3D QSAR study, synthesis, and in vitro evaluation of (+)-5-FBVM as potential PET radioligand for the vesicular acetylcholine transporter (VAChT)

Kovač, Maja; Mavel, Sylvie; Deuther‐Conrad, Winnie; Méheux, Nathalie; Glöckner, Jana; Wenzel, Barbara; Anderluh, Marko; Brust, Peter; Guilloteau, Denis; Emond, Patrick

doi:10.1016/j.bmc.2010.08.028

Cited by 24 publications

(17 citation statements)

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“…Similar affinity and selectivity have been found for (-)-FEOBV [125] , a radioligand first described in 1993 [126] and recently chosen for human VAChT studies [127] . Autoradiographic investigations of the human brain have revealed that region of patients with AD [128] .…”

Section: New Compoundssupporting

confidence: 66%

“…Although this was interpreted as cholinergic depletion, reduced σ 1 receptor binding cannot be excluded, because a 26% loss of this receptor has also been described in the CA1 region of patients with AD [90] . So far, no ideal PET radiotracer for the VAChT has been developed [106] and optimization of the binding affi nity Therefore, molecular modeling approaches have been used to predict the binding affinity of vesamicol-type/like ligands for VAChT from their molecular structures [125,129] .…”

Section: Fig 2 Key Molecules For Development Of New Pet Radiotracermentioning

confidence: 99%

“…Therefore, molecular modeling approaches have been used to predict the binding affinity of vesamicol-type/like ligands for VAChT from their molecular structures [125,129] .…”

Section: New Compoundsmentioning

confidence: 99%

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Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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Section: New Compoundssupporting

confidence: 66%

Section: Fig 2 Key Molecules For Development Of New Pet Radiotracermentioning

confidence: 99%

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Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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“…Binding affinities of sulfur-containing compounds for VAChT. [a] Compound [b] R K i [nm] [c] (À)-vesamicol 15.2 AE 1.1 (À)-FEOBV [14] 19.6 AE 1.1 (AE)-7 SO 2 CH 3 5.4 AE 0.6 (AE)-8 SCH 3 2.4 AE 0.3 (AE)-9 SOCH 3 6.5 AE 0.9 (AE)-11 a SO 2 NHCH 3 6.…”

Section: In Vitro Binding Affinity Studiesmentioning

confidence: 99%

“…[ c] Expressed human VAChT was used for the VAChT bindinga ssays. [14] 19.6 AE 1.1 209 AE 94 -10.7 -YUN-122 [15] -3.6 AE 1. [e] Homogenate of rat liver was used for s 2 bindinga ssays.…”

Section: In Vitro Binding Affinity Studiesmentioning

confidence: 99%

Exploration of Sulfur‐Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain

et al. 2018

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Sixteen new sulfur-containing compounds targeting the vesicular acetylcholine transporter (VAChT) were synthesized and assessed for in vitro binding affinities. Enantiomers (-)-(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-(methylthio)phenyl)methanone [(-)-8] and (-)-(4-((2-fluoroethyl)thio)phenyl)(1-(3-hydroxy-1,2,3,4-tetrahydronaph-thalen-2-yl)piperidin-4-yl)methanone [(-)-14 a] displayed high binding affinities, with respective K values of 1.4 and 2.2 nm for human VAChT, moderate and high selectivity for human VAChT over σ (≈13-fold) and σ receptors (>420-fold). Radiosyntheses of (-)-[ C]8 and (-)-[ F]14 a were achieved using conventional methods. Ex vivo autoradiography and biodistribution studies in Sprague-Dawley rats indicated that both radiotracers have the capacity to penetrate the blood-brain barrier, with high initial brain uptake at 5 min and rapid washout. The striatal region had the highest accumulation for both radiotracers. Pretreating the rats with the VAChT ligand (-)-vesamicol decreased brain uptake for both radiotracers. Pretreating the rats with the σ ligand YUN-122 (N-(4-benzylcyclohexyl)-2-(2-fluorophenyl)acetamide) also decreased brain uptake, suggesting these two radiotracers also bind to the σ receptor in vivo. The microPET study of (-)-[ C]8 in the brain of a non-human primate showed high striatal accumulation that peaked quickly and washed out rapidly. Although preliminary results indicated these two sulfur-containing radiotracers have high binding affinities for VAChT with rapid washout kinetics from the striatum, their σ receptor binding properties limit their potential as radiotracers for quantifying VAChT in vivo.

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PET Imaging of Autonomic Innervation and Receptors

Thackeray

Bengel

2019

Cardiac CT, PET &Amp; MR

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3D QSAR study, synthesis, and in vitro evaluation of (+)-5-FBVM as potential PET radioligand for the vesicular acetylcholine transporter (VAChT)

Cited by 24 publications

References 51 publications

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

Exploration of Sulfur‐Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain

PET Imaging of Autonomic Innervation and Receptors

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