The project goal is to develop the first low molecular weight (< 500) radioligands that bind with high affinity and selectivity to neuronal alpha-7 nicotinic acetylcholine receptors (nAChRs). Ultimately, the developed radioligands may prove useful for in vivo tomographic imaging studies of this important nAChR subtype in humans. Interest in such studies is warranted for several reasons. First, these homomeric channels appear to mediate some of the presynaptic effects of nicotine; therefore, an in vivo probe for alpha-7 nAChRs would enable non-invasive study of a principal site of pharmacological action of nicotine. For example, the proposed alpha-7 radioligands might enable measurement of dose occupancy of nicotine at the alpha-7 site in tobacco users and patients undergoing nicotine-replacement therapy. Second, alpha-7-imaging tracers might aid in the validation of new alpha-7 therapeutic agents for the treatment of neurodegenerative disease and alcohol abuse. Third, such radioligands would aid in corroborating in the living brain the purported deficit of alpha-7 nAChRs in schizophrenia. Presently, alpha-7 radioligands are limited to high molecular weight probes (e.g. I-125 alpha-bungarotoxin, [I-125]otBTX) that are unable to cross the blood-brain barrier and suffer from a high degree of non-specific binding in in vitro assays. This proposal seeks to overcome the deficiencies of the existing alpha-7 radioligands and to explore the potential of the proposed alpha-7 radioligands to label the target nAChR subtype in vivo. High affinity alpha-7 ligands from a 3-(cinnamylidene)anabaseine and quinuclidine-based series will be synthesized. These two structural classes of alpha-7 specific nAChR agonists will be screened in in vitro homogenate binding assay. (Such assays will enable us to report the first qualitative structure-alpha-7 affinity relationship for these potent alpha-7 ligands). Alpha-7 ligands that possess high affinity and selectivity for the alpha-7 nAChR subtype will be labeled with positron emitting radionuclides (C-ll, F-18) or with radioiodine (I-125, I-123). The most promising I-125 labeled alpha-7 ligands will be tested in saturation binding assay and autoradiography assay using rat brain. From these studies, the specific binding signal afforded with the novel radioligands will be compared to the commonly used [I-125]a-BTX. The radioligands will be tested in rodent biodistribution studies to detenrune if the developed radioligands can localize alpha-7 sites in vivo. Completion of the project should provide the neuroscience research community with new and improved radioprobes that can be used for in vitro studies of the alpha-7 nAChR subtype. Additionally, this exploratory project will address the feasibility of in vivo labeling of alpha-7 nAChR sites.
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