Exp Mol Med.
2005 Aug;37(4):269-275.
In vivo targeting of ERGpotassiumchannels inmice and dogs by a positron-emitting analogue of fluoroclofilium
- Affiliations
-
- 1Radiaton Application Research Division, Korea Atomic Energy Research Institute, 150, Dukjin-dong, Yuseong, Daejeon 305-353, Korea.
- 2Laboratory of Accelerator Development, Korea Institute of Radiological & Medical Sciences, 215-4 Gongleung-dong, Nowon-gu, Seoul 139-706, Korea.
- 3Department of Chemistry, Dongguk University, 3 Pil-dong, Chung-gu, Seoul 100-715, Korea. yukook@dongguk.edu
- 4Department of Nuclear Medicine, Seoul National University College of Medicine, 28 Yeongun-dong, Chongro-gu, Seoul 110-744, Korea.
- 5Research Unit Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747 Jena, Germany.
- 6Institut fur Anorganische und Angewandte Chemie, Universitat Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany.
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. Fluoroclofilium (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 Fclofilium is a potent hERG1 and hEAG1 channel blocker once it has reached the intracellularly accessible target site at the channel. Using the 18Flabeled 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.
Keyword
MeSH Terms
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Animals
Anti-Arrhythmia Agents/pharmacokinetics/*pharmacology
Cell Line
Dogs
Electrons
Ether-A-Go-Go Potassium Channels/*antagonists & inhibitors
Female
Inhibitory Concentration 50
Kidney/metabolism
Mice
Mice, Inbred BALB C
Myocardium/metabolism
*Positron-Emission Tomography
Potassium Channel Blockers/pharmacokinetics/*pharmacology
Quaternary Ammonium Compounds/pharmacokinetics/pharmacology
Research Support, Non-U.S. Gov't
Tissue Distribution
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