scholarly journals Update on PET Tracer Development for Muscarinic Acetylcholine Receptors

2021 ◽  
Vol 14 (6) ◽  
pp. 530
Author(s):  
Marius Ozenil ◽  
Jonas Aronow ◽  
Marlon Millard ◽  
Thierry Langer ◽  
Wolfgang Wadsak ◽  
...  
Keyword(s):  
Nervous System ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Muscarinic Acetylcholine ◽  
Pet Tracer ◽  
Positron Emission ◽  
Muscarinic Cholinergic ◽  
Imaging Properties ◽  
Tracer Development

The muscarinic cholinergic system regulates peripheral and central nervous system functions, and, thus, their potential as a therapeutic target for several neurodegenerative diseases is undoubted. A clinically applicable positron emission tomography (PET) tracer would facilitate the monitoring of disease progression, elucidate the role of muscarinic acetylcholine receptors (mAChR) in disease development and would aid to clarify the diverse natural functions of mAChR regulation throughout the nervous system, which still are largely unresolved. Still, no mAChR PET tracer has yet found broad clinical application, which demands mAChR tracers with improved imaging properties. This paper reviews strategies of mAChR PET tracer design and summarizes the binding properties and preclinical evaluation of recent mAChR tracer candidates. Furthermore, this work identifies the current major challenges in mAChR PET tracer development and provides a perspective on future developments in this area of research.

scholarly journals Preparation of a First 18F-Labeled Agonist for M1 Muscarinic Acetylcholine Receptors

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2880 ◽  
Author(s):  
Boris D. Zlatopolskiy ◽  
Felix Neumaier ◽  
Till Rüngeler ◽  
Birte Drewes ◽  
Niklas Kolks ◽  
...  
Keyword(s):  
Acetylcholine Receptors ◽  
Radiochemical Yield ◽  
Muscarinic Acetylcholine Receptors ◽  
Preparative Scale ◽  
Muscarinic Acetylcholine ◽  
Pet Tracer ◽  
Positron Emission ◽  
Diagnostic Applications ◽  
M1 Muscarinic ◽  
Subtype Selective

M1 muscarinic acetylcholine receptors (mAChRs) are abundant in postsynaptic nerve terminals of all forebrain regions and have been implicated in the cognitive decline associated with Alzheimer’s disease and other CNS pathologies. Consequently, major efforts have been spent in the development of subtype-selective positron emission tomography (PET) tracers for mAChRs resulting in the development of several 11C-labeled probes. However, protocols for the preparation of 18F-labeled mAChR-ligands have not been published so far. Here, we describe a straightforward procedure for the preparation of an 18F-labeled M1 mAChR agonist and its corresponding pinacol boronate radiolabeling precursor and the non-radioactive reference compound. The target compounds were prepared from commercially available aryl fluorides and Boc protected 4-aminopiperidine using a convergent reaction protocol. The radiolabeling precursor was prepared by a modification of the Miyaura reaction and labeled via the alcohol-enhanced Cu-mediated radiofluorination. The developed procedure afforded the radiotracer in a non-decay-corrected radiochemical yield of 17 ± 3% (n = 3) and in excellent radiochemical purity (>99%) on a preparative scale. Taken together, we developed a straightforward protocol for the preparation of an 18F-labeled M1 mAChR agonist that is amenable for automation and thus provides an important step towards the routine production of a 18F-labeled M1 selective PET tracer for experimental and diagnostic applications.

scholarly journals The Role of Spinal Muscarinic Acetylcholine Receptors in Clonidine-Induced Anti-nociceptive Effects in Rats

2003 ◽  
Vol 26 (8) ◽  
pp. 1178-1180 ◽  
Author(s):  
Kenji Honda ◽  
Namiko Murao ◽  
Takae Ibuki ◽  
Hiro-o Kamiya ◽  
Yukio Takano
Keyword(s):  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Muscarinic Acetylcholine

scholarly journals Synthesis, Biological, and Computational Evaluation of Antagonistic, Chiral Hydrobenzoin Esters of Arecaidine Targeting mAChR M1

