Molecular imaging of alpha 7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [18F]NS10743

Purpose: The outstanding diversity of cellular properties mediated by neuronal and nonneuronal alpha 7 nicotinic acetylcholine receptors ( alpha 7 nAChR) points to the diagnostic potential of quantitative nuclear molecular imaging of alpha 7 nAChR in neurology and oncology. It was our goal to radiolabel the alpha 7 nAChR agonist 4-[5-(4-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-1,4-diaza-bicyclo[3. 2 .2]nonane (NS10743) and to assess the selectivity of [18F]NS10743 binding site occupancy in animal experiments. Methods: [18F]NS10743 was synthesized by nucleophilic substitution of the nitro precursor. In vitro receptor affinity and selectivity were assessed by radioligand competition and autoradiography. The radiotracer properties were evaluated in female CD-1 mice by brain autoradiography and organ distribution. Target specificity was validated after treatment with SSR180711 (10 mg/kg, intraperitoneal), and metabolic stability was investigated using radio-HPLC. Results: The specific activity of [18F]NS10743 exceeded 150 GBq/ mu mol at a radiochemical purity >99%. In vitro, NS10743 and [18F]NS10743 showed high affinity and specificity towards alpha 7 nAChR. The brain permeation of [18F]NS10743 was fast and sufficient with values of 4.83 and 1.60% injected dose per gram and brain to plasma ratios of 3.83 and 2.05 at 5 and 60 min after radiotracer administration. Brain autoradiography and organ distribution showed target-specific accumulation of [18F]NS10743 in brain substructures and various alpha 7 nAChR-expressing organs. The radiotracer showed a high metabolic stability in vivo with a single polar radiometabolite, which did not cross the blood-brain barrier. Conclusion: The good in vitro and in vivo features of [18F]NS10743 make this radioligand a promising candidate for quantitative in vivo imaging of alpha 7 nAChR expression and encourage further investigations.