In vivo targeting of ERG potassium channels in mice and dogs by a positron-emitting analogue of fluoroclofilium

Abstract

The antiarrhythmic clofilium is an efficient blocker of hERG1 potassium channels that are strongly expressed in the heart. Therefore, derivatives of clofilium that emit positrons might be useful tools for monitoring hERG1 channels in vivo. Fluoro- clofilium (F-clofilium) was synthesized and its channel-blocking properties were determined for hERG1 and hEAG1 channels expressed in HEK?293 cells and in Xenopus oocytes. When applied extracellularly in the whole-cell patch-clamp configuration, F-cloflium exhibited a slower onset of block when compared with clofilium, presumably owing to its lower membrane permeability. When applied in the inside-out configuration at the intracellular membrane side, it blocked hEAG1 channels almost as efficiently as clofilium (IC50 1.37 nM and 0.83 nM, respectively). Similar results were obtained for hERG1, showing F-clofilium is a potent hERG1 and hEAG1 channel blocker once it has reached the intracellularly accessible target site at the channel. Using the (18)F-labeled analog we studied the in vivo binding and distribution of F-clofilium in mice and a dog. Greatest activity was found in kidneys and bones. A small but significant enrichment of activity in the dog myocardium known for its expression of cERG1 channels allowed to depict the myocardium of a living dog by PET. Thus, F-clofilium is a useful tool for imaging hERG channels in living organisms.

Novel and Simple Carbon-11-Labeled Ammonium Salts as PET Agents for Myocardial Perfusion Imaging

“…Two fluorine-18-labeled myocardial ammonium salts were synthesized, but unfortunately, both gave unsatisfactory results. The first, based on the antiarrhythmic drug clofilium [31], had high levels of activity accumulation in the kidneys, intestines, and bones-indicating possible defluorination and poor signal/ noise ratios. The second, 4-[ 18 F]fluorophenyl-trimethylammonium iodide [32] ([ 18 F]FPTMA) had high accumulation in the liver and intestines and did not yield satisfactory accumulation in cardiac tissue.…”

PET and PET/CT in cardiovascular disease

“…The relative drawbacks of available perfusion tracers have fueled an intensive search for novel compounds with the ability to overcome the previously mentioned limitations. [ 62 Cu]Pyruvalaldehyde‐bis‐(N4‐methylthio‐semicarbazone) ([ 62 Cu]PTSM) 48 and 18 F‐labeled amines and quaternary ammonium salts 49,50 have been proposed as alternative perfusion tracers but have not found their way into clinical practice due to unfavorable radiokinetic or biodistribution properties. Others, such as the 18 F‐labeled p ‐fluorobenzyl triphenyl phosphonium cation ([ 18 F]FBnTP), 51 or [ 18 F]fluorodihydrorotenone, 52 are still in early preclinical stages of evaluation.…”