## 2 Radiolabeled Tacrine and Its Derivatives Used in Alzheimer's Disease
### Radiotracers Based on Tacrine  
One of the first tacrine-based radiopreparations was the [9-14C]tacrine radiotracer (Figure 1A) [20; 21]. The authors examined the distribution of this radiotracer in the rat body after both intravenous and oral administration using a quantitative whole-body autoradiographic method [20]. Based on the results obtained, the authors concluded that, in both cases, [14C]tacrine ([14C]THA) crosses the blood--brain barrier; the biodistribution of the radiotracer is similar, although after oral administration, the absorption of the radiotracer persists in the organs noticeably longer. Due to the potential use of ([14C]THA) in the diagnosis of neurological diseases, the authors examined the regional distribution of the radiotracer in the brain--the highest levels of radioactivity were detected in the cortex, hippocampus, cerebellum and striatum. Analyzing the distribution of the radiotracer in individual parts of the brain, the authors found that it did not correlate consistently with the distribution of acetylcholinesterase (AChE), which may suggest that the effect of tacrine in the treatment of senile dementia may occur in a way other than by inhibiting the enzyme. Based on the high level of activity detected in the kidneys and ureters, the authors also concluded that the radiotracer is excreted primarily in the urine, although they also noted that there are indications of excretion of the radiotracer and its metabolites into the intestines. Further research by [PERSON] et al. on the application of the radiotracer [9-14C]tacrine (Figure 1A) in the study of THA distribution in the brain is presented in [21]. Using oral administration (by oral gavage) and single or multiple (twice daily for 3 days) doses (SD or MD, respectively), the authors performed in vivo studies of the distribution of [9-14C]JHA and its main metabolite [9-14C]1-OH-tacrine ([9-14C]1-OH-THA, Figure 1B) in rats. At selected time intervals, ranging from 0.5 h to 96 h, they examined the level of radioactivity in blood, plasma, the heart, the lungs, the kidneys, the liver, the pancreas and various brain regions (brainstem, cerebellum, cortex, hippocampus, striatum and thalamus) using the autoradiography method. The authors also performed in vitro studies of the process of tacrine metabolism in the brain. The rat brain homogenate was incubated with the [9-14C]THA radiotracer and its metabolite [9-14C]1-OH-THA. Then, after the incubation, the products of tacrine metabolism were identified using the HPLC method in specially prepared samples. For this purpose, various products of tacrine metabolism ([9-14C]1-OH-THA, [9-14C]2-OH-THA and [9-14C]4-OH-THA) and their reference compounds (1-OH-THA, 2-OH-THA and 4-OH-THA) were previously characterized by HPLC. Based on the results obtained, [PERSON] et al. drew a number of conclusions. They found that, for both doses used (SD and MD), the distribution of [9-14C]THA in the brain was similar, although in the case of MD, the radioactivity levels in the tested organs were visibly higher. After oral administration of [9-14C]THA, the radiotracer penetrates very quickly into the brain and accumulates in the cortex and hippocampus, i.e., in the areas responsible for the cognitive functions of the brain. In vitro studies of tacrine metabolism in the brain performed using rat brain homogenate showed that this process practically does not occur in the brain and that metabolite [9-14C]1-OH-THA has a very limited ability to cross the blood-brain barrier. This difference in the ability to cross the blood-brain barrier correlates well with the log p values calculated by the authors for THA and its metabolite 1-OH-THA (3.30 and 1.66, respectively).