In vivo targeting of ERG potassium channels in mice and dogs by a positron-emitting analogue of fluoroclofilium.
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.
Kim
Sang Wook
SW
Radiaton Application Research Division, Korea Atomic Energy Research Institute, 150, Dukjin-dong, Yuseong, Daejeon 305-353, Korea.
Yang
Seung Dae
SD
Ahn
Byung Jae
BJ
Park
Jeong Hoon
JH
Lee
Dong Soo
DS
Gessner
Guido
G
Heinemann
Stefan H
SH
Herdering
Wilhelm
W
Yu
Kook Hyun
KH
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004583:Electrons; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000378:metabolism; D049268:Positron-Emission Tomography; D026902:Potassium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution; D014981:Xenopus
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606915:Kcnh2 protein, mouse; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; C022799:clofilium