## 2 Radiolabeled Tacrine and Its Derivatives Used in Alzheimer's Disease
### Radiotracers Based on Tacrine Derivatives  
Some of the first reports on radionuclide-labeled tacrine derivatives are the papers presenting 1,2,3,4-tetrahydro-9-methyl-amino acridine (N-methyl-THA, MTHA) labeled with \({}^{11}\)C radionuclide, synthesized by [PERSON] et al. [26] and studied in vivo in non-human primates by [PERSON] et al. [27] and in healthy human volunteers by [PERSON] et al. [28]. In vitro testing of tacrine (THA) and its N-methyl derivative MTHA showed that both compounds have very similar inhibitory properties towards acetylcholinesteraseicninesterase (AChE) [27]. The authors conducted a study of the distribution of the [methyl-\({}^{11}\)C]1,2,3,4-tetrahydro-9-methyl-amino acridine radiotracer ([\({}^{11}\)C]MTHA, Figure 2A) in rats (radioactivity was measured in blood, plasma, the heart, the liver, the kidneys, the lungs, skeletal muscles and the brain (separately in the pons, cerebellum, colliculi, hypothalamus, hippocampus, striatum and anterior and posterior cortices)), and positron emission tomography (PET) imaging was performed on two male adult baboons. In these experiments (distribution study in rats and PET imaging in baboons), both [\({}^{11}\)C]MTHA radiotracer alone and [\({}^{11}\)C]MTHA radiotracer together with unlabeled THA administered simultaneously or 20 min before tracer injection were used. The results, in the case of using the [\({}^{11}\)C]MTHA radiopreparation and in the case of administering the [\({}^{11}\)C]MTHA radiopreparation and then unlabeled THA, showed significantly different amounts of radioactivity accumulated in the examined organs, significantly lower in the case of using unlabeled THA in the experiment, e.g., radioactivity accumulated in all brain regions studied in the case of coinjection of THA together with [\({}^{11}\)C]MTHA was 40-50% lower. This allows for us to conclude that these two molecules ([\({}^{11}\)C]MTHA and THA) compete for the same binding sites. Based on these results, the authors concluded that the [\({}^{11}\)C]MTHA radiotracer could be considered a promising PET ligand for studying THA binding in the brain. Figure 2: Radiotracers based on tacrine derivatives: (**A**) [methyl-\({}^{11}\)C]1,2,3,4-tetrahydro-9-methyl-amino acridine [26; 27; 28]; (**B**) 9-amino-8-fluoro-2,4-methane-1,2,3,4-[9-\({}^{14}\)C]tetrahydroacridine [29]; (**C**) 7-[\({}^{123}\)I]iodotacrine [30]. The first studies of the [\({}^{11}\)C]MTHA radiotracer (Figure 2A) in position emission tomography (PET) imaging in healthy volunteers are presented in the publication by [PERSON] et al. [28]. The study involved four healthy men who had never been diagnosed with [PERSON]'s disease or other chronic diseases. The [\({}^{11}\)C]MTHA radiotracer was used in PET and magnetic resonance imaging (MRI) methods in order to obtain individual cerebral anatomy. At specific time intervals (up to 70 min after intravenous administration of the tracer), the authors determined the level of radioactivity in the blood and in the selected areas of the brain (white matter, putamen, thalamus, brainstem, cerebellum, cortex). The determined radioactivity in the brain was relatively high and amounted to approximately 6% of the administered dose. Radioactivity in the blood, after a rapid increase (approximately 1.5 min after administration) and then an equally rapid decline (approximately 5 min after administration), increased very slightly; this is related to the circulation of radiotracer metabolites ([\({}^{11}\)C]1-hydroxy-MTHA) in the blood [21], which are, however, capable of crossing the blood-brain barrier to a significantly lesser extent than the administered radiotracer [21]. [PERSON]'s study also showed that brain accumulation of the radiotracer [\({}^{11}\)C]MTHA differs from the sites of action and/or sites of elevated AChE concentrations detected post-mortem in human brains.