The project goal is to development novel positron emission (PET) and single photon emission computed tomography (SPECT) radiotracers that (1) label central nicotinic acetyl cholin receptors (nAChRs) in vivo, (2) can be administered in subpharmacologic doses with a high margin of safety, (3) can detect changes in nAChR binding site concentration (via emission tomography) non-invasively in non-human primate brain. There is a need for development and validation of such radiotracers since human tomographic imaging studies of central nAChRs have been hampered b an absence of radioligands that label nAChRs in vivo with high specificity. Th proposed radiotracers will ultimately prove useful as in vivo probes for the study of nAChRs in healthy people and in patients suffering from neurodegenerative disease such as Alzheimer's. Moreover, the ability to assess nAChR sites by tomography will also aid new drug discovery efforts in smoking cessation therapy and cholinergic replacement therapy. A focused, medicinal chemistry approach will be undertaken in the development efforts. Analogs of high affinity nAChR agonist, epibatidine, homoepibatidine, and A-85380 will be synthesized, characterized and labeled with positron emitting radionuclides (C-11, F-18) or with radioiodine (I-125, I-123). Preliminary results show that all three classes of compounds (in radiolabeled form) can label central anchors in vivo. The novel radioligands will be screened to define in vitro and in vivo binding profiles, metabolism, and radiation chemistry. Also, the applicants will demonstrate that the high specific activity radioligands can be administered in subpharmacologic doses with a high margin of safety. The most promising radioligands will be evaluate in imaging trials in baboons, and from these imaging experiments a lead PET radiotracer will be identified. This lead PET radioligand will be tested further via PET for its ability to detect changes in nAChR binding site concentration in the brains of baboons chronically treated with (-)-nicotine. This project will provide radioligands useful for in vitro and in vivo studies of nAChRs and will lay the foundation for PET and SPECT studies of nAChRs in humans