Radiochemical synthesis and biodistribution of a novel maxi-K potassium channel opener.
The racemate 1, ((+/-)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)- 2H-indol-2-one), is a potent, specific and novel opener of cloned large-conductance, calcium-activated (maxi-K) potassium channels. One of its enantiomers, BMS-204352 (MaxiPost), is undergoing clinical evaluation for efficacy in patients with suspected acute stroke. In the current study, we have prepared [(18)F]-labeled 1 using a silver assisted nucleophilic substitution to examine its distribution and disposition in the rat, with particular emphasis on the brain. Biodistribution studies in rats confirm that brain uptake is rapid and occurs at high levels, and indicate that a major fraction of the compound in the brain does not accumulate by a specific, saturable mechanism.
Kiesewetter
Dale O
DO
Positron Emission Tomography Department, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1180, USA. dk7k@nih.gov
Jagoda
Elaine M
EM
Starrett
John E
JE
Gribkoff
Valentin K
VK
Hewawasam
Piyasena
P
Srinivas
Nugahally
N
Salazar
Daniel
D
Eckelman
William C
WC
D000818:Animals; D001921:Brain / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D015221:Potassium Channels / Q000187:drug effects; D051381:Rats; D014018:Tissue Distribution
C424388:BMS204352; D007211:Indoles; D018696:Neuroprotective Agents; D015221:Potassium Channels