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

Sven Rötering; Winnie Deuther-Conrad; Paul Cumming; Cornelius K Donat; Matthias Scheunemann; Steffen Fischer; Guoming Xiong; Jörg Steinbach; Dan Peters; Osama Sabri; Jan Bucerius; Peter Brust

doi:10.1186/s13550-014-0043-5

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

EJNMMI Res. 2014 Aug 5:4:43. doi: 10.1186/s13550-014-0043-5. eCollection 2014.

Authors

Affiliations

¹ Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.
² Department of Nuclear Medicine, Friedrich-Alexander-Universität, Ulmenweg 18, Erlangen 91054, Germany ; Department of Pharmacology and Neuroscience, Copenhagen University, Blegdamsvej 3B, Copenhagen 2200, Denmark.
³ Department of Nuclear Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 15, Munich 83177, Germany.
⁴ DanPET AB, Rosenstigen 7, Malmö SE-21619, Sweden.
⁵ Department of Nuclear Medicine, Universität Leipzig, Liebigstr. 18, Leipzig 04103, Germany.
⁶ Department of Nuclear Medicine, Maastricht University Medical Center, P. Debeylaan 25, Maastricht 6229, The Netherlands ; Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, P. Debeylaan 25, Maastricht 6229, The Netherlands ; Department of Nuclear Medicine, University Hospital RWTH Aachen, Pauwelstr. 30, Aachen 52074, Germany.

Abstract

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, [(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.

Methods: Automated 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 μmol(-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 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 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 α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.

Keywords: Alpha7 nicotinic acetylcholine receptors; Alzheimer's disease; Blood-brain barrier; Cancer; Diazabicyclononane; Metabolism; PET; Stroke.