Classics in Neuroimaging: Development of PET Tracers for Imaging Monoamine Oxidases

Narayanaswami, Vidya; Drake, Lindsey; Brooks, Allen F.; Meyer, Jeffrey H.; Houle, Sylvain; Kilbourn, Michael R.; Scott, Peter J. H.; Vasdev, Neil

doi:10.1021/acschemneuro.9b00081

Cited by 44 publications

(39 citation statements)

References 6 publications

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“… 7 , 8 Recent studies by an author of this article also demonstrated that the tau PET tracers also target the same binding site as the MAO-B inhibitors. 9 , 10 Moreover, we have found that the PET tracers such as SL25.1188 11 also bind to the same substrate binding site. It is also speculated that when the substrate site is not available due to the binding of irreversible MAO-B inhibitors or because the ligand molecular volume is larger than the cavity volume then the entrance cavity is the preferred site for ligand binding.…”

Section: Introductionmentioning

confidence: 89%

Multiscale Modeling of Two-Photon Probes for Parkinson’s Diagnostics Based on Monoamine Oxidase B Biomarker

Murugan

Zaleśny

2020

J. Chem. Inf. Model.

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Monoamine oxidase B (MAO-B) is a potential biomarker for Parkinson’s disease (PD), a neurodegenerative disease associated with the loss of motor activities in human subjects. The disease state is associated with dopamine deprival, and so the inhibitors of MAO-B can serve as therapeutic drugs for PD. Since the expression level of MAO-B directly correlates to the disease progress, the distribution and population of this enzyme can be employed to monitor disease development. One of the approaches available for estimating the population is two-photon imaging. The ligands used for two-photon imaging should have high binding affinity and binding specificity toward MAO-B along with significant two-photon absorption cross sections when they are bound to the target. In this article, we study using a multiscale modeling approach, the binding affinity and spectroscopic properties (one- and two-photon absorption) of three (Flu1, Flu2, Flu3) of the currently available probes for monitoring the MAO-B level. We report that the binding affinity of the probes can be explained using the molecular size and binding cavity volume. The experimentally determined one-photon absorption spectrum is well reproduced by the employed QM/MM approaches, and the most accurate spectral shifts, on passing from one probe to another, are obtained at the coupled-cluster (CC2) level of theory. An important conclusion from this study is also the demonstration that intrinsic molecular two-photon absorption strengths (δ 2PA ) increase in the order δ 2PA (Flu1) > δ 2PA (Flu2) > δ 2PA (Flu3). This is in contrast with experimental data, which predict similar values of two-photon absorption cross sections for Flu1 and Flu3. We demontrate, based on the results of electronic-structure calculations for Flu1 that this discrepancy cannot be explained by an explicit account for neighboring residues (which could lead to charge transfer between a probe and neighboring aromatic amino acids thus boosting δ 2PA ). In summary, we show that the employed multiscale approach not only can optimize two-photon absorption properties and verify binding affinity, but it can also help in detailed analyses of experimental data.

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Section: Introductionmentioning

confidence: 89%

Multiscale Modeling of Two-Photon Probes for Parkinson’s Diagnostics Based on Monoamine Oxidase B Biomarker

Murugan

Zaleśny

2020

J. Chem. Inf. Model.

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“…Although MAO inhibitors are valuable therapeutic agents for disorders such as Parkinson’s disease, they are not candidates for specific dopaminergic imaging agents due to this widespread distribution. Nevertheless, they are an important component of the dopamine system, and have been the target for in vivo PET radiotracer development [ 68 , 69 ]. There have been three approaches to MAO radioligands for PET: suicide inhibitors, reversible antagonists, and metabolic substrates.…”

Section: Monoamine Oxidases (Mao): Inhibitors and Substratesmentioning

confidence: 99%

“…For this approach, radiotracers were selected or designed to be BBB permeable and subject to metabolism by MAO in brain tissues, with the resultant radiolabeled metabolites irreversibly trapped in the tissues in proportion to the enzymatic activity. None of these potential MAO radiotracers have yet been taken to human studies, but they might provide a different measure of MAO enzymatic activities than the radiolabeled enzyme inhibitors [ 69 ].…”

Section: Monoamine Oxidases (Mao): Inhibitors and Substratesmentioning

confidence: 99%

11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

Kilbourn

2021

Biomedicines

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The applications of positron emission tomography (PET) imaging to study brain biochemistry, and in particular the aspects of dopamine neurotransmission, have grown significantly over the 40 years since the first successful in vivo imaging studies in humans. In vivo PET imaging of dopaminergic functions of the central nervous system (CNS) including dopamine synthesis, vesicular storage, synaptic release and receptor binding, and reuptake processes, are now routinely used for studies in neurology, psychiatry, drug abuse and addiction, and drug development. Underlying these advances in PET imaging has been the development of the unique radiotracers labeled with positron-emitting radionuclides such as carbon-11 and fluorine-18. This review focuses on a selection of the more accepted and utilized PET radiotracers currently available, with a look at their past, present and future.

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“…These radiotracers have been employed to monitor NET availability in different related diseases, including obesity, major depressive disorder, and Parkinson’s disease. Likewise, radiotracers, for instance, [ 11 C]Harmine demonstrated clinical success for in vivo brain imaging of MAO-A, respectively [ 55 , 56 , 57 ]. [ 11 C]Harmine has been applied in several-PET neuroimaging studies to study the role of MAO-A in different pathological conditions, including nicotine/alcohol dependence, and Alzheimer’s disease.…”

Section: Introductionmentioning

confidence: 99%

PET Radiotracers for CNS-Adrenergic Receptors: Developments and Perspectives

et al. 2020

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Epinephrine (E) and norepinephrine (NE) play diverse roles in our body’s physiology. In addition to their role in the peripheral nervous system (PNS), E/NE systems including their receptors are critical to the central nervous system (CNS) and to mental health. Various antipsychotics, antidepressants, and psychostimulants exert their influence partially through different subtypes of adrenergic receptors (ARs). Despite the potential of pharmacological applications and long history of research related to E/NE systems, research efforts to identify the roles of ARs in the human brain taking advantage of imaging have been limited by the lack of subtype specific ligands for ARs and brain penetrability issues. This review provides an overview of the development of positron emission tomography (PET) radiotracers for in vivo imaging of AR system in the brain.

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Classics in Neuroimaging: Development of PET Tracers for Imaging Monoamine Oxidases

Cited by 44 publications

References 6 publications

Multiscale Modeling of Two-Photon Probes for Parkinson’s Diagnostics Based on Monoamine Oxidase B Biomarker

Multiscale Modeling of Two-Photon Probes for Parkinson’s Diagnostics Based on Monoamine Oxidase B Biomarker

11C- and 18F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

PET Radiotracers for CNS-Adrenergic Receptors: Developments and Perspectives

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