Molecular Imaging of &amp;#963;&lt;sub&gt;1&lt;/sub&gt; Receptors In Vivo: Current Status and Perspectives

Brust, Peter; Deuther‐Conrad, Winnie; Lehmkuhl, Kirstin; Jia, Hongmei; Wünsch, Bernhard

doi:10.2174/09298673113209990214

Cited by 37 publications

(42 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Proof Of Target-specifi C Binding In Animalsmentioning

confidence: 68%

“…These receptors have an unusual multi-drug binding spectrum and the respective ligands cover diverse structural classes [89] . Therefore, selectivity not only for the other subtype (σ 2 receptor) but also for a great variety of further potential binding sites needs to be considered.…”

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

confidence: 99%

“…The ratio between the region with lowest radiotracer accumulation (olfactory bulb) and that with highest accumulation (facial nucleus) was chosen for the estimation of specifi c receptor binding. Consistent with the highest brain-to-plasma ratio at 60 min post-injection and the highest target affi nity, this ratio was highest for the ethyl derivative [ 18 F]fl uspidine [89] .Besides the use of reference regions for the evaluation of specific receptor binding in brain, blocking studies are recommended. A high concentration of a drug that binds specifi cally to the receptor site is injected before or together with the radiotracer and thereby prevents its specifi c binding to the target [100] .…”

mentioning

confidence: 95%

“…2. Notably, many of them are identical though occurring in different contexts.Therefore, it is highly likely that radiotracers designed, for instance, for imaging a certain key protein in the etiology of Alzheimer´s disease (AD) may also be of major importance for other diseases, which further justifies the efforts expended on radiotracer development.For example, sigma 1 (σ 1 ) receptors are chaperones involved in the suppression of oxidative stress, a feature that links them to numerous brain diseases [89] . Postmortem studies have shown loss of σ 1 binding sites in the hippocampus of patients with AD [90] and in the cortex of patients with schizophrenia [91] .…”

mentioning

confidence: 99%

“…Overexpression of σ receptors has been found in many brain tumor cell lines and in human brain tumors [92] . The neuroprotective potential of σ 1 receptor agonists has been shown in different models of neurodegeneration [89,93] and is expected to be important for cancerous diseases as well [92,94] .As another example, impaired cholinergic neurotransmission is a key feature of AD and the related cognitive impairment is at least partially associated with loss of cortical nicotinic acetylcholine receptors (nAChRs) [6,95] .There is evidence that both subtypes with the highest expression in the brain are involved: α4β2 and α7 nAChRs.Accordingly, these subtypes have been chosen for radiotracer development [6,96,97] . However, these nAChRs are not only key proteins in neurodegenerative diseases ( Fig.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

2014

View full text Add to dashboard Cite

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 ...

show abstract

Section: Proof Of Target-specifi C Binding In Animalsmentioning

confidence: 68%

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

confidence: 99%

mentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

2014

View full text Add to dashboard Cite

show abstract

Comparison of in Silico, Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ₁ Receptor Ligands Designed for Positron Emission Tomography

et al. 2016

View full text Add to dashboard Cite

The imaging of σ receptors in the brain by fluorinated radiotracers will be used for the validation of σ receptors as drug targets as well as for differential diagnosis of diseases in the central nervous system. The biotransformation of four homologous fluorinated PET tracers 1'-benzyl-3-(ω-fluoromethyl to ω-fluorobutyl)-3H-spiro[2]benzofuran-1,4'-piperidine] ([ F]1-4) was investigated. In silico studies using fast metabolizer (FAME) software, electrochemical oxidations, in vitro studies with rat liver microsomes, and in vivo metabolism studies after application of the PET tracers [ F]1-4 to mice were performed. Combined liquid chromatography and mass spectrometry (HPLC-MS) analysis allowed structural identification of non-radioactive metabolites. Radio-HPLC and radio-TLC provided information about the presence of unchanged parent radiotracers and their radiometabolites. Radiometabolites were not found in the brain after application of [ F]2-4, but liver, plasma, and urine samples contained several radiometabolites. Less than 2 % of the injected dose of [ F]4 reached the brain, rendering [ F]4 less appropriate as a PET tracer than [ F]2 and [ F]3. Compounds [ F]2 and [ F]3 possess the most promising properties for imaging of σ receptors in the brain. High σ affinity (K =0.59 nm), low lipophilicity (logD =2.57), high brain penetration (4.6 % of injected dose after 30 min), and the absence of radiometabolites in the brain favor the fluoroethyl derivative [ F]2 slightly over the fluoropropyl derivative [ F]3 for human use.

show abstract

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

et al. 2017

View full text Add to dashboard Cite

Spirocyclic thiophene derivatives represent promising σ ligands with high σ affinity and selectivity over the σ subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9 a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ affinity, σ /σ selectivity, lipophilicity (logD ), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ affinity (K =1.3 and 1.9 nm), high σ /σ selectivity (>1500-fold), low lipophilicity (logD =1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy.

show abstract

Molecular Imaging of σ<sub>1</sub> Receptors In Vivo: Current Status and Perspectives

Cited by 37 publications

References 0 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

Comparison of in Silico, Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ₁ Receptor Ligands Designed for Positron Emission Tomography

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

Contact Info

Product

Resources

About

Molecular Imaging of &#963;<sub>1</sub> Receptors In Vivo: Current Status and Perspectives

Cited by 37 publications

References 0 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

Comparison of in Silico, Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ1 Receptor Ligands Designed for Positron Emission Tomography

Thiazole‐Based σ1 Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions

Contact Info

Product

Resources

About

Molecular Imaging of σ<sub>1</sub> Receptors In Vivo: Current Status and Perspectives

Comparison of in Silico, Electrochemical, in Vitro and in Vivo Metabolism of a Homologous Series of (Radio)fluorinated σ₁ Receptor Ligands Designed for Positron Emission Tomography

Thiazole‐Based σ₁ Receptor Ligands: Diversity by Late‐Stage C−H Arylation of Thiazoles, Structure–Affinity and Selectivity Relationships, and Molecular Interactions