Alpha7 nicotinic acetylcholine receptors as a potential target for imaging of brain disorders with Positron Emission Tomography

Molecular imaging of brain structures by non-invasive techniques offers unique possibilities in the understanding of physiological and pathological processes in the central nervous system. In particular, the quantitative analysis by positron emission tomography (PET) of alpha7 nicotinic acetylcholine receptors (α7nAChR) could provide important information on the relation between receptor dysfunction and the pathogeneses of neurodegenerative brain diseases. However, the applicability of PET for α7nAChR imaging is still hampered by a lack of validated radiotracer for human use.
As radiotracers for imaging α7nAChR, 18F- and 11C-labelled 1,4-diazabicyclo-[3.2.2]nonane derivatives (NS10743 and NS14492) were developed and investigated for in vivo imaging characteristics. Brain autoradiography and organ distribution in mice showed specific accumulation of [18F]NS10743 in α7nAChR expressing brain substructures and peripheral organs. In pigs [18F]NS10743 readily entered the brain (peak SUV ~2.5), with the highest uptake in α7nAChR expressing brain regions such as the colliculi, thalamus, temporal lobe, and hippocampus. Pretreatment followed by constant infusion of NS6740, a selective α7nAChR antagonist, significantly reduced the specific binding of [18F]NS10743 in receptor-dense regions of pigs.
[11C]NS14492, a radioligand of similar high affinity and selectivity in vitro, also showed high uptake in the pig brain (peak SUV ~2.2) with a distribution pattern in accordance with α7nAChR expression. Homologous blocking or pretreatment with the α7nAChR partial agonist SSR180711 both reduced distribution volumes of [11C]NS14492 in all examined regions in a dose-dependent manner.
In conclusion, because of their high brain uptake and regional distribution in accordance with α7nAChR expression pattern in the pig brain, 1,4-diazabicyclo-[3.2.2]nonane derivatives are promising PET radioligands for in vivo mapping and quantitative imaging of α7nAChR. Furthermore, in vivo in pigs the PET radioligand brain binding can be dose-dependently blocked by α7nAChR antagonists.