[18F]NS10743: Characterisation Of A Selective a7 Nicotinic Acetylcholine Receptor (a7 nAChR) Radioligand In Pig Brain By PET

Introduction: Alterations of a7 nAChR have been observed in schizophrenia, brain trauma and neurodegenerative diseases. For PET imaging of a7 nAChR [18F]NS10743 has been successfully developed evaluated in mice by tissue distribution and specificity studies. Here we report on baseline and blocking PET studies with [18F]NS10743 in pig brain.
Methods: [18F]NS10743 was synthesized with high specific activity (>150 GBq/μmol) and radiochemical purity (>99%). Dynamic PET scanning was performed in anaesthetized female piglets (13-15 kg), intravenously injected with ~ 330 MBq [18F]NS10743 (total mass ~ 472 ng) for 120 min. Three animals additionally received 3 mg/kg of the a7 nAChR partial antagonist NS6740 at 10 min pre-tracer injection followed by a continuous infusion (1 mg/kg/h). Plasma samples were taken and metabolite-corrected input functions were estimated. Individual regions of interest were defined using an MRI-based template of pig brain. SUV and distribution volume (VT = K1/k2) were estimated. The ratio of specifically bound radioligand and non-displaceable radioligand in brain tissue was calculated from the VT values by BPND = (VT region - VT reference)/VT reference.
Results: [18F]NS10743 readily passed the blood-brain barrier and the uptake of radioactivity peaked with SUV = 2.23 ± 0.71 at 8 min in the baseline scan while in NS6740-blocking studies the radioactivity levels peaked significantly earlier (SUV = 3.02 ± 1.28 at 5 min) and decreased faster. At the end of study (between 90 and 120 min p.i.) SUV was significantly decreased by NS6740 in allinvestigated brain regions except olfactory bulb, which was chosen as reference region for calculation of BPND. At baseline, a VT value of 6.07 ± 1.54 was estimated for the whole brain with the highest radiotracer accumulation in the temporal, parietal, and occipital lobe, thalamus, striatum, and middle cortex (VT = 7.27 ± 1.95 – 7.10 ± 1.58). Intermediate binding was observed in hippocampus, colliculi, midbrain, frontal lobe, and ventral cortex (VT = 6.76 ± 1.71 – 6.09 ± 1.05), and lowest values were assessed in the cerebellum, pons, and olfactory bulb (VT = 5.71 ± 1.18 – 4.11 ± 0.96). Baseline BPND values for high (temporal lobe), median (hippocampus) and low specific binding (cerebellum) were 0.76 ± 0.07, 0.54 ± 0.08, and 0.39 ± 0.08, respectively. NS6740 significantly reduced the binding potential BPND in regions with high [18F]NS10743 binding (temporal lobe: -29 %, p = 0.01; midbrain: -35 %, p = 0.02) while the decrease in regions with low binding was not significant (cerebellum: -16 %, p = 0.2).
Conclusion: These data make [18F]NS10743 a reasonable candidate for further development of in vivo a7 nAChR imaging by PET. The challenge to improve the binding potential of [18F]NS10743, limited mainly by the low density of a7 nAChR expression in the brain and reflected by rather small regional differences in baseline uptake of [18F]NS10743, will be met by further modifications of the NS10743 core structure intended to increase the target affinity of the tracer compound.
the target affinity of the tracer compound.