Radiochemical synthesis and biodistribution of a novel maxi-K potassium channel opener

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Abstract

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 [18F]-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.

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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