Synthesis and biological evaluation of PET tracers designed for imaging of calcium activated potassium channel 3.1 (K3.1) channels .

Expression of the Ca activated potassium channel 3.1 (K3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival. Therefore, a positron emission tomography (PET) tracer targeting this ion channel could serve as a potential diagnostic tool by imaging the K3.1 channel . It was envisaged to synthesize [F]senicapoc ([F]1) since senicapoc (1) shows high affinity and excellent selectivity towards the K3.1 channels. Because problems occurred during F-fluorination, the [F]fluoroethoxy senicapoc derivative [F]28 was synthesized to generate an alternative PET tracer targeting the K3.1 channel. Inhibition of the K3.1 channel by 28 was confirmed by patch clamp experiments. stability in mouse and human serum was shown for 28. Furthermore, biodistribution experiments in wild type mice were performed. Since [F]fluoride was detected after application of [F]28, an metabolism study was conducted. A potential degradation route of fluoroethoxy derivatives was found which in general should be taken into account when designing new PET tracers for different targets with a [F]fluoroethoxy moiety as well as when using the popular prosthetic group [F]fluoroethyl tosylate for the alkylation of phenols.