Imaging of the calcium activated potassium channel 3.1 (KCa 3.1) 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 half-life of [¹⁸ F]fluorine. Biodistribution experiments in wild-type mice were promising, showing rapid and predominantly renal excretion. An in vivo study using A549-based 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 triarylacetamide-based fluorinated PET tracers for imaging of the K_Ca 3.1 channel in vivo.

Keywords: KCa3.1 channel; click chemistry; in vivo tumor imaging; radiosynthesis; senicapoc-derived PET tracer.