Update on PET Tracer Development for Muscarinic Acetylcholine Receptors

Ozenil, Marius; Aronow, Jonas; Millard, Marlon; Langer, Thierry; Wadsak, Wolfgang; Hacker, Marcus; Pichler, Verena

doi:10.3390/ph14060530

Cited by 12 publications

(15 citation statements)

References 114 publications

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“…As mentioned above, a new method for identifying mAChR subtypes involved in specific functions involves the use of allosteric ligands (PAMs and NAMs), as recently demonstrated in M 4 and M 5 mAChR determination as important structures in alcohol-seeking behaviors ( Walker et al, 2021 ). Similarly, some new positron emission tomography (PET) tracers have exhibited promising selectivity ( Ozenil et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Mysliveček¹

2022

Front. Physiol.

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Muscarinic receptors (mAChRs) are typical members of the G protein-coupled receptor (GPCR) family and exist in five subtypes from M1 to M5. Muscarinic receptor subtypes do not sufficiently differ in affinity to orthosteric antagonists or agonists; therefore, the analysis of receptor subtypes is complicated, and misinterpretations can occur. Usually, when researchers mainly specialized in CNS and peripheral functions aim to study mAChR involvement in behavior, learning, spinal locomotor networks, biological rhythms, cardiovascular physiology, bronchoconstriction, gastrointestinal tract functions, schizophrenia, and Parkinson’s disease, they use orthosteric ligands and they do not use allosteric ligands. Moreover, they usually rely on manufacturers’ claims that could be misleading. This review aimed to call the attention of researchers not deeply focused on mAChR pharmacology to this fact. Importantly, limited selective binding is not only a property of mAChRs but is a general attribute of most neurotransmitter receptors. In this review, we want to give an overview of the most common off-targets for established mAChR ligands. In this context, an important point is a mention the tremendous knowledge gap on off-targets for novel compounds compared to very well-established ligands. Therefore, we will summarize reported affinities and give an outline of strategies to investigate the subtype’s function, thereby avoiding ambiguous results. Despite that, the multitargeting nature of drugs acting also on mAChR could be an advantage when treating such diseases as schizophrenia. Antipsychotics are a perfect example of a multitargeting advantage in treatment. A promising strategy is the use of allosteric ligands, although some of these ligands have also been shown to exhibit limited selectivity. Another new direction in the development of muscarinic selective ligands is functionally selective and biased agonists. The possible selective ligands, usually allosteric, will also be listed. To overcome the limited selectivity of orthosteric ligands, the recommended process is to carefully examine the presence of respective subtypes in specific tissues via knockout studies, carefully apply “specific” agonists/antagonists at appropriate concentrations and then calculate the probability of a specific subtype involvement in specific functions. This could help interested researchers aiming to study the central nervous system functions mediated by the muscarinic receptor.

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Section: Discussionmentioning

confidence: 99%

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Mysliveček¹

2022

Front. Physiol.

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“…The development of PET radioligands to image mAChRs has a long history beginning in the late 1970s (79,91). As with the…”

Section: Pet Radioligands For Imaging Machrsmentioning

confidence: 99%

“…1) June 2022 nAChR-targeting radioligands, the first radiotracers developed to image mAChRs suffered from insufficient subtype selectivity and unfavorable tracer kinetics, resulting in complicated modeling analyses (79,91). The development of subtype-specific radiotracers is still a work in progress (91). There are promising candidates for imaging M1, M2, and M4 mAChRs (Table 4; Fig.…”

Section: Smentioning

confidence: 99%

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PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders

et al. 2022

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As a neuromodulator, the neurotransmitter acetylcholine plays an important role in cognitive, mood, locomotor, sleep/wake, and olfactory functions. In the pathophysiology of most neurodegenerative diseases, such as Alzheimer disease (AD) or Lewy body disorder (LBD), cholinergic receptors, transporters, or enzymes are involved and relevant as imaging targets. The aim of this review is to summarize current knowledge on PET imaging of cholinergic neurotransmission in neurodegenerative diseases. For PET imaging of presynaptic vesicular acetylcholine transporters (VAChT), (2)-18 F-fluoroethoxybenzovesamicol ( 18 F-FEOBV) was the first PET ligand that could be successfully translated to clinical application. Since then, the number of 18 F-FEOBV PET investigations on patients with AD or LBD has grown rapidly and provided novel, important findings concerning the pathophysiology of AD and LBD. Regarding the a4b2 nicotinic acetylcholine receptors (nAChRs), various second-generation PET ligands, such as 18 F-nifene, 18

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“…3-50 nM) for a potential application as a PET imaging probe [14]. Such a probe in turn could, for example, facilitate compound selection for clinical trials by providing in vivo occupancy data [15].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

et al. 2022

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Due to their important role in mediating a broad range of physiological functions, muscarinic acetylcholine receptors (mAChRs) have been a promising target for therapeutic and diagnostic applications alike; however, the list of truly subtype-selective ligands is scarce. Within this work, we have identified a series of twelve 4,4’-difluorobenzhydrol carbamates through a rigorous docking campaign leveraging commercially available amine databases. After synthesis, these compounds have been evaluated for their physico–chemical property profiles, including characteristics such as HPLC-logD, tPSA, logBB, and logPS. For all the synthesized carbamates, these characteristics indicate the potential for BBB permeation. In competitive radioligand binding experiments using Chinese hamster ovary cell membranes expressing the individual human mAChR subtype hM1-hM5, the most promising compound 2 displayed a high binding affinitiy towards hM1R (1.2 nM) while exhibiting modest-to-excellent selectivity versus the hM2-5R (4–189-fold). All 12 compounds were shown to act in an antagonistic fashion towards hM1R using a dose-dependent calcium mobilization assay. The structural eligibility for radiolabeling and their pharmacological and physico–chemical property profiles render compounds 2, 5, and 7 promising candidates for future position emission tomography (PET) tracer development.

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Update on PET Tracer Development for Muscarinic Acetylcholine Receptors

Cited by 12 publications

References 114 publications

Multitargeting nature of muscarinic orthosteric agonists and antagonists

Multitargeting nature of muscarinic orthosteric agonists and antagonists

PET Imaging of Cholinergic Neurotransmission in Neurodegenerative Disorders

Design, Synthesis, and Biological Evaluation of 4,4’-Difluorobenzhydrol Carbamates as Selective M1 Antagonists

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