is worth presenting the radioconjugates synthesized and tested by [PERSON] et al. [36]. Compared to previously used tacrine derivatives [33; 34; 35], the structural modification of tacrine additionally consisted of replacing the six-membered tetrahydroacridine ring with a five-membered ring. As previously reported [33; 34; 35], 6-hydroxazinonicotinamide (HYNIC, radionuclide \({}^{99\text{m}}\)Tc complexing agent) was attached to the amino group of tacrine through a hydrocarbon chain with a different number of (CH\({}_{2}\))\({}_{n}\) groups, where n = 2 \(\div\) 9.