Receptors for the neurotransmitter acetylcholine have been divided into muscarinic and nicotinic. The muscarinic acetylcholine receptors are further divided into four pharmacological subtypes and five distinct muscarinic acetylcholine receptor proteins. Through use of selective antibodies, the proportion of each of the molecular receptors in each of the brain regions has been determined. A post-mortem study of acetylcholine binding sites in Alzheimer's disease, revealed deviations in the amounts of various subtypes compared to normals. This has led to the theory that Alzheimer's disease is a function of the loss of presynaptic M2 receptor function. Others at NIH believe the m3 receptor may be important in the etiology and treatment of salivary disorders such as Sjogren's Syndrome. The goal of this project is to prepare fluorine containing agonists or antagonists which may be labeled with F-18 for imaging by positron emission tomography (PET). We have prepared fluorine containing analogs of the antagonist quinuclidinyl benzilate of known configuration at the two chiral centers and observed differences in subtype affinities. In addition we have prepared fluorine-containing analogs of a class of agonists based on thiadiazolyl tetrahydopyridine (TZTP) and studied their subtype selectivity. The two compounds which display the highest M2 selectivity in vitro were labeled with F-18 and evaluated in vivo in rats for biodistribution, metabolism, and pharmacological inhibition of uptake. The F-18 analog of fluoropropylthio TZTP displays in vivo properties in rats consistent with M2 selectivity. Biodistribution studies have been conducted in non-human primates.