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

Abstract

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

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

“…radiochemical yield (decay corrected) 13 � 4.6,%, over two steps. [40] ChemMedChem penetrate into the cell and enter the ion channel from the inside of the channel pore. For this purpose, the dye should possess well-balanced lipophilic properties allowing it to penetrate the membrane but not to stick in the membrane.…”

“…N 3 CH 2 CH 2 OTs+[ 18 F]KF, K222, CH 3 CN, 110 °C, 3 min, distillation under helium flow; 2. prepared N 3 CH 2 CH 2 18 F+ 6 , CuSO 4 , sodium ascorbate, H 2 O, DMF 60 °C, 30 min. radiochemical yield (decay corrected) 13±4.6,%, over two steps [40] …”

“…The fluorinated PET tracer [ 18 F] 7 showed considerable tumor uptake, but moderate tumor‐to‐muscle ratios. The moderate tumor‐to‐muscle ratio may be due to the wide expression of the targeted K Ca 3.1 channel [40] …”

“…The moderate tumor-to-muscle ratio may be due to the wide expression of the targeted K Ca 3.1 channel. [40] Imaging of the K Ca 3.1 channel by small-molecule fluorescent probes A fluorescent probe, which is able to label selectively K Ca 3.1 channels, represents a valuable tool to detect cells with high density of the ion channel. Compared to labeling with antibodies, in vitro staining with fluorescent probes is cheap, simple, efficient and fast (ca.…”

“…The moderate tumor‐to‐muscle ratio may be due to the wide expression of the targeted K Ca 3.1 channel. [40] …”