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Molecular imaging of α7 nicotinic acetylcholine receptors: design and evaluation of the potent radioligand [18F]NS10743
Deuther-Conrad, W.; Fischer, S.; Hiller, A.; Ostergaard Nielsen, E.; Brunicardi Timmermann, D.; Steinbach, J.; Sabri, O.; Peters, D.; Brust, P.;
Purpose
The outstanding diversity of cellular properties mediated by neuronal and nonneuronal α7 nicotinic acetylcholine receptors (α7 nAChR) points to the diagnostic potential of quantitative nuclear molecular imaging of α7 nAChR in neurology and oncology. It was our goal to radiolabel the α7 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/μmol at a radiochemical purity >99%. In vitro, NS10743 and [18F]NS10743 showed high affinity and specificity towards α7 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 α7 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 α7 nAChR expression and encourage further investigations.
Keywords: Alpha7 nicotinic acetylcholine receptors . PET. Diagnostic imaging . Nonneuronal . Oncology . Neurology. Diazabicyclononane

Publ.-Id: 12669 - Permalink