Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [¹⁸F]NS14490

Background: The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly-specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [¹⁸F]NS14490 has been shown to yield reliable results in organ distribution studies; however, dynamic PET investigations required the establishment of an automated radiosynthesis.

Methods: Automated radiosynthesis of [¹⁸F]NS14490 has been performed by [¹⁸F]fluoroalkylation of the tosylate precursor in the TRACERlabTM FX-N synthesis module. After optimization, the radiochemical yield of [¹⁸F]NS14490 was consistently ~35% and the total synthesis time was about 90 min. The radiotracer was prepared with >92% radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq µmol-1. PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [¹⁸F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions.

Results: The total distribution volume relative to the metabolite-corrected arterial input was 3.5-4.0 mL g-1 throughout telencephalon, and was reduced to 2.6 in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained.

Conclusion: [¹⁸F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but could besides be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.