New PET agent helps target epilepsy seizures

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For 3 percent of Australians with epilepsy, early results in a clinical research study of a new nuclear medicine imaging agent, 18F labelled Flumazenil (18FMZ) for PET imaging, promises better treatment by more accurately pinpointing the area of seizure in the brain, according to a study presented last week at the ANZ Nuclear Medicine conference in Sydney, Australia.

The study is being conducted by the University of Melbourne/Royal Melbourne Hospital with contributions from the CRC for Biomedical Imaging Development (CRCBID), which includes the Australian Nuclear Science and Technology Organisation (ANSTO) and Peter MacCallum Cancer Centre, which worked together to prepare 18FMZ; and commercial radiopharmaceutical supplier Cyclotek, which could eventually market and supply the product.

Rob Ware, PhD, CRCBID's clinical director, said using 18FMZ in PET imaging appears to provide additional information to current methods such as MRI, by identifying the seizure focus in a significant number of patients.

"By being able to exactly see where the seizure point is, doctors can more accurately prescribe and monitor treatment or recommend surgery, ultimately improving the lives of patients, who often have significant medical psychological and economic difficulties as a result of their disorder," he said.

Ware added that 18FMZ may help to provide better treatment for epilepsy patients who cannot be adequately controlled with medications, or who experience unacceptable side effects. "In addition, although neurological surgery can be a very effective treatment for these medication-resistant patients, surgery can only be applied in a small proportion because of problems localizing the source of the seizure," he said.

Currently, MRI cannot identify the seizure focus in a significant number of patients. 18FDG PET is helpful in many of these MRI negative patients but it often shows a relatively wide area of abnormality. This area does not need to be totally surgically removed for effective seizure control and the subtlety of FDG PET scan abnormalities can complicate image analysis.

ANSTO Radiopharmaceutical Research Institute's Chief and conference presenter, Ron Weiner, PhD, explained that strong evidence has shown that seizure foci can be accurately localized by PET scans using FMZ, "even when these patients had inconclusive MRI and 18FDG PET findings."

"To date however, FMZ PET studies have used the radioactive tracer 11C-FMZ but radioactive carbon (11C), used to synthesize this PET radiotracer has only a 20 minute half life. Therefore, it is radioactive for a very short period time and can not be transported." he said. "This practical limitation confined 11C-FMZ PET scanning for epilepsy patients to the few research centers that have sophisticated radiotracer synthetic capabilities plus an onsite cyclotron for supply of 11C.

"The challenge for ANSTO and our other CRC colleagues at Peter MacCallum Cancer Centre was to replace the fluorine atom in this molecule with an atom of radioactive 18Fluorine. Once achieved it could then be optimized and the synthesis of 18FMZ can be automated," Weiner said.

Members of the CRCBID team demonstrated that 18FMZ has high level of receptor specific uptake in a rodent epilepsy model. This work was vital to establish that 18FMZ is highly effective at targeting the brain receptor of clinical interest, as previous human trials have demonstrated the effectiveness of 11C-FMZ at localizing seizure foci.  As 11C-FMZ loses half its radioactivity every 20 minutes, this form of FMZ is only suitable for investigating epilepsy patients in a very small number of research centers.

As 18FMZ has a radioactive half life of 109 minutes, widespread clinical application of this agent in the care of epilepsy patients is feasible, if as expected, the previous benefits of PET scanning using 11C-FMZ are replicated using 18FMZ, the study authors noted.