[18F]F-DPA for the detection of activated microglia in a mouse model of Alzheimer's disease

Keller, Thomas H.; López-Picón, Francisco R.; Krzyczmonik, Anna; Forsbäck, Sarita; Kirjavainen, Anna; Takkinen, Jatta; Alzghool, Obada M.; Rajander, Johan; Teperi, Simo; Cacheux, Fanny; Damont, Annelaure; Dollé, Frédéric; Rinne, Juha O.; Solin, Olof; Haaparanta‐Solin, Merja

doi:10.1016/j.nucmedbio.2018.09.001

Cited by 33 publications

(52 citation statements)

References 24 publications

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“…TSPO density was measured by [ 3 H]PK11195 and [ 3 H]PBR28 in this study. Although renewed efforts are still ongoing to develop and evaluate more potent and specific TSPO radiotracers, [ 3 H]PK11195 is widely used, and is accepted as the “gold standard”, to measure TSPO density both in vitro and in vivo. However, we observed a relatively high nonspecific binding level and lower signal‐noise ratio using [ 3 H]PK11195.…”

Section: Discussionmentioning

confidence: 99%

Translocator protein in late stage Alzheimer’s disease and Dementia with Lewy bodies brains

Sun

Perrin

et al. 2019

Ann Clin Transl Neurol

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Objective Increased translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), in glial cells of the brain has been used as a neuroinflammation marker in the early and middle stages of neurodegenerative diseases, such as Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB). In this study, we investigated the changes in TSPO density with respect to late stage AD and DLB. Methods TSPO density was measured in multiple regions of postmortem human brains in 20 different cases: seven late stage AD cases (Braak amyloid average: C; Braak tangle average: VI; Aged 74–88, mean: 83 ± 5 years), five DLB cases (Braak amyloid average: C; Braak tangle average: V; Aged 79–91, mean: 84 ± 4 years), and eight age‐matched normal control cases (3 males, 5 females: aged 77–92 years; mean: 87 ± 6 years). Measurements were taken by quantitative autoradiography using [3H]PK11195 and [3H]PBR28. Results No significant changes were found in TSPO density of the frontal cortex, striatum, thalamus, or red nucleus of the AD and DLB brains. A significant reduction in TSPO density was found in the substantia nigra (SN) of the AD and DLB brains compared to that of age‐matched healthy controls. Interpretation This distinct pattern of TSPO density change in late stage AD and DLB cases may imply the occurrence of microglia dystrophy in late stage neurodegeneration. Furthermore, TSPO may not only be a microglia activation marker in early stage AD and DLB, but TSPO may also be used to monitor microglia dysfunction in the late stage of these diseases.

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Section: Discussionmentioning

confidence: 99%

Translocator protein in late stage Alzheimer’s disease and Dementia with Lewy bodies brains

Sun

Perrin

et al. 2019

Ann Clin Transl Neurol

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“…[12] The metabolism of tryptophan, ap roteinogenic amino acid with an indole ring in the side chain, is significantly alteredi nn umerousn eurological disorders and tumors. [16] Preparation of this probe via conventional nucleophilic 18 F-fluorinationo ft he respective iodonium, trimethylammonium, and nitro precursors resulted in am aximum 18 F-incorporation of 3%. [14] Figure 3.…”

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confidence: 99%

Alcohol‐Enhanced Cu‐Mediated Radiofluorination

Zischler

Kolks

Modemann

et al. 2017

Chemistry A European J

118

134

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The potential of many F-labeled (hetero)aromatics for applications in positron emission tomography remains underexplored because convenient procedures for their radiosynthesis are lacking. Consequently, simple methods to prepare radiofluorinated (hetero)arenes are highly sought after. Herein, we report the beneficial effect of primary and secondary alcohols on Cu-mediated F-labeling. This observation contradicts the assumption that such alcohols are inappropriate solvents for aromatic fluorination. Therefore, we developed a protocol for rapid radiolabeling of an extraordinarily broad scope of boronic and stannyl substrates under general reaction conditions. Notably, radiofluorinated indoles, phenols, and anilines were synthesized directly from the corresponding unprotected precursors. Furthermore, the novel method enabled the preparation of radiofluorinated tryptophans, [ F]F-DPA, [ F]DAA1106, 6-[ F]FDA, and 6-[ F]FDOPA.

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“…Although the findings of an increased uptake of this tracer in these pathologies, limitations including low signalto-noise ratio and high non-specific binding has addressed for the synthesis of second-and third-generation TSPO-specific radiopharmaceuticals, linked to [ 11 C] or [ 18 F] and including (Luo et al, 2018;Singhal et al, 2018;Best et al, 2019). Similarly, different studies have reported selective microglial uptake of these tracers in multiple sclerosis animal models and patients (Hagens et al, 2018;Herranz et al, 2019;Nack et al, 2019), amyotrophic lateral sclerosis (Zürcher et al, 2015;Datta et al, 2017), Alzheimer's disease (Alam et al, 2017;Keller et al, 2018;Focke et al, 2019), and Lyme disease on humans (Coughlin et al, 2018), and stroke experimental models (Miyajima et al, 2018), with more discordant results for psychiatric patients, suffering from schizophrenia (Di Biase et al, 2017;Hafizi et al, 2017;Ottoy et al, 2018;Selvaraj et al, 2018) and major depression (Li et al, 2018), probably due to the different stage of disease. Interestingly, one study on fibromyalgia subjects attempts to demonstrate specificity of TSPO tracers for microglia, considering that an high expression of this molecule was also detected in activated astrocytes (Albrecht et al, 2019).…”

Section: Pet and Mr Imaging Of Microglial Activationmentioning

confidence: 99%

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

Cavaliere

Tramontano

Fiorenza

et al. 2020

Front. Cell. Neurosci.

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Glial activation characterizes most neurodegenerative and psychiatric diseases, often anticipating clinical manifestations and macroscopical brain alterations. Although imaging techniques have improved diagnostic accuracy in many neurological conditions, often supporting diagnosis, prognosis prediction and treatment outcome, very few molecular imaging probes, specifically focused on microglial and astrocytic activation, have been translated to a clinical setting. In this context, hybrid positron emission tomography (PET)/magnetic resonance (MR) scanners represent the most advanced tool for molecular imaging, combining the functional specificity of PET radiotracers (e.g., targeting metabolism, hypoxia, and inflammation) to both high-resolution and multiparametric information derived by MR in a single imaging acquisition session. This simultaneity of findings achievable by PET/MR, if useful for reciprocal technical adjustments regarding temporal and spatial cross-modal alignment/synchronization, opens still debated issues about its clinical value in neurological patients, possibly incompliant and highly variable from a clinical point of view. While several preclinical and clinical studies have investigated the sensitivity of PET tracers to track microglial (mainly TSPO ligands) and astrocytic (mainly MAOB ligands) activation, less studies have focused on MR specificity to this topic (e.g., through the assessment of diffusion properties and T2 relaxometry), and only few exploiting the integration of simultaneous hybrid acquisition. This review aims at summarizing and critically review the current state about PET and MR imaging for glial targets, as well as the potential added value of hybrid scanners for characterizing microglial and astrocytic activation.

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[18F]F-DPA for the detection of activated microglia in a mouse model of Alzheimer's disease

Cited by 33 publications

References 24 publications

Translocator protein in late stage Alzheimer’s disease and Dementia with Lewy bodies brains

Translocator protein in late stage Alzheimer’s disease and Dementia with Lewy bodies brains

Alcohol‐Enhanced Cu‐Mediated Radiofluorination

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

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