An update into the medicinal chemistry of translocator protein (TSPO) ligands

Barresi, Elisabetta; Robello, Marco; Costa, Barbara; Pozzo, Eleonora Da; Baglini, Emma; Salerno, Silvia; Settimo, Federico Da; Martini, Claudia; Taliani, Sabrina

doi:10.1016/j.ejmech.2020.112924

Cited by 41 publications

(30 citation statements)

References 128 publications

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“…Plus, in vivo preclinical studies are more feasible by using the fluorine-18 radioisotope, compared to carbon-11 (109 min compared to 20 min for carbon-11). Our study expands on work of Barresi et al [9] of TSPO ligands as potential therapeutic or diagnostic tools. In fact, in their work, benzodiazepines such as temazepam are not reported as ligands.…”

Section: Discussionsupporting

confidence: 69%

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Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam

et al. 2021

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Introduction: Benzodiazepines, including temazepam are described as TSPO antagonists. In fact, TSPO was initially described as a peripheral benzodiazepine receptor (PBR) with a secondary binding site for diazepam. TSPO is a potential imaging target of neuroinflammation because there is an amplification of the expression of this receptor. Objectives: Herein, we developed a novel fluorinated benzodiazepine ligand, [18F]Fluoroethyltemazepam ([18F]F-FETEM), for positron emission tomography (PET) imaging of translocator protein (18 kDa). Methods: [18F]F-FETEM was radiolabelled with an automated synthesizer via a one-pot procedure. We conducted a [18F]F-aliphatic nucleophilic substitution of a tosylated precursor followed by purification on C18 and Alumina N SPE cartridges. Quality control tests was also carried out. Results: We obtained 2.0–3.0% decay-uncorrected radiochemical activity yield (3.7% decay-corrected) within the whole synthesis time about 33 min. The radiochemical purity of [18F]F-FETEM was over 90% by TLC analysis. Conclusion: This automated procedure may be used as basis for future production of [18F]F-FETEM for preclinical PET imaging studies.

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Section: Discussionsupporting

confidence: 69%

“…Over the last few years, numerous ligands (and radioligands) for TSPO have been synthesized and reported in the literature [9]: i.…”

Section: Introductionmentioning

confidence: 99%

Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam

et al. 2021

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“…In addition, the administration of TSPO ligands recovered DW m and ATP production, disrupted by the treatment of Ab in vitro 19 , but also improved cognitive function of transgenic AD model mice 20 . Another recent study also suggest that TSPO ligands may inhibit ROS generation by blocking the interaction between TSPO and VDAC1 21 , supporting that TSPO is a viable target for the treatment AD 22,23 .…”

Section: Introductionmentioning

confidence: 83%

The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents

Kim

Morshed

Londhe

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-b (Ab) induced mitochondrial dysfunction and in acute and transgenic Alzheimer's disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Ab-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.

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“…19 Pharmacological studies also support a potential role for TSPO in regulating glucose and/or energy homeostasis, 24,37 although these studies have used PK11195 which, at high doses, reportedly has off target effects. 38 Further studies are needed with newer generation TSPO ligands with higher specificity and potency. 38 To conclude, the observations made in the present study indicate, contrary to our hypothesis, that global germline TSPO deletion in mice does not affect body weight or food intake, including in response to the alterations in energy availability examined.…”

Section: Discussionmentioning

confidence: 99%

“…38 Further studies are needed with newer generation TSPO ligands with higher specificity and potency. 38 To conclude, the observations made in the present study indicate, contrary to our hypothesis, that global germline TSPO deletion in mice does not affect body weight or food intake, including in response to the alterations in energy availability examined. One limitation of our study was the reliance on a germline deletion model, where developmental compensation/adaptations cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Absence of the mitochondrial translocator protein 18 kDa in mice does not affect body weight or food intake responses to altered energy availability

Morrissey

Beall

Ellacott

2021

J Neuroendocrinology

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An update into the medicinal chemistry of translocator protein (TSPO) ligands

Cited by 41 publications

References 128 publications

Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam

Fully Automated Synthesis of Novel TSPO PET Imaging Ligand [18F]Fluoroethyltemazepam

The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents

Absence of the mitochondrial translocator protein 18 kDa in mice does not affect body weight or food intake responses to altered energy availability

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