BackgroundThe ?7 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 ?7 nAChRs. From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.
MethodsAutomated radiosynthesis of [(18)F]NS14490 has been performed by [(18)F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [(18)F]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 ?mol(-1). PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [(18)F]NS14490 without and with administration of the ?7 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[(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of ?7 nAChR in brain but also could be a potential PET radiotracer for imaging of ?7 nAChR in vulnerable plaques of diseased vessels.
SUBMITTER: Rotering S