18 F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain

Wang, Liang; Ye, Jiajun; He, Yong; Deuther‐Conrad, Winnie; Zhang, Jinming; Zhang, Xiaojun; Steinbach, Jörg; Huang, Yiyun; Brust, Peter; Jia, Hongmei

doi:10.1016/j.bmc.2017.05.019

Cited by 19 publications

(24 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synthesis of the newly developed fluorinated derivatives was performed as described previously for similar compounds with minor modifications [ 27 ]. First, the commercially available fluorinated indoles and azaindoles were deprotonated with sodium hydride and then treated with 1,4-dibromobutane to give intermediates 25 – 33 , which were further coupled with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline ( 43 ) under basic reaction conditions to give final compounds 34 – 42 ( Scheme 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…For this purpose, the boronic acid pinacol ester precursor 45 was synthesized in one step from the corresponding bromoderivative 44 via the Miyaura borylation reaction in high yield (>85%) as shown in Scheme 2 [40]. [27].…”

Section: Automated Radiosynthesis Of [ 18 F]rm273mentioning

confidence: 99%

“…Thus, we intended to develop a brain-penetrant radiotracer based on the well described 18 F-fluoroethoxy-substituted 2-(4-(1 H -indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds (e.g., compounds [ 18 F] 14 and [ 18 F] 15 , Figure 1 ) recently shown to have a significantly higher brain uptake in comparison to [ 18 F]ISO-I (3–4% ID/g at 2 min p.i. [ 27 ] vs. 0.76% ID/g at 5 min p.i. ; [ 25 ]).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

Moldovan

Gündel

Teodoro

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Automated Radiosynthesis Of [ 18 F]rm273mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

Moldovan

Gündel

Teodoro

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Despite good in vitro properties, some of the radiolabeled probes that were developed for in vivo σ2 receptor imaging have not reached the final objective ( Abate et al, 2013 ; Selivanova et al, 2015 ). In contrast, recently reported 18 F-labeled PET probes, with enhanced brain uptake and σ 2 R selectivity (in mice), show promise for in vivo imaging of the receptor in the human brain ( Wang et al, 2017 ). Surely these novel tools will be instrumental to achieve a more detailed mapping of the receptor in the CNS, specially in those areas in which dopamine receptors are expressed.…”

Section: Discussionmentioning

confidence: 99%

Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression

Aguinaga

Medrano

Vega-Quiroga

et al. 2018

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Sigma σ1 and σ2 receptors are targets of cocaine. Despite sharing a similar name, the two receptors are structurally unrelated and their physiological role is unknown. Cocaine increases the level of dopamine, a key neurotransmitter in CNS motor control and reward areas. While the drug also affects dopaminergic signaling by allosteric modulations exerted by σ1R interacting with dopamine D1 and D2 receptors, the potential regulation of dopaminergic transmission by σ2R is also unknown. We here demonstrate that σ2R may form heteroreceptor complexes with D1 but not with D2 receptors. Remarkably σ1, σ2, and D1 receptors may form heterotrimers with particular signaling properties. Determination of cAMP levels, MAP kinase activation and label-free assays demonstrate allosteric interactions within the trimer. Importantly, the presence of σ2R induces bias in signal transduction as σ2R ligands increase cAMP signaling whereas reduce MAP kinase activation. These effects, which are opposite to those exerted via σ1R, suggest that the D1 receptor-mediated signaling depends on the degree of trimer formation and the differential balance of sigma receptor and heteroreceptor expression in acute versus chronic cocaine consumption. Although the physiological role is unknown, the heteroreceptor complex formed by σ1, σ2, and D1 receptors arise as relevant to convey the cocaine actions on motor control and reward circuits and as a key factor in acquisition of the addictive habit.

show abstract

“…The 2-methoxy group of the previous derivatives facilitates the preparation of 11 C-labeladed derivatives due to alkylation of the corresponding 2-hydroxy precursors. In the next generation of radiotracers, the 2-methoxy group was replaced by the 2-fluoroethoxy moiety, because the 18 F-labeled tracers allow imaging studies to be conducted in due course after the radiotracer injection [ 117 ]. MicroPET imaging studies use [ 18 F]ISO-1 in a rodent model of breast cancer and [ 18 F]RHM-4 in a rat model of brain cancer [ 118 ].…”

Section: σ-Receptor (σR) Ligands In Cancer Researchmentioning

confidence: 99%

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

et al. 2017

View full text Add to dashboard Cite

Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy.

show abstract

18 F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain

Cited by 19 publications

References 25 publications

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

Cocaine Effects on Dopaminergic Transmission Depend on a Balance between Sigma-1 and Sigma-2 Receptor Expression

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

Contact Info

Product

Resources

About