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 normal subjects. This has led to the theory that Alzheimer's disease is a function of the loss of presynaptic M2 receptor function. Others believe the m3 receptor may be important in the etiology and treatment of salivary disorders such as Sjogren's syndrome. We have prepared several fluorine-containing analogs of the antagonist quinuclidinyl benzilate of known configuration and fluorine-containing analogs of a class of agonists based on thiadiazolyl tetrahydopyridine (TZTP) and studied their subtype selectivity. We selected one of the TZTP analogs that displayed m2 selectivity in vitro and have conducted a number of studies in monkeys to evaluate the pharmokinetics in the brain. We have studied the effects of other pharmaceuticals known to influence the muscarinic system on the pharmacokinetics of our new TZTP ligand. These studies are an attempt to establish that our compound is exhibiting binding in the muscarinic system and to demonstrate subtype selectivity. Unfortunately, this compound displays uptake highly dependent on blood flow. The studies in monkeys may be compromised by the essential use of anesthesia for conducting these studies.
