In Vivo Responses of Human A375M Melanoma to a σ Ligand: <sup>18</sup>F-FDG PET Imaging

Rybczynska, Anna A.; Bruyn, Marco de; Ramakrishnan, Nisha Kuzhuppilly; Jong, Johan R. de; Elsinga, Philip H.; Helfrich, Wijnand; Dierckx, Rudi; Waarde, Aren van

doi:10.2967/jnumed.113.122655

Cited by 6 publications

(3 citation statements)

References 31 publications

(57 reference statements)

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“…A375 (human malignant melanoma line, ATCC CRL-1619), PC3 (androgen-independent human malignant prostate adenocarcinoma line, ATCC CRL-1435), DU145 (androgen-independent human metastatic prostate adenocarcinoma line, ATCC HTB-81), and MCF7 (human metastatic mammary adenocarcinoma line, ATCC HTB-22) cells were used in this experiment. Substantial expression of σ-receptor subtypes σ 1 and σ 2 as well as binding of specific σ-receptor ligands has been demonstrated in the literature for all selected cell lines. ,, …”

Section: Methodsmentioning

confidence: 96%

“…Substantial expression of σ-receptor subtypes σ 1 and σ 2 as well as binding of specific σ-receptor ligands has been demonstrated in the literature for all selected cell lines. 19,56,57 Cells were routinely cultivated as the reported method. 55 Cells were seeded in 24-well plates at a density of 1.3 × 10 5 cells/mL (A375, PC3, MCF7) and 1.5 × 10 5 cells/mL (DU145) and grown to confluence.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

et al. 2015

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We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ1 receptor ligands. 8-(4-(2-Fluoroethoxy)benzyl)-1,4-dioxa-8-azaspiro[4.5]decane (5a) possessed high affinity (K(i) = 5.4 ± 0.4 nM) for σ1 receptors and selectivity for σ2 receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [(18)F]5a was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25-45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [(18)F]5a to σ1 receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ1 receptors could be used for tumor imaging.

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Section: Methodsmentioning

confidence: 96%

Section: ■ Experimental Sectionmentioning

confidence: 99%

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

et al. 2015

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“…In this publication, we investigated the suitability of both enantiomers of [ 18 F]fluspidine to image Sig1R in different mouse tumor models. Current investigations [ 30 ] show strong expression of Sig1R and correlation with pathologic tumor tissue in human esophageal squamous cell carcinoma [ 36 ], prostate cancer [ 37 , 38 ], myeloma [ 39 ], melanoma [ 20 , 40 ], and glioma [ 41 ]. To assess the expression of the Sig1R protein in different human tumors, cell lines from epidermoid carcinoma, melanoma, and glioblastoma were investigated with Western blot in the current study.…”

Section: Discussionmentioning

confidence: 99%

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

et al. 2018

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Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(−)- and (R)-(+)-[18F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [18F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB).

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Sigma1 Pharmacology in the Context of Cancer

Kim

Maher

2017

Handbook of Experimental Pharmacology

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Sigma1 (also known as sigma-1 receptor, Sig1R, σ1 receptor) is a unique pharmacologically regulated integral membrane chaperone or scaffolding protein. The majority of publications on the subject have focused on the neuropharmacology of Sigma1. However, a number of publications have also suggested a role for Sigma1 in cancer. Although there is currently no clinically used anti-cancer drug that targets Sigma1, a growing body of evidence supports the potential of Sigma1 ligands as therapeutic agents to treat cancer. In preclinical models, compounds with affinity for Sigma1 have been reported to inhibit cancer cell proliferation and survival, cell adhesion and migration, tumor growth, to alleviate cancer-associated pain, and to have immunomodulatory properties. This review will highlight that although the literature supports a role for Sigma1 in cancer, several fundamental questions regarding drug mechanism of action and the physiological relevance of aberrant SIGMAR1 transcript and Sigma1 protein expression in certain cancers remain unanswered or only partially answered. However, emerging lines of evidence suggest that Sigma1 is a component of the cancer cell support machinery, that it facilitates protein interaction networks, that it allosterically modulates the activity of its associated proteins, and that Sigma1 is a selectively multifunctional drug target.

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In Vivo Responses of Human A375M Melanoma to a σ Ligand: ¹⁸F-FDG PET Imaging

Cited by 6 publications

References 31 publications

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

Sigma1 Pharmacology in the Context of Cancer

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In Vivo Responses of Human A375M Melanoma to a σ Ligand: 18F-FDG PET Imaging

Cited by 6 publications

References 31 publications

18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

Sigma1 Pharmacology in the Context of Cancer

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In Vivo Responses of Human A375M Melanoma to a σ Ligand: ¹⁸F-FDG PET Imaging

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

¹⁸F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ₁ Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent