PET (Positron Emission Tomography) imaging of the benzodiazepine (BZ) receptor has been reported to localize the area of seizure focus by decreased radioligand uptake compared to contralateral homotypic cortex (Savic et al., 1988). The overall goal of this proposal is to assess the capability of the cost effective SPECT (Single Photon Emission Computed Tomography) technology to localize seizure focus. We will use the high affinity radioligand 123I-Ro16-0154, state-of-the-art SPECT imaging devices, computer program for co-registration of SPECT and MRI images, quantitative receptor autoradiography, compartmental kinetic modeling, and in vivo cerebral microdialysis. Preliminary data are reported on the density of two BZ receptor subtypes in neurosurgically-obtained hippocampal tissue from the seizure focus of patients with temporal lobe epilepsy (TLE) secondary to sclerosis. In comparison to autopsy and neurosurgical control groups, patients with TLE- sclerosis had regionally selective decreases of """"""""central"""""""" type and increases of """"""""peripheral"""""""" type BZ receptors, and these changes paralleled the regional losses of neurons and proliferation of glia, respectively. Since the PET BZ receptor ligand (11C-Ro15-1788) and our SPECT ligand (123I-Ro16-0154) bind to the """"""""central"""""""" type BZ receptor, these results provide neuropathological data supporting the loss of these sites determined with in vivo imaging techniques. Our studies with 123I-Ro16-0154 in non-human primates have shown that it is a high affinity ligand with pharmacological specificity for the BZ receptor; has high brain uptake (10% of injected dose) with only the parent compound and not metabolites entering brain; has high ratios of specific to non-specific binding (approximately 15:1); and demonstrates a long period of relatively stable brain uptake. As the only US site studying this radiopharmaceutical, we have recently begun human studies, which have shown results comparable to those in non-human primates and demonstrated very favorable radiation dosimetry. In addition, we have studied two patients with temporal lobe epilepsy and shown significantly decreased uptake in the temporal lobe on the side of the epileptic focus. Our preliminary results will be extended by comparing the sensitivity of BZ receptor imaging and blood flow to localize seizure focus and by assessing the accuracy and reproducibility of SPECT imaging to measure BZ receptors.
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