The pharmacological effects of the action of nicotine on nicotinic acetylcholine receptors (nAChR) have been implicated in many diseases such as Alzheimer’s disease, schizophrenia, and tobacco dependence. Brain imaging using positron emission tomography (PET) for each nAChR subtype provides biological information on subtype-specific function and pathological change. While PET studies for the α4β2 nAChR have progressed, the development of PET for α7 nAChR has been hampered due to the lack of suitable radioligands. It is, therefore, important to develop α7 nAChR-selective PET tracers for in vivo imaging studies to better understand the role of α7 nAChR in specific CNS disorders. Furthermore, positron emitter labeled drug that targets α7 nAChR can also contribute to drug development by providing information on in vivo pharmacokinetics.

In this work, we first investigated the drug pharmacokinetics of GTS-21, a partial α7 nAChR agonist drug, using PET in the baboon and rat. GTS-21 was labeled at two different positions with the short-lived isotope C-11. In addition, the two corresponding demethylated metabolites, which have themselves been considered as contributing to the therapeutic effects of GTS-21, were synthesized and labeled with C-11. PET studies revealed extremely rapid uptake and clearance of [2-methoxy-¹¹C]GTS-21 from the brain, and significant brain uptake of the metabolite 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21.

Second, in order to describe α7 nAChR distribution, we synthesized C-11 labeled des-N-ethyl-N-methylmethyllycaconitine based on the known selective antagonist, methyllycaconitine. In its PET study, des(N-ethyl)-N-¹¹ C-methylmehtyllycaconitine showed lack of blood brain barrier permeability at a tracer dose level, possibly due to high molecular weight and low lipophilicity. We also synthesized C-11 nicotine for primate PET study to show nicotine action in conjunction with the cigarette smoking. For [¹¹C]nicotine, compared with maternal brain, slow fetal brain entry and clearance of [ ¹¹C]nicotine was observed, indirectly indicating [¹¹C]nicotine transfer from the maternal to fetal brain during prenatal smoking.

Third, we have been developing putative quinuclidine-based α7 nAChR ligands with the aim of achieving selectivity and binding affinity. We synthesized a PET ligand candidate through reliable Pd catalyzed cross-coupling reactions of heteroaryl bromides and heteroaryl carboxylic acid, which might be useful for the parallel synthesis of quinuclidine-based derivatives.

This dissertation also provides insight for ligand interaction toward α7 nAChR through homology model of mouse α7 nAChR. For rational PET tracer design, a quantitative structure-activity relationship study was performed to provide a putative ligand candidate for α7 nAChR.