## 2 Radiolabeled Tacrine and Its Derivatives Used in Alzheimer's Disease
### Radiotracers Based on Tacrine Derivatives
Biochemical tests performed spectrophotometrically using the Ellman method showed that tacrine derivatives with the long hydrocarbon chain (n = 7 \(\div\) 9) have higher inhibition activity and are more selective towards acetylcholinesterase than tacrine, while all compounds showed less selectivity for butyrylcholinesteraseterase (BChE) compared to tacrine. The docking studies of the new tacrine derivatives to AChE and BChE showed that all tacrine derivatives bound to AChE in a similar way--they extended along the active gorge of the enzyme and interacted with the catalytic and peripheral sites. In the case of BChE, the binding method of the tacrine derivatives to the enzyme was similar with a slight difference regarding the location of the hydrazinicontium fragment in the reduced peripheral anionic site of BChE. Among these tacrine derivatives, for the synthesis of the \({}^{99\text{m}}\)Tc-radioconjugate, the authors chose the derivative that contained two methylene groups in the hydrocarbon chain and was characterized by the highest activity towards BChE (the level of this enzyme varies in different stages of [PERSON]'s disease). The spectrophotometric test of this compound (6-Hydrazino-N-[2-(2,3-dihydro-1\(H\)-cyclopenta[\(b\)]quinolin-9-ylamino)Ethyl]nicotinamide) showed its stability in water. After labeling this compound with \({}^{99\text{m}}\)Tc radionuclide, the obtained radiocarbonjugate [\({}^{99\text{m}}\)Tc]Tc-Hynic-2,3-dihydro-1H-cyclopenta[\(b\)]quinoline (Figure 5) was used to study biodistribution in rats. The greatest accumulation of radioactivity was observed in the liver, followed by the kidneys, lungs and gastrointestinal tract. Unfortunately, the uptake of the radiocarbonjugate in the brain was very low (probably due to the hydrophilic nature of the radiocarbonjugate), which indicates that the tested radioconjugate does not have sufficient ability to cross the blood-brain barrier and cannot be considered as a potential agent in the diagnosis of [PERSON]'s disease. \begin{table}
\begin{tabular}{c c c} \hline \hline
**Tacrine Derivative-Based Radioconjugates** & **Research Purpose and Conclusions** & **References** \\ \hline Synthesis procedure & [26] \\ \hline Studies in vivo in non-human primates: in rats (radioactivity was measured in blood, plasma, heart, liver, kidneys, lungs, skeletal muscles and brain (separately in the pons, cerebellum, colliculi, hypothalamus, hippocampus, striatum and anterior and posterior cortices)), and PET imaging on two male adult baboons using both [11C]MTHA radiotracer alone and [11C]MTHA radiotracer together with unlabeled THA & [27] \\ \(\bullet\) Radioactivity accumulated in all brain regions studied; in the case of co-injection of THA together with [11C]MTHA, accumulation was significantly lower; & [27] \\ \(\bullet\) These two molecules, [11C]MTHA and THA, compete for the same binding sites; & [11C]MTHA radiotracer could be considered a promising PET ligand for studying THA binding in the brain. & \\ \hline Studies in vivo in healthy human volunteers and measurement of radioactivity accumulated in all brain regions studied in the case of co-injection of THA together with [11C]MTHA & \\ \(\bullet\) Determined radioactivity in the brain was relatively high and & \\ \(\bullet\) Amounted to approximately 6\% of the administered dose; & \\ \(\bullet\) Brain accumulation of the radiotracer [11C]MTHA differs from the sites of action and/or sites of elevated AChE concentrations detected & [28] \\ post-mortem in human brains; & \\ \(\bullet\) Cerebral distribution of the [11C]MTHA radiotracer in the human nervous system is not parallel with AChE, so the clinical effect of THA may also occur in a way other than through the cholinergic neuronal system. & \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Radioconjugates based on tacrine derivatives. Figure 5: \({}^{99\text{m}}\)Tc-radioconjugate based on 2,3-dihydro-1H-cyclopenta[b]quinolone [36].