New systematically modified vesamicol analogs and their affinity and selectivity for the vesicular acetylcholine transporter – A critical examination of the lead structure

Barthel, Claudia R.; Sorger, Dietlind; Deuther‐Conrad, Winnie; Scheunemann, Matthias; Schweiger, Stephanie; Jäckel, Petra; Roghani, Ali; Steinbach, Jörg; Schüürmann, Gerrit; Sabri, Osama; Brust, Peter; Wenzel, Barbara

doi:10.1016/j.ejmech.2015.05.033

Cited by 14 publications

(10 citation statements)

References 55 publications

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“…33,34 The binding affinity of (−)-FEOBV has been determined in vitro as 19.6 ± 1.1 and 209 ± 94 nM to rat VAChT and σ 1 receptors, respectively. 33,35 A study by Mulholland et al investigated the effect of different σ ligands on brain uptake and blood activity of [ 18 F]-FEOBV in mice at three different time points after injection using ex-vivo biodistribution. 19 Donepezil and (+)-3-PPP did not influence [ 18 F]-FEOBV uptake in different brain regions or radioactivity levels in blood.…”

Section: ■ Discussionmentioning

confidence: 99%

“…The binding affinity of vesamicol derivatives like [ 18 F]-FEOBV to σ receptors has been a topic of dispute. Some argued that most vesamicol-based radioligands, including [ 18 F]-FEOBV, should not be considered for VAChT imaging because of their binding affinity for σ receptors. , The binding affinity of (−)-FEOBV has been determined in vitro as 19.6 ± 1.1 and 209 ± 94 nM to rat VAChT and σ 1 receptors, respectively. , A study by Mulholland et al investigated the effect of different σ ligands on brain uptake and blood activity of [ 18 F]-FEOBV in mice at three different time points after injection using ex-vivo biodistribution . Donepezil and (+)-3-PPP did not influence [ 18 F]-FEOBV uptake in different brain regions or radioactivity levels in blood.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

et al. 2020

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The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson’s disease has been well established. Here, D2 receptor antagonists were used to assess changes in [18F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate (K i) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [18F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen’s d 0.28–1.89) while the area-under-the-curve (AUC) of the parent fraction of [18F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen’s d = 2.51) than in controls. Compared to controls, the AUC of [18F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen’s d = 1.77) and raclopride (adjusted p = 0.052, Cohen’s d = 1.49) treatment, respectively. No changes in the AUC of [18F]-FEOBV were found in the cerebellum (Cohen’s d 0.63–0.74). Raclopride treatment nonsignificantly increased K i in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen’s d = 1.1) while it reduced K i in the cerebellum by 28% (adjusted p = 0.0004, Cohen’s d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in K i in the striatum (10%, adjusted p = 1, Cohen’s d = 0.44) and a 40–50% lower K i than controls in all other brain regions (adjusted p < 0.0005, Cohen’s d = 3.3–4.7). The changes in K i induced by the selective D2 receptor antagonist raclopride can in part be quantified using [18F]-FEOBV PET imaging. Haloperidol, a nonselective D2/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [18F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [18F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

et al. 2020

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“…Although benzovesamicol (BV) has higher affinity and selectivity for VAChT than vesamicol, several benzovesamicol (BV) analogs were synthesized to improve VAChT affinity and to decrease the affinity for sigma receptors ( σ 1 and σ 2 ). A BV analog with phenylpiperazine instead of phenylpiperidine in BV ( 5 ) [ 51 , 52 ], a BV analog with benzylpiperidine instead of phenylpyridine ( 6 ), and a BV analog with pyridinyl piperidine instead of phenyl piperidine ( 7 ) showed a lower VAChT affinity than BV [ 53 ]. The affinity of 7 to the σ 1 receptor increased.…”

Section: Vacht Imaging Agent Based On Vesamicol Analogsmentioning

confidence: 99%

In Vivo and In Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

Ogawa

Shiba

2018

Contrast Media & Molecular Imaging

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The vesicular acetylcholine transporter (VAChT), a presynaptic cholinergic neuron marker, is a potential internal molecular target for the development of an imaging agent for early diagnosis of neurodegenerative disorders with cognitive decline such as Alzheimer's disease (AD). Since vesamicol has been reported to bind to VAChT with high affinity, many vesamicol analogs have been studied as VAChT imaging agents for the diagnosis of cholinergic neurodeficit disorder. However, because many vesamicol analogs, as well as vesamicol, bound to sigma receptors (σ1 and σ2) besides VAChT, almost all the vesamicol analogs have been shown to be unsuitable for clinical trials. In this report, the relationships between the chemical structure and the biological characteristics of these developed vesamicol analogs were investigated, especially the in vitro binding profile and the in vivo regional brain accumulation.

