Introduction: Positron emission tomography (PET) imaging of the norepinephrine transporter (NET) is still hindered by the availability of useful PET imaging probes. The present study describes the radiosynthesis and pre-clinical evaluation of a new compound, exo-3-(6-methoxypyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane (NS8880), targeting NET. NS8880 has an in vitro binding profile comparable to desipramine and is structurally not related to reboxetine.
Methods: Labeling of NS8880 with [(11)C] was achieved by a non-conventional technique: substitution of pyridinyl fluorine with [(11)C]methanolate in a Boc-protected precursor. The isolated [(11)C]NS8880 was evaluated pre-clinically both in a pig model (PET scanning) and in a rat model (μPET scanning) and compared to (S,S)-[(11)C]-O-methylreboxetine ([(11)C]MeNER).
Results: The radiolabeling technique yielded [(11)C]NS8880 in low (<10%) but still useful yields with high purity. The PET in vivo evaluation in pig and rat revealed a rapid brain uptake of [(11)C]NS8880 and fast obtaining of equilibrium. Highest binding was observed in thalamic and hypothalamic regions. Pretreatment with desipramine efficiently reduced binding of [(11)C]NS8880.
Conclusion: Based on the pre-clinical results obtained so far [(11)C]NS8880 displays promising properties for PET imaging of NET.
Keywords: MeNER; NS8880; Norepinephrine transporter; PET; Preclinical evaluation; Radiosynthesis.
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