Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (K<sub>Ca</sub>3.1) channels <i>in vivo</i>

Brömmel, Kathrin; Konken, Christian Paul; Börgel, Frederik; Obeng-Darko, Henry; Schelhaas, Sonja; Bulk, Etmar; Budde, Thomas; Schwab, Albrecht; Schäfers, Michael; Wünsch, Bernhard

doi:10.1039/d1ra03850h

Cited by 3 publications

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“…Recently, we presented the design and radiosynthesis of potential PET tracers for imaging of the K Ca 3.1 channel in vivo. [ 28 ] The K Ca 3.1 channel inhibitor senicapoc ( 1 ) shows a high affinity toward the K Ca 3.1 channel with an IC 50 value of 11 ± 2 nM (measured on human erythrocytes) and excellent selectivity over related ion channels (Figure 1). [ 29 ] This compound served as a promising starting point for the development of selective imaging probes targeting the K Ca 3.1 channel in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Senicapoc ( 1 ) [ 29 ] as well as positron emission tomography tracers [ 18 F] 2 [ 28 ] and [ 18 F] 3 (this study).…”

Section: Introductionmentioning

confidence: 99%

“…Radiosynthesis of [ 18 F] 2 via aliphatic nucleophilic substitution of a tosylated precursor with [ 18 F]fluoride under mild conditions was performed successfully, but the in vivo application of [ 18 F] 2 resulted in high activity uptake of the bones, likely due to release of [ 18 F]fluoride. [ 28 ]…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the introduction of [ 18 F]fluoride. [28] Herein, we present the development of another alternative triarylacetamide-based PET tracer targeting the K Ca 3.1 channel. It was envisaged to synthesize the 2-[ 18 F]fluoroethyl-triazole derivative [29] as well as positron emission tomography tracers [ 18 F]2 [28] and [ 18 F]3 (this study).…”

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confidence: 99%

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Imaging of the calcium activated potassium channel 3.1 (K_Ca3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Konken

Heßling

Thale

et al. 2022

Archiv der Pharmazie

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The calcium-activated potassium channel 3.1 (K Ca 3.1) is overexpressed in many tumor entities and has predictive power concerning disease progression and outcome. Imaging of the K Ca 3.1 channel in vivo using a radiotracer for positron emission tomography (PET) could therefore establish a potentially powerful diagnostic tool. Senicapoc shows high affinity and excellent selectivity toward the K Ca 3.1 channel. We have successfully pursued the synthesis of the 18 F-labeled derivative [ 18 F]3 of senicapoc using the prosthetic group approach with 1-azido-2-[ 18 F]fluoroethane ([ 18 F]6) in a "click" reaction. The biological activity of the new PET tracer was evaluated in vitro and in vivo. Inhibition of the K Ca 3.1 channel by 3 was demonstrated by patch clamp experiments and the binding pose was analyzed by docking studies. In mouse and human serum, [ 18 F]3 was stable for at least one halflife of [ 18 F]fluorine. Biodistribution experiments in wild-type mice were promising,showing rapid and predominantly renal excretion. An in vivo study using A549based tumor-bearing mice was performed. The tumor signal could be delineated and image analysis showed a tumor-to-muscle ratio of 1.47 ± 0.24. The approach using 1-azido-2-[ 18 F]fluoroethane seems to be a good general strategy to achieve

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Section: Introductionmentioning

confidence: 99%

“…Senicapoc ( 1 ) [ 29 ] as well as positron emission tomography tracers [ 18 F] 2 [ 28 ] and [ 18 F] 3 (this study).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Imaging of the calcium activated potassium channel 3.1 (K_Ca3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Konken

Heßling

Thale

et al. 2022

Archiv der Pharmazie

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“…After optimization of the radiosynthesis, biodistribution studies were performed with [ 18 F] 5 . Unfortunately, high activity uptake by the bones was observed, which indicated the release of [ 18 F]fluoride from the PET tracer [39] …”

