Epilepsy is one of the most common chronic neurological disorders. It is commonly diagnosed after 2 or more unprovoked seizures separated by at least 1 day, and it affects approximately 50 million people worldwide. Epilepsy is a serious and potentially life threatening disease and patients with epilepsy have significantly increased morbidity, including closed head injury, fractures, burns, dental injury and soft tissue injury. Decline in or worsening of memory, cognition, depression and sexual function and other lifestyle limitations occur frequently in patients with epilepsy. Patients with epilepsy also have an increased risk of mortality compared to the general population.
Despite the fact that there are already approved pharmacologic agents to treat epilepsy, many patients are not adequately treated with currently available options. It is estimated that nearly a third of patients with epilepsy have either intractable or uncontrolled seizures or have significant adverse side effects secondary to medication limiting their ability to appropriately control their epilepsy with medication.
Ezogabine or retigabine, also known as ethyl N-[2-amino-4-[(4-fluorophenyl)methylamino]phenyl]carbamate is an anticonvulsant used as a treatment for partial epilepsies. Ezogabine works primarily as a potassium channel opener—that is, by activating KCNQ2/3 voltage-gated potassium channels in the brain. Ezogabine was approved by the FDA on Jun. 10, 2010 and is marketed as Potiga™ and Trobalt™. U.S. Pat. No. 5,384,330 and WO 01/01970 describe ezogabine and its use. The most common adverse events with ezogabine are central nervous system effects, particularly dizziness and somnolence. These side effects are typical for antiepileptic drugs. Occasional instances of urinary difficulty may require surveillance. Ezogabine is predominantly metabolized via glucuronidation. Its half-life is 8 hours.
Despite the beneficial activities of ezogabine, there is a continuing need for new compounds to treat epilepsy and other conditions ameliorated by KCNQ2/3 potassium channel opening.
Fluorine-18 compounds that bind to KCNQ2/3 voltage-gated potassium channels are also needed to non-invasively determine the functional status of the channels by positron emission tomograghy (PET). PET imaging of subjects suffering from epilepsy or other conditions ameliorated by KCNQ2/3 potassium channel opening may provide clinically important information related to diagnosis of the condition, appropriateness and dosing of treatment, as well as facilitating the clinical development of new treatments.