Radiochemical synthesis and biodistribution of a novel maxi-K potassium channel opener
Introduction
More than 500,000 cases of stroke are reported in 2the U.S. each year, of which 70% of patients survive, and 55% of the survivors have some degree of permanent impairment. While many avenues have been explored for pharmacological intervention in acute stroke [3], [5], thus far only a single form of therapy, thrombolysis, has been shown to be effective in improving outcome of acute stroke [4]. A novel approach for neuroprotective therapy in acute stroke is development of drugs that specifically open calcium-dependent neuronal potassium channels. The non-radiolabeled racemate 1 (Scheme 1, (+/-)-(5-Chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one) was discovered as an opener of large conductance calcium-activated potassium channels (maxi-K) with neuroprotective effects in animal models of stroke [7]. Subsequently, the single enantiomer BMS-204352 ((3S)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-trifluoromethyl-2H-indol-2-one) was isolated and found to open maxi-K potassium channels and demonstrated significant neuroprotective properties [7]. BMS-204352 (also known as MaxiPost™) is currently undergoing worldwide efficacy trials in patients with suspected acute stroke.
The present study was designed to determine if the in vivo biodistribution and pharmacokinetic properties of racemic 1 were consistent with its pharmacological actions. Positron emission tomography (PET), a three-dimensional imaging technique, can be applied to the study of pharmacokinetics in vivo. With the ultimate goal of having PET available for studies in higher primates and humans, we developed a radiosynthesis of 1 incorporating the positron emitting radionuclide F-18. The radiolabeled compound was evaluated in rats for a specific uptake mechanism into the brain.
Section snippets
(±)-3-chloro-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one [3]
(±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy- 6-(trifluoromethyl)-2H-indol-2-one (2) was prepared as previously described [8]. Thionyl chloride (0.613 mL, 8.4 mmol, 6 equiv) was added to a -78 °C solution of (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy- 6-(trifluoromethyl)- 2H- indol-2-one (2) (0.500 g, 1.4 mmol) and triethylamine (0.726 mL, 8.4 mmol, 6 equiv) in dichloromethane (25 mL). The cold bath was removed and the reaction mixture was allowed to warm to room
Results and discussion
BMS-204352 has demonstrated the capacity for attenuating cerebral edema and motor impairment following experimental brain injury in rats. Doses of 0.03 mg (80 nmol)/kg reduced cerebral edema and doses of 0.1 mg (300 nmol)/kg improved neurologic motor function in these studies [2]. We wanted to determine if the observed properties were the results of the binding of the compound to a specific site in the brain. Both BMS-204352 and its racemate (1) show similar activity in assays of
Conclusion
We have prepared [18F]-1 in carrier-added and no-carrier-added forms in high radiochemical purity using a silver ion assisted substitution of a tertiary chloride. The radiochemical yield is modest under carrier-added conditions and poor under no-carrier-added conditions. The compound is rapidly and widely distributed and uptake into the brain was rapid and occurred at high levels. The brain uptake was unlikely to be mediated by a saturable, specific uptake process because there was no
Acknowledgements
The authors acknowledge the contributions of the staff of the NIH cyclotron facility for radionuclide production.
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2015, Progress in Medicinal ChemistryCitation Excerpt :The difference in the uptake of the tracer was used to infer the biodistribution of the drug itself. Kiesewetter developed a radiosynthesis of racemic [18F]BMS-204352 for use in biodistribution studies to support the development of MaxiPost™ [108]. Radiometals may also be used for studying biodistribution of drugs.
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