2020 ◽  
Vol 13 (12) ◽  
pp. 437
Author(s):  
Marius Ozenil ◽  
Jonas Aronow ◽  
Daniela Piljak ◽  
Chrysoula Vraka ◽  
Wolfgang Holzer ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Chinese Hamster ◽  
Muscarinic Acetylcholine Receptors ◽  
Ovary Cell ◽  
Computational Evaluation ◽  
Subtype Selectivity ◽  
Pet Tracer ◽  
Positron Emission

Muscarinic acetylcholine receptors (mAChRs) are a pivotal constituent of the central and peripheral nervous system. Yet, therapeutic and diagnostic applications thereof are hampered by the lack of subtype selective ligands. Within this work, we synthesized and chemically characterized three different stereoisomers of hydrobenzoin esters of arecaidine by NMR, HR-MS, chiral chromatography, and HPLC-logP. All compounds are structurally eligible for carbon-11 labeling and show appropriate stability in Dulbecco’s phosphate-buffered saline (DPBS) and F12 cell culture medium. A competitive radioligand binding assay on Chinese hamster ovary cell membranes comprising the human mAChR subtypes M1-M5 showed the highest orthosteric binding affinity for subtype M1 and a strong influence of stereochemistry on binding affinity, which corresponds to in silico molecular docking experiments. Ki values toward M1 were determined as 99 ± 19 nM, 800 ± 200 nM, and 380 ± 90 nM for the (R,R)-, (S,S)-, and racemic (R,S)-stereoisomer, respectively, highlighting the importance of stereochemical variations in mAChR ligand development. All three stereoisomers were shown to act as antagonists toward mAChR M1 using a Fluo-4 calcium efflux assay. With respect to future positron emission tomography (PET) tracer development, the (R,R)-isomer appears especially promising as a lead structure due to its highest subtype selectivity and lowest Ki value.

scholarly journals Role of M1, M3, and M5 muscarinic acetylcholine receptors in cholinergic dilation of small arteries studied with gene-targeted mice

2011 ◽  
Vol 300 (5) ◽  
pp. H1602-H1608 ◽  
Author(s):  
Adrian Gericke ◽  
Jan J. Sniatecki ◽  
Veronique G. A. Mayer ◽  
Evgeny Goloborodko ◽  
Andreas Patzak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscarinic Receptor ◽  
Acetylcholine Receptors ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Wild Type ◽  
Luminal Diameter ◽  
Small Arteries ◽  
Muscarinic Acetylcholine

Acetylcholine regulates perfusion of numerous organs via changes in local blood flow involving muscarinic receptor-induced release of vasorelaxing agents from the endothelium. The purpose of the present study was to determine the role of M1, M3, and M5 muscarinic acetylcholine receptors in vasodilation of small arteries using gene-targeted mice deficient in either of the three receptor subtypes (M1R−/−, M3R−/−, or M5R−/− mice, respectively). Muscarinic receptor gene expression was determined in murine cutaneous, skeletal muscle, and renal interlobar arteries using real-time PCR. Moreover, respective arteries from M1R−/−, M3R−/−, M5R−/−, and wild-type mice were isolated, cannulated with micropipettes, and pressurized. Luminal diameter was measured using video microscopy. mRNA for all five muscarinic receptor subtypes was detected in all three vascular preparations from wild-type mice. However, M3 receptor mRNA was found to be most abundant. Acetylcholine produced dose-dependent dilation in all three vascular preparations from M1R−/−, M5R−/−, and wild-type mice. In contrast, cholinergic dilation was virtually abolished in arteries from M3R−/− mice. Deletion of either M1, M3, or M5 receptor genes did not affect responses to nonmuscarinic vasodilators, such as substance P and nitroprusside. These findings provide the first direct evidence that M3 receptors mediate cholinergic vasodilation in cutaneous, skeletal muscle, and renal interlobar arteries. In contrast, neither M1 nor M5 receptors appear to be involved in cholinergic responses of the three vascular preparations tested.

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