Abstracts

Rationale: The pathophysiological changes seen in the hippocampus of both human and animal models of temporal lobe epilepsy include mossy fibre sprouting, neuronal loss and altered GABAA/cBZR expression. The advent of advanced imaging techniques, particularly small animal scanners for PET and MRI, has enabled the development of radioprobes for serial scanning of specific receptors. This study was designed to investigate the potential of two radiotracers based on the GABAA ligand, flumazenil, 2`-[18F]fluoroflumazenil ([18F]FFMZ) and [18F]flumazenil ([18]FMZ), as candidates for longitudinal studies of GABAA/cBZR expression during epileptogenesis.Methods: Non-epileptic rats were PET scanned over a 60 minute period after injection of: (i) Tracer dose of radioligand; (ii) Pre-treatment with cold radiotracer (100 ug), then injection of a tracer amount of radioligand; and, (iii) Tracer dose of radioligand, followed by a displacement (100ug of cold compound) bolus injection.Results: [18F]FFMZ: In the hippocampus (high GABAA/cBZR density) the signal intensity was higher (10%) than in the whole brain during the first 10 min of uptake. In the pons (low GABAA/cBZR density), the signal intensity was approximately 20% lower than in the whole brain during 25-30 min of the scan. The pre-saturation and displacement studies showed a high non-specific component in the measured signal. [18F]FMZ: At tracer dose, as compared to the whole brain, the kinetic uptake into hippocampus was 30% higher and the pons displayed a decrease from 40% to 10% at 60 minutes post-injection. Pre-saturation data confirmed that non-specific uptake is low and very similar among most of the brain structures. The displacement study showed a quick and major signal decrease: 90% for hippocampus; 79% in the pons. Conclusions: Conclusion: This data shows that [18F]FMZ is a suitable candidate for imaging and quantification of central benzodiazepine GABAA receptors in the rat brain using serial small animal PET co-registered with MRI. This work has been supported through the Peter MacCallum Cancer Institute and the CRC for Biomedical Imaging Development (Australia)