Abstract
BackgroundThe 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, the radiosynthesis of [18F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.MethodsAutomated radiosynthesis of [18F]NS14490 has been performed by [18F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [18F]NS14490 was consistently approximately 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.ResultsThe total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g−1 throughout the telencephalon and was reduced to 2.6 mL g−1 in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in the 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 also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.
Highlights
The α7 nicotinic acetylcholine receptor is an important molecular target in neuropsychiatry and oncology
Neuronal and non-neuronal expression of the α7 nicotinic acetylcholine receptor (nAChR) has been found in peripheral organs [6,10], and the receptors were proposed to be involved in the development of cancer [8,11]
The current study proposes that the new positron emission tomography (PET) radioligand [18F]NS14490 is suitable to image α7 nAChR in the brain and cerebral vasculature of pigs
Summary
The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. The α7 nAChRs are expressed in all cell types present in the brain, including cortical neurons [2], astrocytes [3], microglia [4,5], oligodendrocyte precursor cells [6] and endothelial cells [7]. As recently reviewed [14,15], considerable efforts to develop α7 radioligands suitable for positron emission tomography (PET) imaging have been made in the last decade. This goal is challenging due to the comparably low protein expression under physiological conditions.
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