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“…imaging probe, PET, VAChT, vesamicol analog (Bar & Parsons 1986;Marshall & Parsons 1987), many vesamicol analogs have been developed as potential VAChT imaging agents for PET or SPECT (Azim et al, 2014;Bando et al, 2001;Barthel et al, 2015;Custers, Leysen, Stoof, & Herscheid, 1997;Efange, Michelson, Khare, & Thomas, 1993;Efange et al, 1994, Efange et al, 2000Kitamura et al, 2016;Kozaka et al, 2014;Mulholland et al, 1998;Shiba, Mori, & Tonami, 2003;Sorger et al, 2000Sorger et al, , 2008Sorger et al, , 2009. Furthermore, several reported vesamicol analogs were separated into optical isomers to improve in vitro and in vivo characteristics as VAChT imaging agents (Efange et al, 1994;Jung, Van Dort, Gildersleeve, & Wieland, 1990;Kovac et al, 2010;Li et al, 2013;Mulholland et al, 1998;Shiba et al, 2003Shiba et al, , 2009Tu et al, 2009Tu et al, , 2015Uno et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

(−)‐o‐[¹¹C]methyl‐trans‐decalinvesamicol ((−)‐[¹¹C]OMDV) as a PET ligand for the vesicular acetylcholine transporter

Miwa

Kitamura

Kozaka

et al. 2020

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To develop a PET imaging agent to visualize brain cholinergic neurons and synaptic changes caused by Alzheimer's disease, (−)‐ and (+)‐o‐[11C]methyl‐trans‐decalinvesamicol ([11C]OMDV) were isolated and investigated for differences in not only their binding affinity and selectivity to vesicular acetylcholine transporter (VAChT), but also their in vivo activities. [11C]OMDV has a high binding affinity for VAChT both in vitro and in vivo. Racemic OMDV and o‐trimethylstannyl‐trans‐decalinvesamicol (OTDV), which are precursors for synthesis of [11C]OMDV, were separated into (−)‐optical isomers ((−)‐OMDV and (−)‐OTDV) and (+)‐optical isomers ((+)‐OMDV and (+)‐OTDV) by HPLC. In the in vitro binding assay, (−)‐OMDV(7.2 nM) showed eight times higher binding affinity (Ki) to VAChT than that of (+)‐OMDV(57.5 nM). In the biodistribution study, the blood–brain barrier permeability of both enantiomers ((−)‐[11C]OMDV and (+)‐[11C]OMDV) was similarly high (about 1.0%ID/g) at 2 min post‐injection. However, (+)‐[11C]OMDV clearance from the brain was faster than (−)‐[11C]OMDV. In the in vivo blocking study, accumulation of (−)‐[11C]OMDV in the cortex was markedly decreased (approximately 30% of control) by coadministration of vesamicol, and brain uptake of (−)‐[11C]OMDV was not significantly altered by coadministration of (+)‐pentazocine or (+)‐3‐(3‐hydroxyphenyl)‐N‐propylpiperidine ((+)‐3‐PPP). PET‐CT imaging revealed inhibition of the rat brain uptake of (−)‐[11C]OMDV by coadministration of vesamicol. In conclusion, (−)‐[11C]OMDV, which is an enantiomer of OMDV, selectively binds to VAChT with high affinity in the rat brain in vivo. (−)‐[11C]OMDV may be utilized as a potential PET ligand for studying presynaptic cholinergic neurons in the brain.

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New systematically modified vesamicol analogs and their affinity and selectivity for the vesicular acetylcholine transporter – A critical examination of the lead structure

Cited by 14 publications

References 55 publications

Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

In Vivo and In Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

(−)‐o‐[¹¹C]methyl‐trans‐decalinvesamicol ((−)‐[¹¹C]OMDV) as a PET ligand for the vesicular acetylcholine transporter

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New systematically modified vesamicol analogs and their affinity and selectivity for the vesicular acetylcholine transporter – A critical examination of the lead structure

Cited by 14 publications

References 55 publications

Effect of Dopamine D2 Receptor Antagonists on [18F]-FEOBV Binding

Effect of Dopamine D2 Receptor Antagonists on [18F]-FEOBV Binding

In Vivo and In Vitro Characteristics of Radiolabeled Vesamicol Analogs as the Vesicular Acetylcholine Transporter Imaging Agents

(−)‐o‐[11C]methyl‐trans‐decalinvesamicol ((−)‐[11C]OMDV) as a PET ligand for the vesicular acetylcholine transporter

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Product

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Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

Effect of Dopamine D₂ Receptor Antagonists on [¹⁸F]-FEOBV Binding

(−)‐o‐[¹¹C]methyl‐trans‐decalinvesamicol ((−)‐[¹¹C]OMDV) as a PET ligand for the vesicular acetylcholine transporter