Imaging of Muscarinic Receptors in the Central Nervous System

Abstract

The development of receptor-binding radiotracers has evolved from a goal of high affinity compounds to give high target to non target ratios to compounds of slightly lesser affinity so that they can reach either steady state after bolus injection or equilibrium after infusion. The other important advance is the ability to measure endogenous neurotransmitter, using various lower affinity muscarinic acetylcholine receptor radioligands. There have been a number of clinical studies that elucidated the mechanism of action of new pharmaceuticals in vivo using external imaging. These include studies of drug interaction of olanzapine, risperidone, clozapine, donepezil, and phenserine with the muscarinic receptor. There have been fewer studies monitoring the effect of therapy in Alzheimer's disease, but those pilot studies give great hope that monitoring therapy is a real possibility. Radioligands for the muscarinic receptor, for ACh esterase, and to measure the concentration of acetylcholine have now been developed, A number of studies in small populations have identified changes in mild to moderate Alzheimer's disease and, perhaps more importantly, changes in radioligand binding have been identified in clinically normal subjects genetically predisposed to Alzheimer's disease by virtue of the epsilon 4+ variant of the APOE gene. Large scale clinical studies are now needed to delineate the true value of these radiotracers in clinical situations. PET and SPECT imaging hold the promise of monitoring the effect of pharmaceuticals in a wide variety of diseases using non-invasive external imaging of the muscarinic cholinergic system.

Impaired Off-Line Consolidation of Motor Memories After Combined Blockade of Cholinergic Receptors During REM Sleep-Rich Sleep

“…High levels of ACh during REM sleep affect both the nicotinic and muscarinic cholinergic receptors, which are both distributed widely in brain areas involved in memory and sleep regulation (Court et al, 2000;Eckelman, 2006). Activation of the nicotinic receptors specifically enhances interest afferent input to cortical and hippocampal networks, whereas muscarinic receptor activation inhibits excitatory feedback synapses in these circuits (see Hasselmo, 2006, for a review).…”

“…The muscarinic and nicotinic cholinergic receptors are expressed widely in the brain, particularly in regions considered important for sleep and memory (brain stem, tegmental regions, hippocampus, amygdala, neocortex, etc.) (Court et al, 2000;Eckelman, 2006). To account for the longer time interval of the orally administered drug to reach the brain, mecamylamine was administered immediately after learning (0330 hours), and scopolamine was infused starting 30 min after the end of the learning phase (ie, at the time of lights off; Figure 1).…”

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals — Radiosynthesis and ex vivo biodistribution of [18F]3-(4-(2-(2-(2-fluoroethoxy)ethoxy)ethylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine

“…The diols were disubstituted with benzyl-protecting and tosyloxy-leaving groups (6). Nucleophilic displacement of the tosyloxy group of 6 with fluoride resulted in O-benzyl protected fluoroalkyl and fluoro-PEG chains (7). The hydroxyl analogs (8) were synthesized by reaction of the appropriate diol (5) with 1 (Scheme 3).…”

“…7 Derivatization of the thiadiazolyltetrahydropyridine (TZTP) core 8 has led to the development of muscarinic subtype-selective PET radiotracers. [9][10][11][12] The M 2 -specific agonist radiotracer, fluorine-18 ( 18 F; t 1/2 = 109.7 min) labelled fluoropropylthio-TZTP ([ 18 F]FP-TZTP), 11,13,14 was proven to be selective through knockout mice studies 15,16 and is currently the only M 2 -specific radiotracer established for human PET imaging.…”

The ART of Loss: Aβ Imaging in the Evaluation of Alzheimer’s Disease and other Dementias

“…M1 mAChRs agonists and M2 mAChRs antagonists have been shown to improve cognition by their cholinomimetic effect increasing ACh release in addition to their direct action on the enzymes cleaving Aβ [70][71][72][73][74]. Highly selective subtypespecific radioligands for M1 or M2 mAChRs are not yet available [75], but radiotracers that can assist in both quantifying mAChRs receptor densities and monitoring AD therapy are being developed [76]. Several other neurotransmitter/neuroreceptor systems have also been evaluated in dementing neurodegenative diseases [77][78][79][80][81][82][83].…”