Section: Introductionmentioning

confidence: 99%

Imaging of K_Ca3.1 Channels in Tumor Cells with PET and Small‐Molecule Fluorescent Probes

et al. 2022

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The Ca 2 + activated K + channel K Ca 3.1 is overexpressed in several human tumor cell lines, e. g. clear cell renal carcinoma, prostate cancer, non-small cell lung cancer. Highly aggressive cancer cells use this ion channel for key processes of the metastatic cascade such as migration, extravasation and invasion. Therefore, small molecules, which are able to image this K Ca 3.1 channel in vitro and in vivo represent valuable diagnostic and prognostic tool compounds. The [ 18 F]fluoroethyltriazolyl substituted senicapoc was used as positron emission tomography (PET) tracer and showed promising properties for imaging of K Ca 3.1 channels in lung adenocarcinoma cells in mice. The novel senicapoc BODIPY conjugates with two F-atoms (9 a) and with a F-atom and a methoxy moiety (9 b) at the B-atom led to the characteristic punctate staining pattern resulting from labeling of single K Ca 3.1 channels in A549-3R cells. This punctate pattern was completely removed by preincubation with an excess of senicapoc confirming the high specificity of K Ca 3.1 labeling. Due to the methoxy moiety at the B-atom and the additional oxyethylene unit in the spacer, 9 b exhibits higher polarity, which improves solubility and handling without reduction of fluorescence quantum yield. Docking studies using a cryoelectron microscopy (EM) structure of the K Ca 3.1 channel confirmed the interaction of 9 a and 9 b with a binding pocket in the channel pore.

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Positron emission tomography (PET) tracer enables imaging of high CD73 expression in cancer

Dobelmann,

Schmies,

Rolshoven

et al. 2024

Preprint

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Ecto-5-nucleotidase (CD73) is a potential new drug target for cancer immunotherapy. Its overexpression is associated with various aggressive cancers, including triple-negative breast cancer (TNBC) and pancreatic cancer, making it a promising target for diagnostic imaging. Besides antibodies, small molecule CD73 inhibitors have been developed and are currently in clinical trials. This study aimed to develop and evaluate fluorine-18 labeled high-affinity CD73 inhibitors as tracers for the non-invasive positron emission tomography (PET) imaging of CD73 expression in cancer. Two CD73 inhibitors were selected for radiolabeling based on their high potency (Ki values of ca. 1 nM), and favorable pharmacokinetic properties providing [18F]PSB-19427 ([18F]1) and [18F]MRS-4648 ([18F]2). Ex vivo imaging studies on human breast cancer tissues indicated specific binding of both radiotracers. Subsequent in vivo studies proved [18F]1 to be superior due to its long elimination half-life and its accumulation in TNBC and pancreatic cancer tissues, suggesting its potential as a versatile PET tracer for imaging various solid tumors. [18F]1 significantly outperformed [18F]FDG in visualizing triple-negative breast cancer, offering potential advantages over [18F]FDG in terms of specificity and diagnostic accuracy. Thus, [18F]1 is a PET tracer with outstanding properties suitable for broad application in cancer diagnosis and potentially in therapy control. Based on these results, further clinical development of PET tracers targeting CD73 is warranted.

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Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (K_Ca3.1) channels in vivo

Abstract: Expression of the Ca2+ activated potassium channel 3.1 (KCa3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival.

Cited by 3 publications

References 47 publications

Imaging of the calcium activated potassium channel 3.1 (K_Ca3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Imaging of the calcium activated potassium channel 3.1 (K_Ca3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Imaging of K_Ca3.1 Channels in Tumor Cells with PET and Small‐Molecule Fluorescent Probes

Positron emission tomography (PET) tracer enables imaging of high CD73 expression in cancer

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Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (KCa3.1) channels in vivo

Abstract: Expression of the Ca2+ activated potassium channel 3.1 (KCa3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival.

Cited by 3 publications

References 47 publications

Imaging of the calcium activated potassium channel 3.1 (KCa3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Imaging of the calcium activated potassium channel 3.1 (KCa3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Imaging of KCa3.1 Channels in Tumor Cells with PET and Small‐Molecule Fluorescent Probes

Positron emission tomography (PET) tracer enables imaging of high CD73 expression in cancer

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Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (K_Ca3.1) channels in vivo

Imaging of the calcium activated potassium channel 3.1 (K_Ca3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Imaging of the calcium activated potassium channel 3.1 (K_Ca3.1) in vivo using a senicapoc‐derived positron emission tomography tracer

Imaging of K_Ca3.1 Channels in Tumor Cells with PET and Small‐Molecule Fluorescent Probes