In Vivo Binding of [18F]NS10743 on α7 Nicotinic Acetylcholine Receptors (α7-nAChR) in Pig Brain

Aim: Alterations of α7-nAChR have been observed in schizophrenia, brain trauma and neurodegenerative diseases. For PET imaging of α7 nAChR [18F]NS10743 has been successfully developed and evaluated in mice by tissue distribution and specificity studies. Here we report on baseline and blocking PET studies with [18F]NS10743 in pig brain.

Materials and Methods: Dynamic PET scanning (2h) was performed in anesthetized female piglets (13-15 kg), intravenously injected with ~ 330 MBq [18F]NS10743 (specific activity >150 GBq/µmol). Three animals additionally received 5 mg/kg of the α7 nAChR antagonist NS6740. 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, distribution volume (VT= K1/k2) and binding potential (BPND = (VT region - VT reference)/VT reference) were estimated.

Results: [18F]NS10743 readily passed the blood-brain barrier and the uptake of radioactivity peaked with SUV = 2.23±0.71 at 8-10 min in the baseline scan while in NS6740-blocking studies the radioactivity levels peaked significantly earlier (SUV = 3.02 ± 1.28 at 6 min) and decreased faster. At the end of study (between 90 and 120 min pi) SUV was significantly decreased by NS6740 in all investigated brain regions except olfactory bulb, which was chosen as reference region for calculation of BPND. At baseline, a mean VT value of 6.07±1.54 was estimated with the highest radiotracer accumulation in 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: The data provide clear evidence of in vivo binding of [18F]NS10743 at α7 nAChR. However, with regard to the low density of α7 nAChR expression in the brain further modifications of the NS10743 core structure are needed to increase the target affinity of the tracer compound.