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PET imaging of 5-HT_1A receptor binding in patients with temporal lobe epilepsy

From the Clinical Epilepsy Section, Epilepsy Research Branch (Drs. Toczek, Spanaki, and Theodore, and S. Fazilat), and Biostatistics Branch (Dr. Kopylev), National Institute of Neurological Disorders and Stroke, and Positron Emission Tomography Department (Drs. Carson, Lang, Ma, Der, Herscovitch, and Eckelman), Warren Grant Magnuson Clinical Center, NIH, Bethesda, MD.

Address correspondence and reprint requests to Dr. William H. Theodore, Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive, Building 10, Room 5N250, MSC 1408, Bethesda, Maryland 20892-1408; e-mail: theodorew{at}ninds.nih.gov

Background: Activation of central serotonin (5-HT)_1A receptors, found in high density in brainstem raphe, hippocampus, and temporal neocortex, exerts an anticonvulsant effect in various experimental seizure models. To test the hypothesis that 5-HT_1A receptor binding is reduced in human epileptic foci, PET imaging was performed using the radioligand [¹⁸F]trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide ([¹⁸F]FCWAY), a selective 5-HT_1A receptor antagonist, in patients with temporal lobe epilepsy and normal controls.

Methods: MRI and PET were performed using [¹⁵O]water and [¹⁸F]FCWAY in 10 controls and in 12 patients with temporal lobe epilepsy confirmed on ictal video-EEG; patients also underwent [¹⁸F]fluorodeoxyglucose PET. Using quantitative PET image analysis, regional values were obtained for [¹⁸F]FCWAY volume of distribution (V), cerebral blood flow (CBF), and glucose cerebral metabolic rate (CMRglc). Hippocampal volume (HV) was also measured with MRI. [¹⁸F]FCWAY V PET and MR measures were compared within patients and controls using paired t-tests; grouped comparisons were made with two sample t-tests.

Results: Lower [¹⁸F]FCWAY V was found ipsilateral than contralateral to the epileptic focus in inferior medial (IMT) and lateral (ILT) temporal regions of patients (ILT 47.4 ± 6.1 vs 61.8 ± 6.1, p < 0.01; IMT 52 ± 4.6 vs 67.0 ± 6.0, p < 0.01). [¹⁸F]FCWAY V was 29% lower in raphe and 34% lower in the ipsilateral thalamic region of patients than controls. In ILT, mean [¹⁸F]FCWAY V asymmetry index (AI) was significantly greater than mean CBF and mean CMRglc AI. Mean [¹⁸F]FCWAY V AI in IMT was greater than mean HV AI, but the difference was not significant.

Conclusion: These findings support the hypothesis of reduced serotonin receptor binding in temporal lobe epileptic foci.

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